Resection for extrahepatic recurrence of hepatocellular carcinoma.

A total of 277 patients with hepatocellular carcinoma (HCC) underwent hepatic resection over a 20-year period. Twelve of 36 patients with recurrence confined to extrahepatic organs underwent surgical resection. There were no complications but one patient died in hospital from secondary intrahepatic recurrence. The 1-, 2- and 5-year survival rates for these 12 patients after hepatic resection were 92, 52 and 26 per cent respectively and were better than those of 24 patients who did not undergo resection for recurrence. The mean survival following resection for recurrent disease was 19.7 months and the longest survival time was nearly 8 years. Secondary recurrence after resection of metastases developed more commonly in the liver than in extrahepatic organs. Among the eight patients who survived for more than 4 months after the second operation, secondary recurrence developed in the liver and extrahepatic organs in eight and four patients respectively. In selected patients with isolated extrahepatic recurrence of HCC, surgery is effective in controlling extrahepatic disease and offers the only chance of long-term survival.

Expression of the human beta-amyloid precursor protein gene from a yeast artificial chromosome in transgenic mice.

One hallmark of Alzheimer disease is the formation in the brain of amyloid plaques containing a small peptide derived from the beta-amyloid precursor protein (APP). The APP gene exhibits a complex pattern of expression in peripheral tissues and in the brain. The entire human APP gene was introduced into embryonic stem (ES) cells by co-lipofection of a 650-kb yeast artificial chromosome (YAC). Three ES lines containing an essentially intact YAC were isolated, and expression of human APP mRNAs at levels comparable to those of endogenous mouse APP transcripts was obtained. A transgenic mouse line was established by germ-line transmission of the APP YAC. RNase protection analysis of human APP mRNAs demonstrated appropriate splicing of the primary APP transcript in ES cells and in the brain of a transgenic animal. These mice may be useful for elucidating the function of the various APP isoforms in vivo.

Regional chemotherapy for recurrent squamous head and neck cancers through a saphenous vein interposition graft.

Regional chemotherapy for head and neck cancers is effective, but the intra-arterial catheter is not without problems. We interposed a segment of saphenous vein within the carotid system to administer chemotherapeutic agents percutaneously via the arterialized venous segment. From 1983 to 1990, saphenous vein interposition graft was performed after radiotherapy in 24 patients with persistent or recurrent squamous head and neck cancers, which were also considered unresectable. There was no operative mortality. Two patients developed thrombosed vein graft; another two had wound infection; and one patient had a neck hematoma. Cisplatin was administered percutaneously every week via the saphenous vein graft. The response rate was 64% (complete response, 23%; partial response, 41%), and the 5-year actuarial survival rate was 31%. The 1-year survival rates for patients with complete, partial, and no response were 80%, 33%, and 13%, respectively. Saphenous vein interposition graft is a safe and convenient way of delivering intra-arterial chemotherapy, and it provides significant palliation for patients with recurrent nonresectable squamous head and neck cancers after radiotherapy.

Transgenic mice containing a human heavy chain immunoglobulin gene fragment cloned in a yeast artificial chromosome.

We have developed a method for the introduction of yeast artificial chromosomes (YACs) into transgenic mice. An 85 kilobase (kb) fragment of the human heavy chain immunoglobulin gene was cloned as a YAC, and embryonic stem cell lines carrying intact, integrated YACs were derived by co-lipofection of the YAC with an unlinked selectable marker. Chimaeric founder animals were produced by blastocyst injection, and offspring transgenic for the YAC were obtained. Analysis of serum from these offspring for human heavy chain antibody subunits demonstrated expression of the YAC-borne immunoglobulin gene fragment. Co-lipofection may prove to be a highly-successful means of producing transgenic mice containing large gene fragments in YACs.

Acute cholangitis secondary to hepatolithiasis.

