Inclusion of Tumor Markers Improves the Correlation of the Milan Criteria with Vascular Invasion and Tumor Cell Differentiation in Patients with Hepatocellular Carcinoma Undergoing Liver Resection (#JGSU-D-07–00462)

The currently used criteria, such as the Milan criteria, to select a candidate of liver transplantation for HCC consists of size and number of tumors because vascular invasion and poor differentiation, the strongest prognostic factors, are difficult to be assessed preoperatively. We hypothesized that inclusion of two tumor markers (alpha-fetoprotein and des-γ-carboxy prothrombin) into the criteria would increase the prediction accuracy of these factors. Our hypothesis was tested in 478 HCC patients undergoing liver resection. The models with or without markers, constructed at predicting vascular invasion (n = 150) or poor differentiation (n = 49), were compared. The model including markers was superior at predicting the absence of vascular invasion to either the Milan criteria alone [at 81.2% sensitivity; specificity, 52.4 vs 43.3%; difference, 9.1%(95% CI, 1.3–14.2%)] or a model in which size and number varied freely [AUCs of receiver operating characteristic curves, 75.2 vs 69.1%; difference, 6.1%(2.33–10.7%)]. The model incorporating markers was also superior at predicting well to moderate differentiation to either the Milan criteria [at 74.5% sensitivity; specificity, 57.1 vs 38.8%; difference, 18.3%(2.4–32.7%)] or a model with size and number [AUCs, 71.5 vs 59.0%; difference, 12.5%(5.84–21.4%)]. In conclusion, the tumor marker levels should be considered when selecting patients with HCC for liver transplantation.     

Selection criteria for simultaneous resection in patients with synchronous liver metastasis

HYPOTHESIS: While simultaneous resection has been shown to be safe and effective in patients with synchronous metastasis, neoadjuvant chemotherapy followed by hepatectomy has gradually gained acceptance for both initially nonresectable metastasis and resectable metastasis. The boundary between these treatments is becoming unclear. We hypothesized that factors associated with colorectal cancer may play an important role in the prognosis of patients with synchronous metastasis and may be useful for identifying patients who can be expected to have adequate results following simultaneous resection. DESIGN: Outcome study. SETTING: Tertiary referral center. PATIENTS: From January 1980 to December 2002, 187 patients underwent curative resection for synchronous liver metastasis from colorectal cancer. One hundred forty-two patients received simultaneous resection, 18 underwent staged resection, and 27 underwent delayed hepatic resection. Twenty-one clinicopathological factors were analyzed, and long-term prognosis was assessed. MAIN OUTCOME MEASURES: Prognostic factors and patient survival. RESULTS: There was no in-hospital death. In a multivariate analysis, the factors that significantly affected the prognosis of synchronous metastasis were 4 or more lymph node metastases around the primary cancer (P<.001) and multiple liver metastases (P = .003). In patients with 3 or fewer lymph node metastases around the primary cancer, the 5-year survival rates of those with 1, 2 to 3, and 4 or more liver metastases were 63%, 33%, and 40%, respectively, but these rates were 15%, 22%, and 0%, respectively, in patients with 4 or more lymph node metastases around the primary cancer. CONCLUSIONS: The results support the application of simultaneous resection in patients with 0 to 3 colorectal lymph node metastases. However, in patients with 4 or more colorectal lymph node metastases, biological selection by neoadjuvant chemotherapy may be more suitable.     

Extended Left Hepatectomy by Severing All Major Hepatic Veins with Reconstruction of the Right Hepatic Vein

Curative liver resection is technically challenging when multiple liver metastases from colon cancer involve the confluence of the three major hepatic veins. We report two cases of successful extended left hemihepatectomy achieved by severing all of the major hepatic veins together with the wall of the inferior vena cava, to resect liver metastases from colon cancer. Reconstruction of the right hepatic vein was done after unroofing the right anterior area of the liver with a direct anastomosis of the right hepatic vein. We did not need to perform total vascular exclusion or portovenous shunting during the liver transection. This simple and safe method can increase the surgical indications for previously unresectable tumors.     

