Review article: Asia-Pacific consensus recommendations on endoscopic tissue acquisition for biliary strictures.

BACKGROUND: Pre-operative tissue diagnosis for suspected malignant biliary strictures remains challenging. AIM: To develop evidence-based consensus statements on endoscopic tissue acquisition for biliary strictures. METHODS: The initial draft of statements was prepared following a systematic literature review. A committee of 20 experts from Asia-Pacific region then reviewed, discussed, and modified the statements. Two rounds of independent voting were conducted to reach a final version. Consensus was considered to be achieved when 80% or more of voting members voted "agree completely" or "agree with some reservation." RESULTS: Eleven statements achieved consensus. The choice of tissue sampling modalities for biliary strictures depends on the clinical setting, the location of lesion, and availability of expertise. Detailed radiological and endoscopic evaluation is useful to guide the selection of appropriate tissue acquisition technique. Standard intraductal biliary brushing and/or forceps biopsy is the first option when endoscopic biliary drainage is required with an overall (range) sensitivity and specificity of 45% (26%-72%) and 99% (98%-100%), and 48% (15%-100%) and 99% (97%-100%), respectively, in diagnosing malignant biliary strictures. Probe-based confocal laser endomicroscopy and fluorescence in situ hybridisation using 4 fluorescent-labelled probes targeting chromosomes 3, 7, 17 and 9p21 locus may be added to improve the diagnostic yield. Cholangioscopy-guided biopsy and EUS-guided tissue acquisition can be considered after prior negative conventional tissue sampling with an overall (range) sensitivity and specificity of 60% (38%-88%) and 98% (83%-100%), and 80% (46%-100%) and 97% (92%-100%), respectively, in diagnosing malignant biliary strictures. CONCLUSION: These consensus statements provide evidence-based recommendations for endoscopic tissue acquisition of biliary strictures.

Japanese multicenter experience of endoscopic necrosectomy for infected walled-off pancreatic necrosis: The JENIPaN study.

BACKGROUND AND STUDY AIMS: Only a few large cohort studies have evaluated the efficacy and safety of endoscopic necrosectomy for infected walled-off pancreatic necrosis (WOPN). Therefore, a multicenter, large cohort study was conducted to evaluate the efficacy and safety of endoscopic necrosectomy and to examine the procedural details and follow-up after successful endoscopic necrosectomy. PATIENTS AND METHODS: A retrospective review was conducted in 16 leading Japanese institutions for patients who underwent endoscopic necrosectomy for infected WOPN between August 2005 and July 2011. The follow-up data were also reviewed to determine the long-term outcomes of the procedures. RESULTS: Of 57 patients, 43 (75 %) experienced successful resolution after a median of 5 sessions of endoscopic necrosectomy and 21 days of treatment. Complications occurred in 19 patients (33 %) during the treatment period. Six patients died (11 %): two due to multiple organ failure and one patient each from air embolism, splenic aneurysm, hemorrhage from a Mallory - Weiss tear, and an unknown cause. Of 43 patients with successful endoscopic necrosectomy, recurrent cavity formation was observed in three patients during a median follow-up period of 27 months. CONCLUSIONS: Endoscopic necrosectomy can be an effective technique for infected WOPN and requires a relatively short treatment period. However, serious complications can arise, including death. Therefore, patients should be carefully selected, and knowledgeable, skilled, and experienced operators should perform the procedure. Further research into safer technologies is required in order to reduce the associated morbidity and mortality.

Endoscopic ultrasound-guided celiac ganglia neurolysis vs. celiac plexus neurolysis: a randomized multicenter trial.