In a series of 88 patients with acute cholangitis secondary to hepatolithiasis, 26 (30%) required emergency therapeutic intervention because of septicemic shock (n = 15), persistent fever (n = 8), or spreading peritonitis (n = 3). Analysis was made to define factors that predisposed to failure of conservative treatment and characteristics that could predict the need for emergency biliary decompression. The age, incidence of concomitant medical diseases, previous biliary surgery, positive blood culture, bacterial strains resistant to antibiotics used, and multiplicity of bacterial strains in bile cultures in patients who required emergency intervention were similar to these factors in patients who had elective operations after successful conservative management. The incidence of intrahepatic segmental obstruction by stones or strictures was similar, but many more patients who required emergency intervention had concomitant extrahepatic obstruction due to impacted common ductal stones or strictures. Logistic regression analysis of clinical, hematological, and biochemical data showed that maximum pulse rate within 24 hours of presentation (greater than 100 beats per minute, relative risk, 2.8) and platelet count at the time of admission (less than 150 x 10(9)/L, relative risk, 5.2) were the factors with independent significance in predicting the need for emergency therapeutic procedures. This finding may serve as a guideline for identifying high-risk patients for early intervention.

Treatment of hepatolithiasis: improvement of result by a systematic approach.

In previous decades the result of treatment of hepatolithiasis has been unsatisfactory. The incidence of residual stones after surgery might reach 77%. In the past 6 years we adopted a systematic approach comprised of accurate delineation of disease in the liver and biliary tract by direct cholangiography, ultrasonography, and computed tomography; tailored surgical treatment according to the extent of involvement of the liver and biliary tract; access to the intrahepatic ducts through the left duct or round ligament approach when there was difficulty with common bile duct exposure; routine use of flexible choledochoscopy; and application of electrohydraulic lithotripsy for large and impacted stones. Complete stone clearance was achieved in 114 of 127 patients (89.8%). Of those patients who had incomplete stone clearance, only six cases (4.7%) were related to technical failure of postoperative choledochoscopy. The incidence of stone recurrence was 15.8%, the lowest rate so far reported. It was the same regardless of whether a biliary drainage procedure had been performed, but the treatment for recurrent stones was facilitated by previous hepaticocutaneous jejunostomy. Overall the surgical treatment required for stone recurrence was of a lesser magnitude than that in the past.

Involvement of the cell cycle-regulated nuclear factor HiNF-D in cell growth control of a human H4 histone gene during hepatic development in transgenic mice.

Regulation of the cell cycle-controlled histone gene promoter factor HiNF-D was examined in vivo. Proliferative activity was measured by DNA replication-dependent histone mRNA levels, and HiNF-D binding activity was found to correlate with cell proliferation in most tissues. Furthermore, HiNF-D is down-regulated during hepatic development, reflecting the onset of differentiation and quiescence. The contribution of transcription to histone gene expression was directly addressed in transgenic mice by using a set of fusion constructs containing a human H4 histone gene promoter linked to three different genes. Transgene expression in both fetal and adult mice paralleled endogenous mouse histone mRNA levels in most tissues, consistent with this promoter conferring developmental, cell growth-related transcriptional regulation. Our results suggest that HiNF-D is stringently regulated in vivo in relation to cell growth and support a primary role for HiNF-D in the proliferation-specific expression of H4 histone genes in the intact animal. Further, the data presented here provide an example in which apparent tissue specificity of gene expression reflects the proliferative state of various tissues and demonstrate that multiple levels of histone gene regulation are operative in vivo.

Recurrent pyogenic cholangitis: current management.

Successful treatment of recurrent pyogenic cholangitis depends on the ability to delineate the pathology of the entire biliary system and to eradicate all stones, strictures, and destroyed liver segments. Recent advances in imaging techniques and stone fragmentation technology have been applied successfully in the management of this condition. Apart from direct cholangiography and ultrasonography, valuable information can be obtained from computed tomography which is particularly helpful in patients with recurrent disease after previous biliary surgery. Application of electrohydraulic lithotripsy in this disease solves the problem of difficult stone retrieval due to large size, impaction behind relative strictures and inside angulated segmental bile ducts. Together with construction of a hepaticocutaneous jejunostomy serving as a permanent access to the bile duct, it is anticipated that the incidence of recurrence and reoperation in the future can be reduced.

Plea for selective operative cholangiography.

A prospective study was carried out to evaluate the use of routine operative cholangiography in 382 patients undergoing elective cholecystectomy. Operative cholangiography was performed in 356 patients. In each patient, the presence or absence of clinical and operative indications for common duct exploration was correlated with the result of the operative cholangiography. In 114 patients (32%) there were one or more indications for exploration and only 34 patients showed positive cholangiographic findings and were explored. Ductal stones were found in 25 patients and nine patients had negative explorations. In the remaining 242 patients who had no indication for common duct exploration, normal cholangiogram was obtained in 234 patients and eight had false positive cholangiograms and were explored unnecessarily. No unsuspected common duct stones were detected in the whole series. Based on these results, a plea is made for selective operative cholangiography.

