Hiroaki Kinoshita

Effects of Long-Term Postoperative Interferon-α Therapy on Intrahepatic Recurrence after Resection of Hepatitis C Virus–Related Hepatocellular Carcinoma: A Randomized, Controlled Trial

Hepatitis C virus (HCV) is an important cause of hepatocellular carcinoma in many areas of the world (1). The recurrence rate at 5 years after resection of HCV-related hepatocellular carcinoma has been reported as 70% to 80% (2-4). Recurrences after resection of hepatocellular carcinoma may be either metastases from the primary carcinoma or new foci of carcinomas (multicentric occurrence) (4-8). Chronic active hepatitis is a risk factor for recurrence, including multicentric carcinogenesis, after resection (4, 7, 8). In addition, the recurrence rate after the resection of HCV-related hepatocellular carcinoma is higher in patients with HCV viremia than in those without viremia (4). Interferon treatment decreases the incidence of hepatocellular carcinoma in patients with chronic hepatitis C (9-16). We conducted a randomized, controlled trial to evaluate whether postoperative therapy with interferon- would decrease the incidence of recurrence after resection of HCV-related hepatocellular carcinoma. Methods Patients and Trial Profile Between November 1993 and March 1997, 112 HCV-positive patients underwent resection for hepatocellular carcinoma at Osaka City University Hospital or Osaka City General Hospital, Osaka, Japan. Seventy-seven patients met the eligibility criteria: 1) single tumors less than 5 cm in maximum diameter on preoperative imaging; 2) detectable HCV RNA without hepatitis B surface antigen or HIV antibodies; 3) chronic hepatitis C or a ChildPugh score of A or B for compensated cirrhosis [17]; and 4) no severe thrombocytopenia (platelet count < 50 109 cells/L). Before resection, 31 of the 77 eligible patients gave written informed consent to participate in the trial; however, one patient was later excluded because resection was not curative. Forty-six patients declined to participate because they were unwilling or unable to agree to twice-weekly hospital visits for 2 years or were concerned about widely publicized side effects of interferon use. A curative operation was defined as complete resection of all macroscopically evident tumor tissue. Specifically, no tumors could be detected in the remnant liver on computed tomography performed 3 to 4 weeks after resection. In the one patient excluded from the trial after resection, a residual tumor was found on computed tomography 3 weeks after resection. In all, 30 patients were enrolled and randomly allocated to the interferon- group (n = 15) or a control group (n = 15). Randomization was done by using a random-numbers table, and patient assignments were withheld from the investigators. During the trial, no patient in the control group received any type of treatment; no patient in the interferon group received chemotherapy or any treatment other than interferon-. This study was done in accordance with the Helsinki Declaration and was approved by the ethics committees of our institutions. Interferon- Treatment Patients received 6 MIU of interferon- (human lymphoblastoid interferon, Sumiferon, Sumitomo Pharmaceuticals, Osaka, Japan) intramuscularly every day for 2 weeks, then 3 times weekly for 14 weeks, and finally twice weekly for 88 weeks (total dose, 1572 MIU). Interferon- therapy was started 5 to 15 weeks (mean, 9 weeks) after resection. In 1 of the 15 patients in the interferon- group, treatment was delayed until 7 months after resection at the patients request. Laboratory tests were done at least once monthly during interferon- therapy and at least once every 3 months thereafter for evaluation of the response to therapy and identification of side effects of interferon-. Serum HCV RNA was detected by using a method reported previously (9), and viral load was measured by using a branched-DNA probe assay (Quantiplex HCV-RNA, Chiron Corp., Emeryville, California). Response to Interferon- Therapy A complete response was defined as the absence of serum HCV RNA (virologic remission) and serum alanine aminotransferase (ALT) activity within the reference range ( 750 nkat/L [ 45 U/L]) for at least 6 months after interferon- therapy (biochemical remission) (9). A biochemical response was defined as a decrease in serum ALT activity to within the reference range but with persistently detectable serum HCV RNA. Nonresponse was defined as persistence of HCV RNA and no decrease in ALT activity. Detection of Recurrence Serum concentrations of -fetoprotein and protein induced by vitamin K absence and antagonist II were measured within 2 months of resection and every 3 months thereafter. Ultrasonography, computed tomography, magnetic resonance imaging, or some combination of these tests was done within 2 months after the operation and every 3 months thereafter. These examinations were done until the detection of recurrence or until the trial end point (final examination). When tumor recurrence was suspected on the basis of tumor markers, imaging, or both, angiography, ultrasonography-guided biopsy, or both were done to establish a definitive diagnosis. The radiologists who were responsible