BACKGROUND AND STUDY AIMS: No prospective comparison of endoscopic ultrasonography-guided direct celiac ganglia neurolysis (EUS - CGN) vs. EUS-guided celiac plexus neurolysis (EUS - CPN) has been reported. The aim of the current study was to compare the effectiveness of EUS - CGN and EUS - CPN in providing pain relief from upper abdominal cancer pain in a multicenter randomized controlled trial. PATIENTS AND METHODS: Patients with upper abdominal cancer pain were randomly assigned to treatment using either EUS - CGN or EUS - CPN. Evaluation was performed at Day 7 postoperatively using a pain scale of 0 to 10. Patients for whom pain decreased to ≤ 3 were considered to have a positive response, and those experiencing a decrease in pain to ≤ 1 were considered to be completely responsive. Comparison between the two groups was performed using intention-to-treat analysis. The primary endpoint was the difference in treatment response rates between EUS - CGN and EUS - CPN at postoperative Day 7. Secondary endpoints included differences in complete response rates, pain scores, duration of pain relief, and incidence of adverse effects. RESULTS: A total of 34 patients were assigned to each group. Visualization of ganglia was possible in 30 cases (88 %) in the EUS - CGN group. The positive response rate was significantly higher in the EUS - CGN group (73.5 %) than in the EUS - CPN group (45.5 %; P = 0.026). The complete response rate was also significantly higher in the EUS - CGN group (50.0 %) than in the EUS - CPN group (18.2 %; P = 0.010). There was no difference in adverse events or duration of pain relief between the two groups. CONCLUSIONS: EUS - CGN is significantly superior to conventional EUS - CPN in cancer pain relief. CLINICAL TRIAL REGISTRATION: http://www.umin.ac.jp/ctr/index.htm (ID: UMIN-000002536).

Preoperative routine evaluation of bilateral adrenal glands by endoscopic ultrasound and fine-needle aspiration in patients with potentially resectable lung cancer.

BACKGROUND AND STUDY AIMS: The aim of the current study was to assess the detection rate of the right adrenal gland and the diagnostic ability of endoscopic ultrasound (EUS) and fine-needle aspiration (FNA) for the diagnosis of adrenal metastasis in potentially resectable lung cancer. PATIENTS AND METHODS: This retrospective cohort study included a consecutive series of 150 patients undergoing EUS/EUS - FNA for staging of lung cancer. The detection rate of the right adrenal gland by EUS and the diagnostic accuracies of computed tomography (CT), positron emission tomography-CT (PET-CT), and EUS/EUS - FNA for the diagnosis of adrenal metastasis were evaluated. RESULTS: The right adrenal gland was visualized by EUS in 131 patients (87.3 %); the left adrenal gland was visualized in all patients. Findings suggestive of metastasis in either one of the adrenal glands or in both were observed in 6 patients (4.0 %) by CT, in 5 patients (3.3 %) by PET-CT, and in 11 patients (7.3 %) by EUS. EUS - FNA was performed simultaneously in the 11 patients, and in 4 patients the diagnosis of metastasis was established. The accuracy for the diagnosis of adrenal metastasis was 100 % for EUS/EUS - FNA, 96.0 % for CT, and 97.0 % for PET-CT (P = 0.1146). CONCLUSIONS: As well as the left adrenal gland, the right adrenal gland was also usually visible by EUS. EUS/EUS - FNA provided an accurate diagnosis of adrenal metastasis, although the prevalence of adrenal metastasis was relatively low in these patients with potentially resectable lung cancer.

Combined endobronchial and endoscopic ultrasound-guided fine needle aspiration for mediastinal nodal staging of lung cancer.

