Prognostic grade for resecting hepatocellular carcinoma: multicentre retrospective study.

BACKGROUND: Surgical treatment for hepatocellular carcinoma (HCC) is advancing, but a robust prediction model for survival after resection is not available. The aim of this study was to propose a prognostic grading system for resection of HCC. METHODS: This was a retrospective, multicentre study of patients who underwent first resection of HCC with curative intent between 2000 and 2007. Patients were divided randomly by a cross-validation method into training and validation sets. Prognostic factors were identified using a Cox proportional hazards model. The predictive model was built by decision-tree analysis to define the resection grades, and subsequently validated. RESULTS: A total of 16 931 patients from 795 hospitals were included. In the training set (8465 patients), four surgical grades were classified based on prognosis: grade A1 (1236 patients, 14.6 per cent; single tumour 3 cm or smaller and anatomical R0 resection); grade A2 (3614, 42.7 per cent; single tumour larger than 3 cm, or non-anatomical R0 resection); grade B (2277, 26.9 per cent; multiple tumours, or vascular invasion, and R0 resection); and grade C (1338, 15.8 per cent; multiple tumours with vascular invasion and R0 resection, or R1 resection). Five-year survival rates were 73.9 per cent (hazard ratio (HR) 1.00), 64.7 per cent (HR 1.51, 95 per cent c.i. 1.29 to 1.78), 50.6 per cent (HR 2.53, 2.15 to 2.98), and 34.8 per cent (HR 4.60, 3.90 to 5.42) for grades A1, A2, B, and C respectively. In the validation set (8466 patients), the grades had equivalent reproducibility for both overall and recurrence-free survival (all P < 0.001). CONCLUSION: This grade is used to predict prognosis of patients undergoing resection of HCC.

Randomized clinical trial comparing two vessel-sealing devices with crush clamping during liver transection.

BACKGROUND: Previous RCTs have failed to demonstrate the usefulness of combining energy devices with the conventional clamp crushing method to reduce blood loss during liver transection. Here, the combination of an ultrasonically activated device (UAD) and a bipolar vessel-sealing device (BVSD) with crush clamping was investigated. METHODS: Patients scheduled to undergo hepatectomy at the University of Tokyo Hospital or Nihon University Itabashi Hospital were eligible for this parallel-group, single-blinded randomized study. Patients were assigned to a control group (no energy device used), an UAD group or a BVSD group. The primary endpoint was the volume of blood loss during liver transection. Outcomes of the control group and the combined energy device groups (UAD plus BVSD) were first compared. Pairwise comparisons among the three groups were made for outcomes for which the combined energy device group was superior to the control group. RESULTS: A total of 380 patients were enrolled between July 2012 and May 2014; 116 patients in the control group, 122 in the UAD group and 123 in the BVSD group were included in the final analysis. Median blood loss during liver transection was lower in the combined energy device group (245 patients) than in the control group (116 patients): median 190 (range 0-3575) versus 230 (range 3-1570) ml (P = 0·048). Pairwise comparison revealed that blood loss was lower in the BVSD group than in the control group (P = 0·043). CONCLUSION: The use of energy devices combined with crush clamping reduced blood loss during liver transection. Registration number: C000008372 (www.umin.ac.jp/ctr/index.htm).

Criteria for drain removal following liver resection.

BACKGROUND: Abdominal drains have been placed prophylactically and removed in liver resection without robust evidence. The present study was designed to establish the optimal time for removal of such drains. METHODS: Data on abdominal prophylactic drains were analysed in a consecutive series of patients who underwent liver resection for malignancy between 2006 and 2009. Bilirubin levels in drain fluid were measured and bacteriological cultures were taken on days 1, 3, 5 and 7 after surgery. Drains were removed on day 3 if the drain-fluid bilirubin level was less than 5 mg/dl and bacteriological cultures were negative. Drains remained in situ until these conditions were met. RESULTS: A total of 514 abdominal drains were placed in 316 patients operated on in the study period. Fifty-eight patients (18·4 per cent) had positive drain-fluid cultures and 14 (4·4 per cent) had bile leakage (drain-fluid bilirubin level 5 mg/dl or more). Only one patient required ultrasound-guided abdominal drainage. On multivariable analysis, drain-fluid bilirubin level on day 3 after surgery was the strongest predictor of infection (odds ratio 15·11, 95 per cent confidence interval 3·04 to 92·11; P < 0·001). The area under the receiver operating characteristic curve on day 3 had the highest predictive value: 83·6 per cent accuracy and 3·9 per cent false-positive rate for a drain-fluid bilirubin level of 3·01 mg/dl (51·5 µmol/l). CONCLUSION: The '3 × 3 rule' (drain-fluid bilirubin level below 3 mg/dl on day 3 after operation) is an accurate criterion for removal of prophylactically placed abdominal drains in liver resection.