Predicting Individual Survival After Hepatectomy for Hepatocellular Carcinoma: a Novel Nomogram from the “HCC East &amp; West Study Group”

Introductions

Different staging systems have been devised for patients undergoing resection for hepatocellular carcinoma (HCC) with disparate results. The aim of this study was to create a new nomogram to predict individual survival after hepatectomy for HCC.

Methods

Based on the “Hepatocellular Carcinoma: Eastern & Western Experiences Network,” data from 2046 patients who underwent HCC resections at ten centers were reviewed. Patient survival was analyzed with Cox-regression analysis to construct a unique nomogram and contour plots to predict survival.

Results

The nomograms built on the multivariate analyses, which showed that the independent predictors were tumor size, tumor number, vascular invasion, cirrhosis, preoperative bilirubin value, and esophageal varices, showed good calibration and discriminatory abilities with C-index value of 0.62 (95 % CI, 0.59–0.69) and 0.61 (95 % CI, 0.56–0.64) for overall and disease-free survival, respectively. The 5-year survival contour plots showed that the presence of vascular invasion was associated with decreased survival, regardless of the tumor number or size. Cirrhosis and varices were equally associated with decreased survival, according to the tumor number or size.

Conclusions

These nomograms accurately predict individual prognosis after HCC resection and support an expansion of the selection criteria for resection. They offer useful guidance to clinicians for individual survival prediction.

     

Branch patch reconstruction in living donor liver transplantation: arterialization of grafts with replaced type arteries

We developed a hepatic arterialization technique in living donor liver transplantation. The technique was indicated in patients with a left graft from donors with a right hepatic artery originated from superior mesenteric artery or a right graft from donors with a left hepatic artery from left gastric artery. The donor common hepatic and gastroduodenal arteries were split. On the recipient side, left and right hepatic arteries or branches of the right hepatic artery were split, received patch plasty, and anastomosed with the graft arteries under loupe observation. Livers from 25 donors were procured (16 right livers and 9 left livers) using this technique. There were no vascular complications in the donors. Three recipients died due to infectious disease with arterial patency. The remaining 22 recipients survived without hepatic arterial thrombosis. In limited situations, this technique can be adapted for living donor liver transplantation without increasing donor complications.     

Radiation stimulates HGF receptor/c-Met expression that leads to amplifying cellular response to HGF stimulation via upregulated receptor tyrosine phosphorylation and MAP kinase activity in pancreatic cancer cells

Hepatocyte growth factor (HGF) is a stromal-derived cytokine that plays a crucial role in invasion and metastasis of tumor cells through the interaction with HGF receptor, c-Met, which is frequently overexpressed in pancreatic cancer. The present study was designed to investigate the change in HGF receptor and HGF-mediated signaling after irradiation in pancreatic cancer cells. Six cell lines from human pancreatic cancer were included in the study. Gamma-radiation was used for irradiation treatment. The changes in expression levels of c-Met were evaluated by immunoblot and confirmed morphologically by indirect immunofluorescence staining. Whether the resultant alteration in c-Met would cascade as biologically usable signals upon HGF ligation was traced by receptor tyrosine phosphorylation analysis and mitogen activated protein kinase (MAP kinase or MAPK) activity assay. The various biological responses to HGF (including cell proliferation, cell scattering, migration and invasion) were evaluated as well. We also used a 4-kringle antagonist of HGF, NK4, to block the HGF/c-Met signaling pathway. Both immunoblot and immunofluorescent analysis showed moderate increased expression of c-Met in 3 of 6 pancreatic cancer cell lines after irradiation. The actions seemed to be dose-responsible, which began at 3 hr and reached its peak value at 24 hr following irradiation. The radiation-increased expression of c-Met could transform into magnifying receptor tyrosine phosphorylation reaction and MAP kinase activity once the ligand was added, fairly corresponding with alteration in the receptor. Sequentially, the cellular responses to HGF, including scattering and invasion but not proliferation, were enhanced. Also, in the presence of HGF, the elevated receptor could help to recover the radiation-compromised cell migration. A recombinant HGF antagonist, NK4 could effectively block these aberrant effects activated by irradiation both in molecular and cellular levels, thus suggesting the deep involvement of the c-Met/HGF pathway in the enhanced malignant potential after irradiation. These results suggest that radiation may promote HGF-induced malignant biological behaviors of certain pancreatic cancer cells through the up-regulated HGF/c-Met signal pathway. Selectively targeted blockade of the HGF/c-Met pathway could help to abolish the enforced malignant behavior of tumor cells by irradiation and therefore may improve the efficacy of radiotherapy for pancreatic cancer.     