for diagnosis of tumor recurrences had no contact with the patients and had no information about the trial. Statistical Analysis Time to recurrence was measured from the time of resection to the detection of a recurrent tumor. The recurrence rates (including data on patients who could not complete interferon- therapy) were calculated by using the KaplanMeier method, and significance of between-group differences was assessed by using the log-rank test. All analyses were done by using SAS statistical software, version 6.12 (SAS Institute, Inc., Cary, North Carolina). Role of the Funding Source The funding sources had no role in the collection, analysis, and interpretation of the data or in the decision to submit the paper for publication. Results Most baseline variables were similar in the two groups, as were the operative procedures (Table). The patients who declined participation and the patients who were enrolled were similar with regard to most variables. Table. Patient Demographic and Clinical Characteristics Interferon- could not be administered to one patient because of premature ventricular contractions. Data on this patient were included in the interferon- group for all analyses. Interferon- administration could not be completed in 3 patients because of depression (n = 1, at 17 days), severe general fatigue (n = 1, at 11 months), and renal abscess (n = 1, at 10 months; this patient also had a recurrence detected in the same month). In 4 patients with recurrence, interferon- administration was stopped prematurely to allow treatment of the tumor. In the interferon- group, 2 patients were complete responders, 6 patients were biochemical responders only, and 7 patients were nonresponders. Among the control patients, postoperative serum ALT activity (except immediately after resection) was greater than the reference range, and serum HCV RNA was detected at the follow-up appointments. The median follow-up period (from the operation to the detection of recurrence or to the study end point) was 1087 days (25th and 75th percentiles, 514 and 1376 days) for patients receiving interferon- and 897 days (25th and 75th percentiles, 439 and 1105 days) for the controls. In all patients, examinations for detection of recurrence were done according to schedule. All patients without recurrence were still alive at the end of this trial. Recurrent tumors were detected in 5 patients (including the patient who could not tolerate interferon- therapy) in the interferon- group and in 12 control patients. In the interferon- group, recurrence was definitively diagnosed in 3 patients by using angiography and in 2 patients by using angiography and biopsy. In the control group, definitive diagnoses were made in 8 patients by using angiography, in 3 patients by using biopsy, and in 1 patient by using both methods. No recurrence was detected in either of the 2 complete responders in the interferon- group. One of the 6 biochemical responders and 4 of the 7 nonresponders had recurrent tumors. The recurrence rates increased along similar curves in the two groups in the 2 years after resection; thereafter, 6 controls but no patient receiving interferon- had recurrence (Figure). The recurrence rate was significantly lower in the interferon- group than in the control group (P=0.037). Figure. Recurrence rates in the interferon- ( solid line ) and control ( dotted line ) groups. P Discussion Persistent active hepatitis is a risk factor for development of hepatocellular carcinoma, indicating that treatment of active hepatitis may be important in the management of patients with HCV-related hepatocellular carcinoma (4). In our study, absence of interferon- therapy was a risk factor for recurrence. Although for the first 2 years of follow-up the recurrence rate increased for the two groups in similar curves, the recurrence rate in the interferon- group did not increase after that time. This finding suggests that patients in the interferon- group had been truly cured. Recurrent tumors detected within 2 years of the operation were likely to be either metastases from the primary carcinoma or carcinoma that appeared before or during interferon- therapy but had gone undetected at the operation. Our findings indicate that interferon- therapy does not suppress carcinoma itself. On the other hand, recurrences that appear more than 2 years after resection are likely to have arisen because of new carcinogenesis. Recurrence was detected in 1 of 8 patients with a biochemical remission (including the 2 complete responders) and in 4 of the 7 nonresponders. Recently, several investigators have shown that hepatocellular carcinoma is less likely to develop in patients in whom interferon- decreases ALT activity to within the reference range, even if HCV is not eradicated, probably because of decreased hepatocyte necrosis and liver fibrosis (9, 11, 12, 14-16). Thus, eradication of HCV may not be necessary for reduced risk for recurrenc

A comparison of video-assisted thoracoscopic oesophagectomy and radical lymph node dissection for squamous cell cancer of the oesophagus with open operation.

An Erratum has been published for this article in British Journal of Surgery 90(6) 2003, 764.