Potential responders to FOLFOX therapy for colorectal cancer by Random Forests analysis.

BACKGROUND: Molecular characterisation using gene-expression profiling will undoubtedly improve the prediction of treatment responses, and ultimately, the clinical outcome of cancer patients. METHODS: To establish the procedures to identify responders to FOLFOX therapy, 83 colorectal cancer (CRC) patients including 42 responders and 41 non-responders were divided into training (54 patients) and test (29 patients) sets. Using Random Forests (RF) algorithm in the training set, predictor genes for FOLFOX therapy were identified, which were applied to test samples and sensitivity, specificity, and out-of-bag classification accuracy were calculated. RESULTS: In the training set, 22 of 27 responders (81.4% sensitivity) and 23 of 27 non-responders (85.1% specificity) were correctly classified. To improve the prediction model, we removed the outliers determined by RF, and the model could correctly classify 21 of 23 responders (91.3%) and 22 of 23 non-responders (95.6%) in the training set, and 80.0% sensitivity and 92.8% specificity, with an accuracy of 69.2% in 29 independent test samples. CONCLUSION: Random Forests on gene-expression data for CRC patients was effectively able to stratify responders to FOLFOX therapy with high accuracy, and use of pharmacogenomics in anticancer therapy is the first step in planning personalised therapy.

Molecular karyotyping of human hepatocellular carcinoma using single-nucleotide polymorphism arrays.

Genomic amplification of oncogenes and inactivation of suppressor genes are critical in the pathogenesis of human cancer. To identify chromosomal alterations associated with hepatocarcinogenesis, we performed allelic gene dosage analysis on 36 hepatocellular carcinomas (HCCs). Data from high-density single-nucleotide polymorphism arrays were analysed using the Genome Imbalance Map (GIM) algorithm, which simultaneously detects DNA copy number alterations and loss of heterozygosity (LOH) events. Genome Imbalance Map analysis identified allelic imbalance regions, including uniparental disomy, and predicted the coexistence of a heterozygous population of cancer cells. We observed that gains of 1q, 5p, 5q, 6p, 7q, 8q, 17q and 20q, and LOH of 1p, 4q, 6q, 8p, 10q, 13q, 16p, 16q and 17p were significantly associated with HCC. On 6q24-25, which contains imprinting gene clusters, we observed reduced levels of PLAGL1 expression owing to loss of the unmethylated allele. Finally, we integrated the copy number data with gene expression intensity, and found that genome dosage is correlated with alteration in gene expression. These observations indicated that high-resolution GIM analysis can accurately determine the localizations of genomic regions with allelic imbalance, and when integrated with epigenetic information, a mechanistic basis for inactivation of a tumor suppressor gene in HCC was elucidated.

Dysregulated expression of P1 and P2 promoter-driven hepatocyte nuclear factor-4alpha in the pathogenesis of human cancer.

Hepatocyte nuclear factor-4alpha (HNF4alpha) exists in multiple isoforms that are generated by alternative promoter (P1 and P2) usage and splicing. Here we establish monoclonal antibodies (mAbs) for detecting P1 and P2 promoter-driven HNF4alpha, and evaluate their expression in normal adult human tissues and surgically resected carcinomas of different origins. Using immunohistochemical analysis, we demonstrate that, while P1 promoter-driven HNF4alpha is expressed in hepatocytes, small intestine, colon, kidney and epididymis, P2 promoter-driven HNF4alpha is expressed in bile duct, pancreas, stomach, small intestine, colon and epididymis. Altered expression patterns of P1 and P2 promoter-driven HNF4alpha were observed in gastric, hepatocellular and colorectal carcinomas. HNF4alpha was expressed in lung metastases from renal cell, hepatocellular and colorectal carcinoma but was not observed in lung tumours. The P1 and P2 promoter-driven HNF4alpha expression pattern of tumour metastases correlated with the primary site of origin. P1 promoter-driven HNF4alpha was also found in intestinal metaplasia of the stomach. These data provide evidence for the tissue distribution of P1 and P2 promoter-driven HNF4alpha at the protein level and suggest that HNF4alpha may be a novel diagnostic marker for metastases of unknown primary. We propose that the dysregulation of alternative promoter usage of HNF4alpha is associated with the pathogenesis of certain cancers.

