Minekatsu Nishida

Oligonucleotide microarray for prediction of early intrahepatic recurrence of hepatocellular carcinoma after curative resection

BACKGROUND Hepatocellular carcinoma has a poor prognosis because of the high intrahepatic recurrence rate. There are technological limitations to traditional methods such as TNM staging for accurate prediction of recurrence, suggesting that new techniques are needed. METHODS We investigated mRNA expression profiles in tissue specimens from a training set, comprising 33 patients with hepatocellular carcinoma, with high-density oligonucleotide microarrays representing about 6000 genes. We used this training set in a supervised learning manner to construct a predictive system, consisting of 12 genes, with the Fisher linear classifier. We then compared the predictive performance of our system with that of a predictive system with a support vector machine (SVM-based system) on a blinded set of samples from 27 newly enrolled patients. FINDINGS Early intrahepatic recurrence within 1 year after curative surgery occurred in 12 (36%) and eight (30%) patients in the training and blinded sets, respectively. Our system correctly predicted early intrahepatic recurrence or non-recurrence in 25 (93%) of 27 samples in the blinded set and had a positive predictive value of 88% and a negative predictive value of 95%. By contrast, the SVM-based system predicted early intrahepatic recurrence or non-recurrence correctly in only 16 (60%) individuals in the blinded set, and the result yielded a positive predictive value of only 38% and a negative predictive value of 79%. INTERPRETATION Our system predicted early intrahepatic recurrence or non-recurrence for patients with hepatocellular carcinoma much more accurately than the SVM-based system, suggesting that our system could serve as a new method for characterising the metastatic potential of hepatocellular carcinoma.

Intraarterial combined immunochemotherapy for unresectable hepatocellular carcinoma: preliminary results

An important objective for patients with unresectable hepatocellular carcinoma (HCC) is the development of effective chemotherapy. We administered a combination of biological response modifiers and anticancer agents to 24 patients with unresectable HCC. Each case had an implanted infuser port which was connected to a catheter placed in the hepatic artery for the intraarterial (i.a.) administration of chemotherapy. The following agents were administered to each patient: recombinant interleukin-2 (800 000 JRU/day infused i. a. continuously for 6 days/week); OK-432 (5 KE injected i. a. twice in 4 weeks and i. m. three times per week); Adriamycin (10 mg injected i.a. twice in 4 weeks); cyclophosphamide (300 mg injected i. a. twice in 4 weeks), and famotidine (40 mg/day administered orally). Objective response was assessed according to tumor size measured by computed tomography and angiography before and after treatment. We observed a complete response (CR) in 4, partial response (PR) in 3, minor response (MR) in 7, no change (NC) in 7, and progressive disease (PD) in 3. The response rate (CR+PR+MR) was 58.3%. The overall 2-year survival rate was 52%. The 2-year survival rate of the responders (CR+PR+MR) was 80%, while that of the non-responders (NC+PD) was 0%. There was a significant difference between the responders and non-responders in respect to survival rate (P<0.05). The percentages of CD25+ cells, CD56+ cells, and Leu7-CD16+ cells and NK activity in the peripheral blood showed a significant increase following the regimen. Serum levels of tumor necrosis factor α TNFα rose after the initiation of OK-432. TNFα levels were higher in the responders than in the non-responders. Adverse effects included high fever (all patients) and severe transient hypotension (15 patient) that was controlled by convervative therapy. Combined immunochemotherapy administered intraarterially may be a new strategy for treating unresectable HCC.

Effect of Cautery with Irrigation Forceps on the Remnant Liver after Hepatectomy in Rats

Monopolar cautery with irrigation forceps (CIF) was devised for use in liver resection that does not require occlusion of inflow to the remnant liver. However, a high power output is required to divide the hepatic parenchyma which boils the irrigation water. This study was performed to investigate the effects of using CIF on the hepatic parenchyma. Histologic and biochemical examination was performed in rats which had undergone hepatectomy using the CIF, irrigating bipolar (IB), Pringle’s maneuver with blunt dissection (group P), or a sham operation. A greater cautery distance was obtained with the CIF than the IB. There was no significant difference in the remnant liver function after the 1st postoperative day in any of the groups. CIF is an effective instrument for anatomic or nonanatomic hepatic resection.

Introduction of monoclonal antibodies to bromodeoxyuridine to monitor hepatic regeneration

The effect on the liver of portal vein and/or bile duct branch ligation was examined in rabbits by measuring cellular kinetics using the bromodeoxyuridine labeling index. Twenty-four days after ligation of a portal vein and/or bile duct branch, similar degrees of compensatory regeneration were observed. However, there were significant differences in the pattern in which regeneration developed. Compensatory regeneration after ligation of a bile duct follows a different pattern than that after portal vein branch ligation.

The effect of temporary hepatic artery or portal vein occlusion in obstructive jaundice

Hepatic hemodynamics before vascular occlusion and the effect of transient hepatic artery or portal vein occlusion on the liver were investigated in normal dogs and dogs with experimentally induced obstructive jaundice by measurement of hepatic tissue blood flow (HTBF), index of hemoglobin concentration (IHb), oxygen saturation (ISO2), serum glutamic pyruvic transaminase (SGPT) concentration, and malonaldehyde (MDA) concentration in liver tissue. Livers with obstructive jaundice had increased blood flow and a lower hemoglobin concentration compared with normal livers at baseline before vascular occlusion. Percentage change of ISO2 from baseline was higher than percentage change of HTBF after reperfusion in both normal and obstructive jaundiced liver, although they were decreased to almost similar proportions during vascular occlusion. MDA concentration in obstructive jaundice after reperfusion following vascular occlusion was higher than in normal liver. Furthermore, MDA concentration after reperfusion following hepatic artery occlusion was increased compared with after reperfusion following portal venous occlusion in obstructive jaundice. There was no evidence of massive liver necrosis which was newly developed by transient vascular occlusion. These results represent the pathological condition in the liver before transient vascular occlusion and after reperfusion in obstructive jaundice.