A Prospective Randomized Trial of the Preventive Effect of Pre‐operative Transcatheter Arterial Embolization against Recurrence of Hepatocellular Carcinoma

To clarify whether pre‐operalive transcatheter arterial embolization (TAE) improves survival after hepatectomy, a prospective randomized comparative study was done. Of a total of 115 registered patients having solitary hepatocellular carcinoma (HCC) 2 to 5 cm in diameter, 18 (15.7%) were excluded after randomization. As a result, 97 patients were chosen as subjects and divided into two groups: hepatectomy with (group A: n = 50) and without (group B: n=47) pre‐operative TAE. The period of observation of the patients who survived the surgery was between 4.0 and 6.6 years. The randomization appeared to have provided well‐balanced groups of patients and the clinico‐pathological characteristics of the two groups were quite similar. The necrotic part of the cancerous lesions, as confirmed by operative specimens, amounted to 74.8 ±33.4% (mean±SD) in group A and 6.8 ±7.2% in group B (P<0.01). However, the cancer‐free survival rates after hepatectomy in both groups showed little difference (39.1±7.0 (%±SE) and 31.1±0.1, respectively). We speculate that TAE is not effective against such HCC accessory lesions as minute intrahepatic metastasis and tumor thrombus and that pre‐operative TAE does not improve post‐operative survival.

Incidence and management of Bile leakage after hepatic resection for malignant hepatic tumors

BACKGROUND Bile leakage is one of the frequent and disturbing complications of hepatic resection. STUDY DESIGN Clinical records of the 363 patients who underwent hepatic resections without biliary reconstruction for hepatic cancers between January 1994 and June 2001 were reviewed. Postoperative bile leakage was defined as continuous drainage with a bilirubin concentration of 20 mg/dL or 1,500 mg/d lasting 2 days. Leakage that continued longer than 2 weeks or that required surgical intervention was defined as uncontrollable. Differences in incidence and frequency of uncontrollable leakage for the different types of hepatic resection, tumors, and underlying liver disease were investigated. Outcomes after treatment for uncontrollable bile leakage were also reviewed. RESULTS Postoperative bile leakage occurred in 26 of 363 patients (7.2%). Although the incidence in patients with cholangiocellular carcinoma (3/9 [33%]) was higher (p = 0.03) than in patients with hepatocellular carcinoma, rates of occurrence were similar among the different types of hepatic resection and underlying liver disease. Eight of the 26 patients (31%) had uncontrollable leakage. Two patients required reoperation to control leakage; one of these developed hepatic failure and died 2 months after surgery. Four patients underwent endoscopic nasobiliary drainage 21 to 34 days after hepatectomy, and the leakage resolved within 3 to 21 days. Fibrin glue sealing was effective in two patients whose leaking bile ducts were not connected to the common bile duct. CONCLUSIONS Although meticulous surgical technique can minimize the risk of postoperative bile leakage, some instances of leakage are unavoidable. Nonsurgical treatments, such as nasobiliary drainage or fibrin glue sealing, are preferable to reoperation.

Learning curve of video-assisted thoracoscopic esophagectomy and extensive lymphadenectomy for squamous cell cancer of the thoracic esophagus and results

Background: The efficacy of thoracoscopic radical esophagectomy for cancer of the thoracic esophagus and the learning curve required have yet to be clearly established. Methods: Eighty treatment-naive patients with esophageal cancer without contiguous spread underwent esophageal mobilization and extensive mediastinal lymphadenectomy through a 5-cm minithoracotomy and four trocar ports. The outcomes in the first 34 patients (group 1) and the last 46 patients (group 2) were compared. Results: There were no differences in background or clinicopathologic factors between the two groups. The duration of the thoracoscopic procedure and blood loss were less (p <0.0001), the incidence of postoperative pulmonary infection was less (p = 0.0127), and the number of mediastinal nodes retrieved was greater (p = 0.0076) in group 2. Multivariate analysis demonstrated that surgical experience (number of cases performed) predicted the risk of pulmonary infection (p = 0.0331). Conclusion: Video-assisted thoracoscopic radical esophagectomy can be performed with safety and efficacy comparable to those of open esophagectomy. Morbidity decreases with the surgeons experience.