Inflammatory pseudotumors of the liver: prevalence and clinical impact in surgical patients.

BACKGROUND/AIMS: Progress in diagnostic imaging has increased the number of focal liver lesions detected and reports of an occasional finding of inflammatory pseudotumors of the liver are becoming numerous. To estimate their prevalence and clinical impact in surgical series we evaluate retrospectively our experience. METHODOLOGY: Four hundred and three patients carriers of a total of 717 focal liver lesions underwent liver resection consecutively in our Department from October 1995 to August 1999. All these patients underwent surgery. RESULTS: After surgical resection, 3 patients each proved to be carrying an IPT nodule accounting for 0.7% of all patients and 0.4% of all focal liver lesions. One inflammatory pseudotumor was only disclosed intraoperatively in a patient with an hepatocellular carcinoma. The other 2 accounted for 20% of the patients whose preoperative diagnoses were wrong. The operative procedures for the inflammatory pseudotumor nodules were: wedge resection, because the inflammatory pseudotumor was considered a new malignancy, a limited resection and a left extended hepatectomy with bilioenteric anastomosis, distal gastrectomy and lymphoadenectomy in one patient each. Inflammatory pseudotumors accounted for 33% of wrong indication for surgery. CONCLUSIONS: Our experience shows that, despite the low prevalence of hepatic inflammatory pseudotumors, their impact in the appropriate management of patients with focal liver lesions is not irrelevant.

Liver resection without total vascular exclusion: hazardous or beneficial? An analysis of our experience.

OBJECTIVE: To evaluate retrospectively the safety and radicality of liver resection performed without total vascular exclusion (TVE). SUMMARY BACKGROUND DATA: TVE is recommended for safe liver surgery, at least in the case of resection of the paracaval portion of the liver. However, it has some drawbacks because of its invasiveness. METHODS: The authors retrospectively evaluated 329 of 471 consecutive patients who underwent liver resection from October 1994 to October 1999. All of these patients had tumors involving segments 1, 7, or 8 or the cranial portion of segment 4, or underwent major hepatectomies that required exposure of the inferior vena cava (IVC), the main trunks of the hepatic veins, or both. Sixty-four patients underwent resection that included segment 1, with or without the reconstruction of the IVC, the hepatic vein, or both. RESULTS: Three hundred twenty-four of 329 procedures were done under intermittent warm ischemia; no clamping methods were used in 6. TVE was never needed. There were no postoperative 30-day deaths. The complication rate was 25.5%, and only 2.1% had major complications. Only 13 (3.9%) patients required whole blood transfusion. Part of the wall of the IVC was resected in six patients, and the hepatic veins were reconstructed in four. Surgical clearance was achieved in all patients undergoing surgery for a tumor. CONCLUSIONS: These results show that liver surgery performed without TVE is safe and effective even in aggressive procedures for liver tumors involving the cavohepatic junction. Therefore, TVE should be further restricted to exceptional patients.

Mass-forming inflammatory periductal fibrosis mimicking hilar bile duct carcinoma.

A case of a rare benign biliary lesion at the hepatic hilum mimicking hilar bile duct carcinoma is reported. A 73-year-old man was found to have gastric cancer by gastrointestinal fiberscopy. Dilated right intrahepatic bile ducts and a 2-cm mass in the right hepatic duct were demonstrated by further imaging investigations. He was finally diagnosed as having hilar bile duct and gastric carcinomas, and underwent right portal vein embolization followed by a single-stage extended right hepatectomy and total gastrectomy. Pathologically, however, the lesion in the right hepatic duct showed inflammatory changes with periductal fibrosis, without any signs of malignancy. A literature search revealed 11 such cases including the present one.

Hepatocellular carcinoma followed by Waldenström's macroglobulinemia: a case report.

A case of hepatocellular carcinoma associated with Waldenström's macroglobulinemia is reported. During treatment and follow-up of hepatocellular carcinoma, a 54-year-old man was found to have a progressive monoclonal increase in serum IgM level and subsequently was diagnosed as having Waldenström's macroglobulinemia. Chemotherapy was carried out to prevent hyperviscosity syndrome due to Waldenström's macroglobulinemia without any surgical management for hepatocellular carcinoma. The association of these diseases is quite rare; only 6 cases have been reported in the literature, and this is the first case in which hepatocellular carcinoma preceded Waldenström's macroglobulinemia.

