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A decade ago we proposed to enlist for transplantation those patients with resected hepatocellular carcinoma in whom pathology registered pejorative histological markers (microvascular invasion and/or satellites; ab initio indication) and not wait for the appearance of recurrence. This study evaluates the outcome of this approach. From 1995 to 2012, 164 patients with hepatocellular carcinoma underwent resection. Eighty-five patients were potential candidates for liver transplantation and were considered for it upon detection of pejorative histological markers. Patients without these markers were followed, and salvage liver transplantation was considered upon development of tumor recurrence/liver function impairment. Thirtyseven patients were at high risk and 48 at low risk of recurrence at pathology. Twenty-three out of 37 high-risk patients recurred during follow-up, but in nine of them the tumor burden extent contraindicated liver transplantation. Seventeen were finally transplanted: 10 of them presented recurrence at imaging/explant. After a median posttransplant follow-up of 50.9 months, hepatocellular carcinoma had recurred in two patients and five patients had died, the 5-year survival being 82.4%. Twenty-six of the 48 low-risk patients developed recurrence, and 11 of them were transplanted. After a median posttransplant follow-up of 59 months, two patients developed recurrence and five died, their 5-year survival being 81.8%. Conclusion: Enlistment of patients at high risk of HCC recurrence after resection but before recurrence development seems a valid strategy and is associated with excellent long-term outcome; as early (<6 months) recurrence reflects an aggressive tumor behavior leading to tumor extent exceeding transplant criteria, we propose to wait at least 6 months before enlistment; however, once included on the waiting list, priority strategies should be implemented in order to reach effective transplantation prior to the appearance of recurrence. (HEPATOLOGY 2016;63:839-849) H epatocellular carcinoma (HCC) is the most common primary tumor of the liver. The incidence of HCC is increasing in the United States and Europe, and it is currently the third leading cause of cancer-related death globally.(1,2) Liver transplantation (LT) is theoretically the treatment of choice because it allows removal not only of the tumor but also of the underlying cirrhosis. It offers a high survival rate and a low recurrence rate in well-selected cases. (3,4) Although Spain has the highest rate of

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Bladder cancer is one of the most common causes of death in industrialized countries. New tumor markers and therapeutic approaches are still needed to improve the management of bladder cancer patients. Choline kinase-a (ChoKa) is a metabolic enzyme that has a role in cell proliferation and transformation. Inhibitors of ChoKa show antitumoral activity and are expected to be introduced soon in clinical trials. This study aims to assess whether ChoKa plays a role in the aggressiveness of bladder tumors and constitutes a new approach for bladder cancer treatment. We show here that ChoKa is constitutively altered in human bladder tumor cells. Furthermore, in vivo murine models, including an orthotopic model to mimic as much as possible the physiological conditions, revealed that increased levels of ChoKa potentiate both tumor formation (Pp0.0001) and aggressiveness of the disease on different end points (P ¼ 0.011). Accordingly, increased levels of ChoKa significantly reduce survival of mice with bladder cancer (P ¼ 0.05). Finally, treatment with a ChoKa-specific inhibitor resulted in a significant inhibition of tumor growth (P ¼ 0.02) and in a relevant increase in survival (P ¼ 0.03).

Cancer may be diagnosed in advanced stages, when the patient has already developed metastasis, with symptoms that can be also observed in benign diseases. The objective of this study was to evaluate tumor marker sensitivity and specificity in the differential diagnosis of patients with suspected signs of cancer. We studied 2.711 consecutive patients admitted to the Internal Medicine Department of our hospital with suspected cancer; 1.240 patients had non-malignant processes and 1.471 had malignant disease. Determinations were considered positive for suspected malignancy when serum levels were carcinoembryonic antigen >15 ng/ml (>20 in patients with renal failure or liver disease), alpha fetoprotein >40 ng/ml (>80 ng/ml in patients with liver diseases), carbohydrate antigen (CA) 19.9 > 200 U/ml (>500 U/ml in patients with liver diseases or gamma glutamyl transpeptidase (GGT) <150 UI/L or effusions; >1.000 U/ml in patients with jaundice or GGT > 150 UI/L), neuron-specific enolase >45 ng/ml (renal failure >50 ng/ml; samples with hemolysis were excluded), prostate-specific antigen > 30 ng/ml (excluding acute prostatitis), tumor-associated glycoprotein-72 >80 U/ml, cytokeratin 19 fragment 21-1 > 7.5 ng/ml (>19 ng/ml in patients with renal failure; >11 ng/ml in patients with liver cirrhosis or jaundice), >3.5 ng/ml for squamous cell carcinoma (excluding patients with renal failure or skin disorders), CA 15.3 >100 U/ml, and CA 125 >350 U/ml (>600 U/ml in patients with pleural effusion and >900 U/ml in those with ascites). There was a specificity of 97.6% in patients without malignancy, 67.4% of sensitivity in patients with malignancy, and 75.4% of sensitivity in the 1,280 patients with epithelial tumors (53.7% in patients with locally advanced tumors and 79.4% in patients with metastases). Sensitivity was 81.4% in patients with cancer of unknown primary site. Tumor markers were useful in the differential diagnosis between epithelial and non-epithelial tumors, brain masses (metastases vs. primary tumors), and between benign or malignant origin of different clinical situations such as wasting syndrome, effusions, liver or bone lesions, and effusions with a positive predictive value higher than 95%. Tumor markers are useful as an aid in the evaluation of the risk of cancer of these patients with suspected cancer and may be useful to reduce the hospitalization time, morbidity, and the number of diagnostic tests required for diagnosis.