Hepatectomy for large hepatocellular carcinoma: the optimal resection margin.

The necessary resection margin (RM) for cure during hepatectomy for hepatocellular carcinoma (HCC) remains conjectural. From January, 1972 to June, 1988, a total of 96 patients who had complete macroscopic extirpation of their large tumor (greater than or equal to 5 cm in largest diameter) were studied retrospectively to determine the macroscopic distance of RM required to secure histological disease clearance. Positive histological RM, which was found in 31 (32.3%) patients, had significantly compromised both disease-free survival (p less than 0.04) and overall survival (p less than 0.006) of these patients. Among the 65 patients with detailed measurement of macroscopic RM, a significant reduction of residual histological disease was observed when a 0.5 cm margin had been established (p less than 0.05). Further extension of margin had no additional benefit. The presence of microsatellite (p less than 0.03) and multiple tumor nodules (p less than 0.03) was associated with an increased risk of positive histological margins among the 15 pathological parameters evaluated, including macroscopic RM. Since measurement of RM is an unreliable guide, histological confirmation is the only means for establishing the diagnosis of complete tumor clearance. Within safety limits dictated by anatomical factors and severity of underlying cirrhosis, aggressive surgery should be offered for patients with large HCC; however, resection is not advisable unless a 0.5 cm margin can be secured with certainty, especially for multinodular lesions.

Extended hepatectomy for hepatocellular carcinoma.

The results of extended hepatectomy in 25 patients with hepatocellular carcinoma performed over a 16 year period have been reviewed, analysed and compared with those of 144 patients who underwent lesser liver resection. Five left and 20 right extended hepatectomies were performed for tumours ranging from 3 to 20 cm in diameter. Seventeen (68 per cent) of the patients had non-cirrhotic livers. The major postoperative complications were: haemorrhage in five cases, major bile duct injury in three, subphrenic abscess in two, liver failure in one and wound dehiscence in one. The 30-day (operative) mortality rate was 12 per cent and the median survival duration, including operative mortality, was 9.7 (range 0.2-32.1) months. The survival rate was 46 per cent at 1 year, 33 per cent at 2 years and 22 per cent at 3 years. The morbidity, mortality and survival data of extended hepatectomy were comparable with the results of lesser hepatic resections for hepatocellular carcinoma. We conclude that extended hepatectomy is a worthwhile operation for large hepatocellular carcinomas and a viable alternative to liver transplantation.

Doxorubicin for unresectable hepatocellular carcinoma. A prospective study on the addition of verapamil.

A prospective study was conducted to assess the safety and efficacy of the addition of oral verapamil to intravenous Adriamycin (doxorubicin) for the management of patients with unresectable hepatocellular carcinoma (HCC). All 28 patients studied had histologically verified disease, and cirrhosis was present in 20 of the 21 patients with adequate tissue sampling. The overall median survival was 57 days. Chemotherapy was terminated in seven patients after one course of treatment. Partial response and complete response were noted in four patients (19%) and one patient (4.8%), respectively, among the 21 patients evaluated. Side effects related to the chemotherapy were present in all patients studied. Death from fulminating sepsis occurred in three of the 13 patients with leukopenia. Symptomatic myocardial dysfunction developed in one patient. The addition of verapamil apparently did not potentiate the tumoricidal effect of systemic Adriamycin on HCC but probably did increase its complications.

Role of computed tomography in the management of recurrent pyogenic cholangitis.

A retrospective analysis was performed to define the indications and usefulness of computed tomography (CT) in the management of 62 patients with recurrent pyogenic cholangitis. When performed in 18 patients in the acute phase for persistent fever inexplicable by ultrasonography and cholangiography, CT scans identified the cause of sepsis to be liver abscesses (n = 7), impacted stones in left lateral segments (n = 3) and right posterior inferior duct (n = 1). When performed in 44 patients during remission, CT scans detected impacted intrahepatic stones as the cause of non-opacification of segmental bile ducts on cholangiograms (n = 15), demonstrated liver volume changes (segmental atrophy, n = 31; hypertrophy, n = 5), differentiated intrahepatic stones from pneumobilia (n = 5) and revealed stones in segregated intrahepatic bile ducts (n = 4). Overall 75.8% of CT scans showed valuable intrahepatic findings which were useful in guiding the appropriate treatment for the intrahepatic pathology. In the others without demonstrable intrahepatic pathology on CT, patients were adequately treated for common bile duct pathology alone. It is recommended that CT should be performed when ultrasonography and cholangiography cannot elucidate the cause of persistent fever, when the cholangiogram shows non-opacification of segmental bile ducts, or fails to demonstrate the cause of recurrent acute cholangitis, particularly in patients who have had previous bilio-enteric drainage procedures.