BACKGROUND: Recently, transesophageal endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has been evaluated for mediastinal nodal staging (N staging) of lung cancer, as this technique is less invasive than mediastinoscopy and possibly more accurate than 18F-fluorodeoxyglucose positron emission tomography with computed tomography (PET-CT). However, EUS-FNA does not provide access to pretracheal and hilar lymph nodes. More recently, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been introduced as a novel technique for accessing pretracheal and hilar lymph nodes. Although the combined endoscopic approach of EUS-FNA and EBUS-TBNA is presumably more accurate than PET-CT, only a few reports have quantitatively evaluated its diagnostic ability. Therefore, we prospectively assessed the diagnostic yield of this combined endoscopic approach for mediastinal N staging of lung cancer. METHODS: A consecutive series of 120 patients with suspected resectable lung cancer on CT findings underwent PET-CT and combined EUS-FNA/EBUS-TBNA. The accuracy and other diagnostic indices of the combined approach in mediastinal N staging were compared with those of PET-CT. RESULTS: Among the enrolled patients, a final pathological N stage was established in 110 patients. The accuracy of the combined approach using EUS-FNA and EBUS-TBNA was significantly higher than that of PET-CT (90.0 % vs. 73.6 %; P < 0.0001). The sensitivity, specificity, and positive and negative predictive values were respectively 71.8 %, 100 %, 100 %, and 86.6 % for the combined approach vs. 47.4 %, 87.5 %, 66.7 %, and 75.9 % for PET-CT. CONCLUSIONS: The combined endoscopic approach using EUS-FNA and EBUS-TBNA provided excellent diagnostic performance. Therefore, this approach is strongly recommended before surgery or mediastinoscopy to avoid futile thoracotomy and surgical intervention.

Carbon dioxide insufflation vs. conventional saline irrigation for peroral video cholangioscopy.

BACKGROUND AND STUDY AIMS: Recent studies have evaluated the efficacy of peroral cholangioscopy (POCS) for diagnosis of biliary diseases. In order to obtain clear images with POCS, saline irrigation, which is performed to replace yellow bile, is carried out for an extended duration. The aim of this study was to evaluate the feasibility of replacing saline irrigation with CO2 insufflation during POCS. PATIENTS AND METHODS: A total of 36 patients who had bile duct lesions and were due to undergo POCS were enrolled in the study. Of these patients, 18 underwent POCS using saline irrigation followed by CO2 insufflation, and 18 patients underwent the reverse approach. The two methods were compared with regard to the time required to obtain a clear endoscopic image and the quality of the images. RESULTS: The median time required to obtain a clear endoscopic image using CO2 insufflation (5.0 min) was significantly shorter than that required for saline irrigation (22.5 min; P < 0.001). The quality of the endoscopic images obtained was similar in 27 cases. However, CO2 insufflation provided better images in four cases that showed an abundance of mucin or biliary sludge, and saline irrigation was superior to CO2 insufflation in five cases that showed severe stricture with bleeding and tall papillary lesions. CONCLUSIONS: CO2 insufflation during POCS can reduce procedure time and simplify cholangioscopy. The overall image quality was similar to that obtained with conventional saline irrigation.

Endoscopic ultrasound-guided fine needle aspiration biopsy for splenic tumor: a case series.

Splenic tumors are occasionally found in clinical practice but the diagnosis is often difficult if only serologic and imaging tests are used. Therefore, pathologic sampling is required in such cases. Endoscopic ultrasonography (EUS) provides a good image of the spleen through the gastric wall, and a transgastric EUS-guided fine needle aspiration (EUS-FNA) biopsy may be easier than the percutaneous approach. Furthermore, a large-gauge needle may raise the capability of EUS-FNA for the histopathologic diagnosis. The aim of this study was to evaluate the yield of EUS-FNA using a large-gauge needle for a splenic tumor. Five patients with splenic tumor were subjected to EUS-FNA with a 19-gauge needle to obtain histopathologic materials. A pathologic sample was obtained in all cases, and the diagnoses were lymphoma (n = 2), sarcoidosis (n = 2), and inflammatory pseudotumor (n = 1). EUS-FNA using a 19-gauge needle is safe and useful for the diagnosis of splenic tumors.

The yield of endoscopic ultrasound-guided fine needle aspiration for histological diagnosis in patients suspected of stage I sarcoidosis.