[Home care of patients with advanced terminal cancer who had improved QOL after undergoing gastrostomy for gastrointestinal obstruction caused by peritonitis carcinomatosa].

Patients with gastrointestinal obstruction caused by peritonitis carcinomatosa suffer from chronic nausea, abdominal distension and inability to ingest food. Patients can receive home care only in rare cases. We performed a gastrostomy for the purpose of reducing gastrointestinal pressure in three patients with gastrointestinal obstruction caused by peritonitis carcinomatosa. The three patients had decreased mental and physical suffering and were able to be discharged from the hospital. We report the efficacy of gastrostomy because of the improvements in the three patients QOL at home.

A comparative study of postoperative complications after hepatectomy in patients with and without chronic liver disease.

BACKGROUND: Although hepatic resection is the most reliable treatment for hepatocellular carcinoma, impaired liver function because of cirrhosis or chronic hepatitis contributes to relatively high rates of postoperative complications. We have reviewed a series of hepatectomies at our institution and investigated risk factors for complications after hepatectomy in patients with impaired liver compared with patients with normal liver. METHODS: From October 1994 to March 1998, 277 hepatectomies for hepatocellular carcinoma, cholangiocellular carcinoma, metastatic liver tumors, and other hepatic diseases were performed. In an attempt to clarify the safety of hepatectomy for the impaired liver at our institution, we did a comparative study of postoperative complications after hepatectomy in 2 groups: patients with impaired livers (187 hepatectomies) and patients with normal livers (90 hepatectomies). RESULTS: Of the 277 hepatectomies, bile leakage occurred in 25 patients (16 in impaired livers vs 9 in normal livers), abdominal infection in 45 patients (30 vs 15 patients), wound infection in 13 patients (9 vs 4 patients), pleural effusion in 52 patients (35 vs 17 patients), atelectasis in 26 patients (17 vs 9 patients), pneumonia in 4 patients (3 vs 1 patients), ileus in 6 patients (3 vs 3 patients), intra-abdominal hemorrhage in 3 patients (0 vs 3 patients), and hyperbilirubinemia in 5 patients (4 vs 1 patients). Hepatic insufficiency and hospital death were not experienced in this series. The mean postoperative hospital stay was 22.9 days (23.5 vs 23.1 days), and except for intra-abdominal hemorrhage there was no statistically significant difference between the 2 groups. CONCLUSIONS: Hepatectomy for the impaired liver is now as safe a procedure as for the normal liver, provided the overall guidelines outlined in our algorithm are followed.

Propofol prevents delayed neuronal death following transient forebrain ischemia in gerbils.

PURPOSE: This study was conducted to ascertain whether propofol may protect against delayed neuronal death in the hippocampal CA1 subfield in gerbils. METHODS: Thirty-five gerbils were randomly assigned to five groups: Group I, the control group, a sham operation treated with physiological saline solution (PSS); Group II, ischemia/reperfusion treated with PSS; Group III, ischemia/reperfusion treated with 50 mg x kg(-1) propofol; Group IV, ischemia/reperfusion treated with 100 mg x kg(-1) propofol; Group V ischemia/reperfusion treated with 150 mg x kg(-1) propofol. Transient forebrain ischemia was induced by occluding the bilateral common carotid arteries for four minutes under N2O/O2/halothane anesthesia after administration of propofol or PSS. Five days later, histopathological changes in the hippocampal CA1 subfield were examined using a light microscope and degenerative ratio of the pyramidal cells were measured according to the following formula: (number of degenerative pyramidal cell/total number of pyramidal cells per 1 mm of hippocampal CA1 subfield) x 100. RESULTS: In group II, the pyramidal cells were atrophic and pycnotic; vacuolation and structural disruption of the radial striated zone was observed. In the other four groups, these changes were not observed. The degenerative ratios of pyramidal cells were as follows; group I: 5.9 +/- 1.9%, group II: 94.6 +/- 2.5% (P < 0.01), group III: 10.7 +/- 1.7%, group IV: 9.7 +/- 1.8%, group V: 9.2 +/- 1.9%. CONCLUSION: This study suggests that propofol may prevent delayed neuronal death in the hippocampal CA1 subfield after cerebral ischemia/reperfusion in gerbils.