Prognostic significance of the MIB‐1 proliferation index for patients with squamous cell carcinoma of the esophagus

Background. A number of studies have indicated that the ki‐67 proliferation index is of important prognostic significance for a variety of neoplasias. It was the aim of this study to investigate whether any correlation exits between the MIB‐1 proliferation index and various clinicopathologic parameters in squamous cell carcinomas of the esophagus from 72 patients (20 women: median age, 64 years; range, 45–79 years; and 52 men: median age, 61 years; range, 43–77 years).

The relation between carcinoma of the gallbladder and an anomalous connection between the choledochus and the pancreatic duct.

An anomalous connection between the choledochus and the pancreatic duct may be associated etiologically or pathogenetically with congenital biliary dilation and carcinoma of the dilated bile duct. During the past 10 years, a total of 14 cases of carcinoma of the gallbladder with an anomalous connection between the choledochus and the pancreatic duct were encountered. These cases were studied in reference to their clinical features and histological findings. An experimental model of pancreatic juice inflow into the gallbladder of mongrel dogs was produced and the histological changes of the mucosa of that organ was observed. The intent was to elucidate the relationship between carcinoma of the gallbladder and this anomaly. The results of this clinical and experimental study suggest that reflux and stasis of pancreatic juice in the gallbladder induce chronic cholecystitis with intestinal metaplasia. This may be important in the pathogenesis of well-differentiated carcinoma of the gallbladder.

Reconstructive Procedure after Distal Gastrectomy for Gastric Cancer that Best Prevents Duodenogastroesophageal Reflux

Billroth I and II reconstructions are commonly performed after distal gastrectomy. Both may cause duodenogastric and duodenogastro-esophageal reflux, conditions reported to have carcinogenetic potential. The aim of this study was to investigate which reconstructive procedure would most effectively prevent bile reflux into the gastric remnant and esophagus after distal gastrectomy. A group of 92 patients who underwent curative distal gastrectomy for gastric cancer were subjected and classified into three groups retrospectively by the reconstructive procedure undertaken: group A, Roux-en-Y (Roux-Y) reconstruction (n=29); group B, Billroth I reconstruction (n=41); group C, Billroth II reconstruction (n=22). The bile reflux periods (percent time) for the gastric remnant and esophagus were measured with the Bilitec 2000 under standardized conditions. The percent time for the gastric remnant was significantly less in group A than in group B or C. In 61% of all patients, bile reflux into the esophagus was found to be more than 5.0% of the time; it was less in group A than in group B or C (p=0.057). A questionnaire revealed a good correlation between the incidence of reflux symptoms and the percent time for the gastric remnant and esophagus. Roux-Y reconstruction is superior to either Billroth I or II reconstruction for preventing bile reflux into the gastric remnant and esophagus after distal gastrectomy.RésuméLe rétablissement de continuité après gastrectomie distale est habituellement selon Billroth I ou selon Billroth II. Cependant, les deux types de reconstruction peuvent être responsables de reflux duodénogastrique et de reflux duodénogastroesophagien, avec un risque plus élevé de développer un cancer. Le but de cette étude a été de déterminer quel type de rétablissement serait le plus efficient dans la prévention du reflux de bile dans le moignon gastrique et dans l’œsophage après gastrectomie distale. Quatre-vingt-deux patients qui ont eu une gastrectomie distale à visée curatrice pour cancer ont été inclus et classés rétrospectivement en trois groupes selon le type de reconstruction: groupe A, reconstruction par anse en Y (n=29); groupe B, rétablissement de continuité selon Billroth I (n=41); et groupe C, rétablissement selon Billroth II (n=22). La durée du reflux (en pourcentage de temps) au niveau du moignon gastrique et de l’œsophage a été mesurée dans des conditions standardisées Bilitec 2000. Le pourcentage de temps pour le moignon gastrique a été signifieativement plus bas dans le groupe A que dans les groupes B et C. La durée du reflux de bile dans l’œsophage a dépassé 5% chez 61% des patients: elle a été moins longue dans le groupe I que dans les groupes B et C (p=0.057). Grâce à un questionnaire on a pu trouver une bonne corrélation entre l’incidence des symptômes de reflux et la durée du temps de reflux dans le moignon gastrique et dans l’œsophage. Le rétablissement de continuité par anse en Y est supérieur aux rétablissements de types Billroth I et II en ce qui concerne la prévention de reflux de bile dans le moignon gastrique et dans l’œsophage après gastrectomie distale.ResumenLas reconstrucciones tipos Billroth I y II son las más comunes cuando se practica una gastrectomía. Sin embargo, ambas pueden causar reflujo duodenogástrico y duodeno gastroesofágico, fenómeno que se reconocen como de potencial efecto carcinogenético. El propósito del presente estudio fue investigar cuál procedimiento de reconstrucción podría prevenir el reflujo al remanente gástrico y al esófago luego de una gastrectomía distal. Noventa y dos pacientes sometidos a gastrectomía distal curativa por cáncer fueron clasificados retrospectivamente en 3 grupos: grupo A, reconstrucción de Roux-en-Y (n=29); grupo B, reconstrucción Billroth I (n=41); grupo C, reconstrucción Billroth II (n=22). El periodo de reflujo biliar (por ciento del tiempo) al estómago residual y al esófago fue determinado mediante Bilitec 2000 bajo condiciones estandarizadas. El porcentaje de tiempo para el estómago residual fue significativamente menor en el grupo A en comparación con los grupos B y C. En 61% de la totalidad de los pacientes se encontró reflujo al esófago por más del 5% del tiempo; fue menor en el grupo A que en los grupos B y C (p=0.057). La aplicación de un cuestionario reveló buena correlación entre la incidencia de los síntomas de reflujo y el porcentaje de tiempo del reflujo al remanente gástrico y al esófago. La reconstrucción de Roux-en-Y es superior a las reconstrucciones Billroth I y II en cuanto a la prevención del reflujo biliar al remanente gástrico y al esófago luego de una gastrectomía distal.