A case of hepatocellular carcinoma with tuberculoma within tumor tissue

We made a diagnosis of hepatocellular carcinoma and performed partial resection of the liver in a 72 year-old woman. Granulomas were observed within hepatocellular carcinoma in the surgical specimen. Microscopic findings demonstrated the granulomas particularly within the tumor, and showed that they were composed of epithelioid cells with caseous necrosis. These tuberculomas compressed the tumor cells, and many lymphocytes had infiltrated the tumor around the tuberculomas. The cancer stage of the patient was early and her prognosis is good.

Surgical Treatment of Hepatocellular Carcinoma

Hepatic resection is currently performed for the treatment of hepatocellular carcinoma (HCC), which is associated with a high incidence of postoperative recurrence. The aim of this study was to clarify the prognostic factors after hepatic resection for HCC. A total of 144 patients who underwent hepatic resection for HCC were studied. Eight factors including albumin, tumor size, intrahepatic metastasis (IM), invasion into the portal vein (Vp), type of hepatectomy, operative time, blood loss, and tumor margin were analyzed with multivariate analysis using a stepwise multivariate logistic regression model to evaluate the prognostic factors after hepatic resection. The relationship between operative procedures and the type of treatment modalities was also investigated, and the outcome of treatment modalities was analyzed using the survival rate after recurrence. Multivariate analysis revealed the type of hepatectomy, Vp, and IM to be independent factors related to recurrence and prognosis. The 5-year survival rate in patients without Vp and without IM was significantly higher than in patients with Vp and with IM (P > .05). The 5-year survival rate and 5-year disease-free survival rate in patients who underwent subsegmentectomy or segmentectomy or lobectomy (anatomic resection) was significantly higher than in patients who underwent partial resection (P > .01 and P > .05). Eleven (31.4%) patients with intrahepatic recurrence after anatomic resection were treated with repeat hepatectomy but only 2 (8.3%) after nonanatomic resection. Moreover, repeat hepatectomy was significantly related to the prognosis after recurrence compared with chemolipiodolization and locoregional chemotherapy (P > .05). These results suggest that anatomic resection, which was related to a low recurrence rate as well as a greater chance of reresection, may be a useful surgical treatment for hepatocellular carcinoma.

A case report of mixed type hepatocellular carcinoma with early recurrence in the form of peritoneal dissemination after hepatectomy.

症例は59歳女性で, 47歳時B型急性肝炎発症, 54歳時に肝硬変の診断を受け, 経過観察されていた. 有茎性肝細胞癌の診断にて当科紹介され, 肝部分切除を施行し, 低分化型肝細胞癌の一部に胆管細胞成分を含む混合型肝癌と診断された. 術後75日目に癌性腹膜炎にて死亡し, 剖検で高度な腹腔内播種が確認されたが, 他に肉眼的転移を認めなかった. 播種巣の組織像はごく一部に胆管細胞成分がみられたが, 原発巣と同様の低分化型肝細胞癌が優勢であった. 肝細胞癌の播種性転移の頻度は低いとされているが, 常にその可能性を念頭に置き対策を講ずる必要がある.

Compensatory hepatic hypertrophy after occlusion of branches of the portal vein or bile duct

The effect on the liver of portal or bile duct branch occlusion was examined in rabbits by measuring hepatic tissue blood flow and cellular kinetics, using the bromodeoxyuridine labeling index. The portal branch bile duct branch, or both, to the main lobe and caudate lobe (80.4% of total liver weight) were ligated or embolized just above the right posterior lobe (19.6%), resulting in compensatory hypertrophy of the right posterior lobe and atrophy of the main and caudate lobes. Twenty-four days after ligation, the degree of compensatory hypertrophy in the different groups was comparable. There were significant differences in the pattern of the development of hypertrophy. Ligation of both a portal branch and the corresponding bile duct resulted in more rapid hypertrophy and atrophy than ligation of a portal branch alone. Ligation of a branch of the bile duct resulted in slow development of hypertrophy and atrophy. In the embolization group, the increase in the right posterior lobe stopped 6 days after the operation, resulting that it was about 40% thereafter. Histological findings showed that the fibrin clot had contracted and was floating in the portal branch to the main lobe. These results suggested that portal blood flow to the main lobe had resumed and was gradually increasing as the clot contracted. Portal branch ligation gave results superior to those with portal branch embolization with regard to application to preoperative procedure in extended hepatobiliary surgery.

Improved liver function due to decompression of the hepatic veins after extended left hepatectomy

Extended left hepatectomy was performed on a patient with hepatocellular carcinoma in the median segment of the liver. The impaired hepatic venous outflow demonstrated by preoperative duplex Doppler ultrasonography improved after surgery due to decompression of the hepatic veins, and liver function improved. A certain volume of hepatic venous outflow may be necessary to maintain liver function and allow compensatory hypertrophy after partial hepatectomy.