Advanced primary Hodgkin's disease of the spleen cured by surgical resection: report of a case.

We describe herein the case of a 61-year-old man who underwent successful resection of advanced primary Hodgkin's disease of the spleen. On admission, computed tomography and ultrasonography showed a fist-sized, slightly enhanced mass, and angiography demonstrated a typical neoplastic tumor stain in the spleen. Exploratory laparotomy revealed a hard mass invading the splenic hilar lymph nodes, gastric upper body, transverse colon, pancreatic tail, and left lateral segment of the liver. The patient underwent splenectomy with combined resection of the surrounding organs invaded by the tumor, followed by postoperative chemotherapy. Histological examination showed many Reed-Sternberg cells, and the tumor was subsequently diagnosed as Hodgkin's disease of the spleen. The patient is currently well without any signs of recurrence 4 years after surgery.

[Influence of nitric oxide on cerebral hemodynamics during endotoxemia in dogs].

The aim of this study is to clarify the influence of nitric oxide (NO) in cerebral circulation during endotoxemia. Two groups of 24 mongrel dogs (N = 12 each) received saline 1 ml.kg-1.h-1 or endotoxin (lipopolysaccharide, LPS) 500 ng.kg-1.h-1 for 3 hours. To determine changes of NO in the systemic and cerebral circulation, we measured NOx (NO2-/NO3-) in the femoral artery and superior sagittal sinus as metabolites of NO using the Griess method. We also measured the concentrations of cerebral oxyhemoglobin (HbO2), deoxyhemoglobin (Hb), total hemoglobin (total Hb) and cytochrome aa3 (Cytaa3) using near-infrared laser spectroscopy. Changes in cerebral blood volume were evaluated from the total Hb. NOx in systemic and cerebral circulation increased significantly after infusion of LPS. Therefore, the increased production of NO in cerebral circulation was consistent with increase of cerebral blood volume. In conclusion, it seems reasonable to assume that increased cerebral blood volume may result from increased production of cerebral NO during endotoxemia.

The seasonal variation in the microbial agents implicated in the etiology of diarrheal diseases among children in Lao People's Democratic Republic.

During 1994-1995, the etiological structure of children's diarrhea was monitored in outpatients at Mahosot Hospital, Vientiane, Lao PDR. Of the 191 children studied, 42% had stool specimens positive for enteropathogens; 22% had rotavirus, 21.5% enteropathogenic E. coli, 4.7% Shigella flexneri, 2.9% Campylobacter jejuni, 2.1% Shigella sonnei, and 0.5% each of Giardia intestinalis and Entamoeba histolytica. No Vibrio cholerae and Salmonella spp. was detected in this monitoring. In children under five years, rotaviruses were detected almost all round the year with a maximum prevalence in January in the dry season. Shigella species were highly detected in June to July in the rainy season.

Inhibition of malaria-infected erythrocytes by deoxyspergualin: effect on in vitro growth of malarial cultures.

The effect of deoxyspergualin (DSG) on the K1 strain of human malarial parasite Plasmodium falciparum in vitro was studied to test a possible new antimalarial chemotherapy. Hypoxanthine labeled with tritium (3H) was used to assess macromolecular synthesis. The inhibitory effects of DSG on the parasite peaked after 72 h of incubation. Parasitemia without DSG treatment was 9%, whereas at a DSG concentration of more than 156 microg/ml it was less than 1%. The amount of [3H]hypoxanthine taken up decreased with increasing DSG concentration. DNA synthesis of malarial activity decreased with increasing DSG concentration. These findings provide more evidence for the effects of DSG on this malarial parasite. As in previous in vivo studies done with DSG, the in vitro findings showed that DSG may be a new antimalarial drug.

Reconstruction of the hepatic and portal veins using a patch graft from the right ovarian vein.

We describe a patch-graft technique using the right ovarian vein for reconstruction of the right hepatic and portal veins after resection in hepatectomy and pancreatoduodenectomy in female patients. After partial resection of the right hepatic vein or portal vein for removing either hepatic or pancreatic tumors, the defects were covered by a patch graft from the right ovarian vein. The proximal part of the vein, 5 cm in length, was harvested, divided longitudinally, and then divided into two equal parts, which were sutured together to give a patch measuring 2.5 x 2.0 cm. This technique can be applied for reconstruction after partial resection of the hepatic or portal vein in hepatectomy and pancreatoduodenectomy.