The present study confirms the technical feasibility and acceptable morbidity associated with LapEn. Intra-operative lymph node sampling and frozen-section examination should be performed at the time of LapEn; when a malignancy is confirmed, oncologically appropriate lymph node dissection should be performed.

CA 19.9 serum levels were prospectively determined in 573 patients admitted to hospital for suspicion of pancreatic cancer. The final diagnosis was 77 patients with no malignancy, 389 patients with pancreatic cancer, 37 neuroendocrine pancreatic cancer, 28 cholangiocarcinomas, 4 gallbladder cancer, 27 ampullary carcinomas, and 11 periampullary carcinomas. CA 19.9 was determined using a commercial assay from Roche Diagnostics, and 37 U/ml was considered as the upper limit of normality. Abnormal CA 19.9 serum levels were found in 27%, 81.5%, 85.7%, 59.3%, 63.6%, and 18.9% of patients with benign diseases, pancreatic cancer, cholangiocarcinomas, and ampullary, periampullary, or neuroendocrine tumors. Significantly higher concentrations of CA 19.9 were found in patients with than in those without malignancy or with neuroendocrine tumors. CA 19.9 serum levels were higher in pancreatic cancer or cholangiocarcinoma than in other malignancies (p < 0.0001). CA 19.9 serum levels were also correlated with tumor stage, treatment (significantly lower concentrations in resectable tumors), and tumor location (the highest in those located in the body, the lowest in those in the tail or uncinate) and site of metastases (highest in liver metastases). A trend to higher CA 19.9 serum concentrations was found in patients with jaundice, but only with statistical significance in the early stages. Using 50 or 100 U/ml in patients with jaundice, CA 19.9 was useful as an aid in the diagnosis of pancreatic cancer (sensitivity 77.9%, specificity 95.9%) as well as tumor resectability in pancreatic cancer with different cutoffs according to tumor location and bilirubin serum levels with specificities ranging from 90% to 100%. CA 19.9 is the tumor marker of choice in pancreatic adenocarcinomas, with a clear relationship with tumor location, stage, and resectability.

Maintenance of the complex phenotype of primary hepatocytes in vitro represents a limitation for developing liver support systems and reliable tools for biomedical research and drug screening. We herein aimed at developing a biosystem able to preserve human and rodent hepatocytes phenotype in vitro based on the main characteristics of the liver sinusoid: unique cellular architecture, endothelial biodynamic stimulation, and parenchymal zonation. Primary hepatocytes and liver sinusoidal endothelial cells (LSEC) were isolated from control and cirrhotic human or control rat livers and cultured in conventional in vitro platforms or within our liver‐resembling device. Hepatocytes phenotype, function, and response to hepatotoxic drugs were analyzed. Results evidenced that mimicking the in vivo sinusoidal environment within our biosystem, primary human and rat hepatocytes cocultured with functional LSEC maintained morphology and showed high albumin and urea production, enhanced cytochrome P450 family 3 subfamily A member 4 (CYP3A4) activity, and maintained expression of hepatocyte nuclear factor 4 alpha (hnf4α) and transporters, showing delayed hepatocyte dedifferentiation. In addition, differentiated hepatocytes cultured within this liver‐resembling device responded to acute treatment with known hepatotoxic drugs significantly different from those seen in conventional culture platforms. In conclusion, this study describes a new bioengineered device that mimics the human sinusoid in vitro, representing a novel method to study liver diseases and toxicology.