Conjoint pathologic cascades mediated by ALS/FTLD-U linked RNA-binding proteins TDP-43 and FUS

The RNA-binding proteins TAR DNA-binding protein (TDP-43) and fused in sarcoma (FUS) play central roles in neurodegeneration associated with familial amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Normally localized in the nucleus, in sites affected by ALS and FTLD-U they are mislocalized to the cytoplasm and form cytoplasmic inclusions. TDP-43 and FUS are transported to the nucleus in a Ran-GTPase-dependent manner via nuclear import receptors, but they also contribute to the formation of stress granules (SGs), which are intracytoplasmic structures incorporating RNA. C-terminal truncations of TDP-43 eliminate the nuclear transport signal and cause mislocalization of the protein to the cytoplasm, where it accumulates and forms SGs. ALS-associated FUS mutations impair nuclear transport and cause mislocalization of FUS to the cytoplasm, where it also contributes to assembly of SGs. Furthermore, the ALS susceptibility factor ataxin-2, recently identified as a potent modifier of TDP-43 toxicity, is also a predicted cytoplasmic RNA-binding protein and a constituent protein of SGs, suggesting that it is a part of the common pathologic cascade formed by TDP-43 and FUS. Thus, we propose that excessive mislocalization of the RNA-binding proteins TDP-43, FUS, and ataxin-2 into the cytoplasm leads to impairment of the RNA quality control system, forming the core of the ALS/FTLD-U degenerative cascade. In this review, we discuss the molecular basis of the novel disease spectrum of ALS/FTLD-U, including the neurodegenerative mechanism of the cytoplasmic RNA-binding proteins TDP-43 and FUS and the possibility of a novel therapeutic strategy.     

Clinical features and varieties of non-motor fluctuations in Parkinson's disease: A Japanese multicenter study

ObjectiveThis multicenter cross-sectional study aimed to investigate the clinical features and varieties of non-motor fluctuation in Parkinson's disease (PD).MethodsTo identify motor and non-motor fluctuation, we employed the wearing-off questionnaire of 19 symptoms (WOQ-19) in 464 PD patients. We compared the frequency of levodopa-related fluctuation as identified by the WOQ-19 with recognition by neurologists. We compared patients with both motor and non-motor fluctuations with those who only had motor fluctuations. Non-motor fluctuations were separated into psychiatric, autonomic, and sensory categories for further analysis.ResultsThe patients' average age was 70.8 ± 8.4 years (mean ± SD) and disease duration was 6.6 ± 5.0 years. The frequency of motor fluctuations was 69% and for non-motor fluctuation 40%. Fifty-three percent of patients with motor fluctuations also had non-motor fluctuations, whereas 93% of patients with non-motor fluctuations also had motor fluctuations. The WOQ-19 showed a sensitivity of 82% but a specificity of only 40%. The patients with both non-motor and motor fluctuations exhibited more severe motor symptoms, more non-motor symptoms and higher levodopa daily doses (p < 0.05). Patients had significantly higher fluctuation rates if they had psychiatric (49%) and sensory (45%) symptoms than patients with autonomic symptoms (32%, p < 0.01). Forty-eight percent of patients with non-motor fluctuations exhibited more than one type of non-motor fluctuation.ConclusionForty percent of PD patients presented with non-motor fluctuations, and almost half of these exhibited more than one type. Appropriate recognition of levodopa-related fluctuations, both motor and non-motor, can lead to treatment modifications in PD patients.