BACKGROUND AND STUDY AIM: Sarcoidosis is a systemic disorder of unknown cause that is characterized by a pathological hallmark, noncaseating granuloma. Bilateral hilar lymphadenopathy (BHL) is a major clinical feature, but it is sometimes difficult to exclude other diseases, especially in cases where there are no pulmonary abnormalities (stage I). Bronchoscopic transbronchial biopsy is currently a popular method by which to obtain pathological material, but its diagnostic power is insignificant. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA), also attempted recently, makes the sampling of pathological material easier and better, but the diagnoses are still based on cytological findings. Our study aimed to evaluate the yield of transesophageal EUS-FNA for histological confirmation of stage I sarcoidosis. METHODS: The study was a prospective comparative study to investigate the diagnostic sensitivities of FNA cytology and FNA histology. Subjects were consecutive patients with BHL without lung lesions on chest radiographs or chest CT who were referred to our hospitals between December 2003 and April 2006. Transesophageal EUS-FNA was performed with 19-gauge needles instead of the conventional 22-gauge needles. RESULTS: Forty-one patients were included in this study, and both histological and cytological materials were obtained successfully by EUS-FNA in all patients. Histopathological examination of the FNA sample showed noncaseating granuloma in 34 (94.4%) of the 36 patients with a final diagnosis of sarcoidosis. In contrast, only 28 of the 36 (77.8%) were diagnosed as having sarcoidosis on the basis of cytological findings. The difference was statistically significant (P = 0.0444). CONCLUSION: FNA histology is better suited than FNA cytology to establishing the diagnosis of stage I sarcoidosis, and EUS-FNA with a 19-gauge needle plays a important role in this process.

Endoscopic ultrasound-guided fine-needle aspiration biopsy for lymphadenopathy of unknown origin.

BACKGROUND AND STUDY AIMS: The diagnosis of mediastinal and intra-abdominal lymphadenopathy is sometimes difficult, especially in patients who have no other primary lesions. Lymphoma is one of the main causes of this condition. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is a safe and accurate diagnostic procedure for lesions surrounding the gastrointestinal tract. However, diagnosing lymphoma using the EUS-FNA technique remains a diagnostic challenge, due to limitations in the amount of material sampled. The aim of the present study was to evaluate the yield of EUS-FNA biopsy (EUS-FNAB) using a large-gauge needle in patients with mediastinal and intra-abdominal lymphadenopathy of unknown origin, especially in relation to subclassification of the lymphomas. PATIENTS AND METHODS: Consecutive patients with mediastinal and intra-abdominal lymphadenopathy of unknown origin who were referred between October 2003 and March 2005 were enrolled in the study. EUS-FNAB was carried out using a 19-gauge needle, passing through the esophageal, gastric, and duodenal walls. Pathological diagnoses were made on the basis of histological findings, including immunopathological staining. RESULTS: A total of 104 patients were included in the study. The locations of the lymph nodes were mediastinal in 50 patients, intra-abdominal in 48 patients, and both mediastinal and intra-abdominal in six patients. The diagnoses made using EUS-FNAB were lymphoma (n = 48), metastasis (n = 16), and benign/reactive (n = 40). The overall accuracy of EUS-FNAB for unknown lymphadenopathy was 98 %, and it was possible to classify the lymphomas in accordance with the World Health Organization classifications in 88 % of cases. No serious complications occurred with the procedure. CONCLUSIONS: Open thoracic surgery, laparotomy, and other invasive diagnostic procedures such as mediastinoscopy and laparoscopy can now be avoided, as EUS-FNAB is potentially a safe and accurate tool for diagnosing unknown lymphadenopathy, including lymphoma.

Usefulness of MR imaging in the postsurgical monitoring of gallbladder cancer in a patient with bile duct cancer that developed 7 years after resection of mucinous adenocarcinoma of the gallbladder.