Hepatic cytochrome P450 is directly inactivated by nitric oxide, not by inflammatory cytokines, in the early phase of endotoxemia

BACKGROUND/AIMS Although the activity of the liver in metabolizing and eliminating various drugs decreases in endotoxemia, the mechanism remains to be elucidated. The generation of nitric oxide by the inducible type of nitric oxide synthase increases in endotoxemia. Nitric oxide readily reacts with heme proteins such as cytochrome P450 that metabolize various compounds, including steroids and eicosanoids. The purpose of this study was to determine the effect of nitric oxide on the function of hepatic cytochrome P450 in endotoxemic rats. METHODS To determine the dynamic aspects of nitric oxide metabolism, hepatic levels of the inducible type of nitric oxide synthase and heme-iron nitrosyl complexes, and plasma levels of nitrite and nitrate were determined in rats before and after intravenous administration of lipopolysaccharide. Changes in the levels of P450 isoforms and testosterone hydroxylation activity in hepatic microsomes were also determined. To evaluate in vivo CYP3A2 activity, midazolam sleep time was measured. RESULTS When lipopolysaccharide increased the hepatic inducible type of nitric oxide synthase and plasma levels of nitric oxide metabolites, the intensity of low-spin signal of electron spin resonance responsible for the ferric form of P450 decreased with a concomitant increase in heme-iron nitrosyl complexes in the liver. Lipopolysaccharide-related nitric oxide generation is followed by an early decrease in the levels of cytochrome P450 and of testosterone hydroxylation activity in liver microsomes. Midazolam sleep time was prolonged by lipopolysaccharide. All these early changes were prevented by the inhibitor of nitric oxide synthase, N(G)-iminoethyl-L-ornithine. Moreover, lipopolysaccharide suppressed the gene expression of CYP2C11 and CYP3A2. Decreases in levels of cytochrome P450 and their mRNAs were more pronounced at 24 h after LPS administration, but apparently they are NO-independent. CONCLUSIONS These results suggest that lipopolysaccharide-induced modulation of cytochrome P450 may occur via the interplay of two different mechanisms and that, especially in the early phase, nitric oxide-dependent inhibition is more important.

Carcinoma of the gallbladder with an anomalous connection between the choledochus and the pancreatic duct. Report of 10 cases and review of the literature in Japan.

During the last 8 years, the authors had experience with 10 cases of carcinoma of the gallbladder with an anomalous connection between the choledochus and the pancreatic duct. These cases were studied in reference to age, sex, frequency of gallstones and dilatation of the bile duct, amylase levels in bile, direct cholangiograms, histologic findings, methods of treatment, and prognosis. Histologically, intestinal metaplasia was noticed in cancerous areas and also in noncancerous areas of differentiated adenocarcinomas. These facts suggest that in carcinoma of the gallbladder with this anomaly, reflux and stasis of pancreatic juice in the gallbladder may induce chronic cholecystitis which leads to mucosal metaplasia and, eventually, to differentiated adenocarcinoma.