Current management of intrahepatic stones.

A high incidence of intrahepatic stones occurs in East Asia. The surgical management of intrahepatic stones is problematic because it is difficult to locate and remove all the stones and relieve the accompanying biliary strictures. Consequently, the rate of recurrent cholangitis is high. Many new techniques have been introduced to locate, fragment, and retrieve gallstones. Operative procedures to relieve biliary strictures have also undergone development. These new procedures and techniques have been applied to intrahepatic stones. The initial results are good. Whether these good results can be maintained in the long-term remains to be seen.

Mesenteric hernias through defects of the mesosigmoid.

Internal herniation through defects in the gastrointestinal mesentery is extremely rare. Two patients with small bowel herniation involving the sigmoid mesocolon are reported. The condition has a high incidence of strangulation, with rapid onset of gangrene of the bowel. The mortality is high and the role of early surgical intervention is stressed.

A new semiquantitative culture method for early detection of surgical incisional wound infection.

A semiquantitative culture technique for early detection of surgical wound infection was done by rolling a segment of a plastic intravenous catheter across a blood agar plate after insertion into the most inflamed part of the wound on postoperative day 3. Patients were monitored daily for purulent discharge until healing. Of the 53 wounds studied, 44 (83%) had no growth or low-density superficial colonization on the blood agar (generally less than 15 colony-forming units and within the upper 1.5 cm of the catheter). None of these 44 wounds was subsequently infected; therefore, these colonies represented colonization. Of the 9 wounds (17%) that yielded greater than 15 colony-forming units and a diffuse subcutaneous pattern (colonies below the upper 1.5 cm of the catheter), all developed purulent discharge with a positive culture of the same organisms found by semiquantitative culture. This result differed significantly (P less than .01) from the 44 wounds without subsequent infection. This semiquantitative technique has the potential to distinguish infection from colonization and may be useful in diagnosing surgical wound infection.

Long-term results of resection for large hepatocellular carcinoma: a multivariate analysis of clinicopathological features.

Recurrent or metastatic disease is frequently encountered among patients who have had resection of their primary hepatocellular carcinoma. A retrospective study on 117 patients (104 men, 13 women; mean age +/- standard deviation: 53.8 +/- 12.4 yr) who had hepatectomy for large hepatocellular carcinoma (diameter greater than or equal to 5 cm) was conducted to identify an at-risk population for tumor recurrence. Disease-free survival was correlated with 22 clinical (n = 5), serological (n = 2), gross pathological (n = 3) and histological (n = 12) features of the resected specimens using Cox's multivariate regression analysis. Recurrent hepatocellular carcinoma was detected in 74 patients within a median follow-up period of 13.7 mo. Although 17 patients had extrahepatic disease alone, recurrence was confined to the hepatic remnant in 40 patients. Disease-free survival rates at 1, 3 and 5 yr were 40%, 19% and 12%, respectively. Two of the five histological parameters isolated, negative resection margin (p less than 0.01) and encapsulation (p less than 0.006), were identified as favorable independent prognostic predictors. When patients with positive margins were excluded from the analysis, repeated calculation showed that encapsulation was the only important determinant. From this analysis, detailed histological study of the resected tumor is seen to be the only satisfactory means for assessing long-term prognosis. An aggressive approach is warranted among patients with encapsulated tumors. Even with a clear resection margin, adjuvant treatment should be considered for those patients who have unencapsulated lesions.

Results of surgical resection for hepatocellular carcinoma.

The results of surgical resection in 174 patients with hepatocellular carcinoma was studied. The patients included 147 male and 27 female with a mean age of 54 years. Serum alfa-fetoprotein was elevated in 74% and 67% had liver cirrhosis. The operative morbidity was 46.6% and 30 day mortality was 13.2%. The most common complications were hemorrhage and liver failure. The five and eight year survival rates were 15% and 12% respectively. Long survival of more than ten years was possible after resection of large tumours, even in patients with liver cirrhosis.