We encountered a case of left hepatic duct cancer that developed 7 years after surgical resection of early-stage adenocarcinoma of the gallbladder. A 65-year-old woman was hospitalized with high fever and general fatigue. She also had elevated serum levels of alkaline phosphatase, gamma-glutamyltranspeptidase, and carbohydrate antigen 19-9. Seven years earlier, she had undergone extended cholecystectomy and resection of the extrahepatic bile duct for early-stage mucinous adenocarcinoma of the gallbladder. Conventional examinations did not reveal any responsible lesions. Magnetic resonance (MR) cholangiography, however, showed a tumor obstructing the left hepatic duct, and dynamic MR images revealed multiple foci of bacterial abscess in the liver. Surgically resected tissue again revealed mucinous adenocarcinoma. The present case is rare in that metachronous mucinous adenocarcinoma of the biliary system occurred after a long interval. This case suggests the usefulness of MR imaging in the postsurgical monitoring of patients with gallbladder carcinoma.

Intrahepatic cholangiocarcinoma arising 10 years after the excision of congenital extrahepatic biliary dilation.

A 52-year-old woman was found to have a liver tumor during treatment for a liver abscess. The tumor was diagnosed as intrahepatic cholangiocarcinoma by closer examinations, including a percutaneous needle biopsy. Ten years previously, she had undergone excision of a choledochal cyst, with reconstruction by Roux-en-Y hepaticojejunostomy, as treatment for Todani's type Ia congenital biliary dilation, which had been confined only to the extrahepatic bile duct. The significant association between congenital biliary dilation and hepatobiliary malignancies is well known. Some patients have been reported to develop biliary cancer long after the excision of the entire extrahepatic bile duct and hepaticoenterostomy. However, in these patients, the development mostly took place in the remnant choledochal cyst, the anastomotic site, or in the dilated intrahepatic bile duct of Todani's type IV-A congenital biliary dilation. The development of intrahepatic cholangiocarcinoma after operation has not been reported previously in a patient with Todani's type I congenital biliary dilation. This case suggests that the entire biliary tree may have a high risk of field cancerization, even in extrahepatic congenital biliary dilation.

Type II citrullinemia in an elderly patient treated with living related partial liver transplantation.

A 60-year-old woman was admitted to our hospital for repeated consciousness disturbance. Blood examination showed hyperammonemia, and plasma amino acid analysis revealed a marked increase in the citrulline level. To establish a diagnosis, a percutaneous needle biopsy of the liver was performed. The determination of the urea cycle enzyme activities revealed a selective marked decrease in argininosuccinate synthetase activity, indicating the final diagnosis of type II citrullinemia. The mean survival period of this disease after the appearance of symptoms has been reported as 26.4 months, and most conservative treatments are not effective. We performed a living related partial liver transplantation. Over the subsequent 13-month follow-up, the patient's condition has remained fairly good.

Inflammatory pseudotumor of the liver with primary sclerosing cholangitis.

Inflammatory pseudotumor (IPT) of the liver is a rare benign variant of hepatic masses, and its exact etiology has not been elucidated. We report a case of IPT associated with primary sclerosing cholangitis (PSC). The patient was a 50-year-old man admitted to our hospital because of jaundice. Abdominal ultrasonography (US) and computed tomography showed multiple dilations of the intrahepatic bile ducts and multiple masses in the liver. On magnetic resonance imaging, the masses were slightly hypointense on T1-weighted images and slightly hyperintense on T2-weighted images. On T1-weighted images after the bolus infusion of Gd chelate, the masses had no contrast enhancement, and they were hypointense in the arterial phase and portal venous phase. However, they were slightly enhanced and became almost isointense relative to the surrounding normal liver parenchyma in the delayed phase. Endoscopic retrograde cholangiography demonstrated multiple irregular strictures and dilations of the intrahepatic bile ducts. Angiography demonstrated no abnormal findings, but, interestingly, subsequent dynamic CO2-enhanced US showed a strongly hyperechoic string, indicating that an artery had penetrated through the hypoechoic mass. A US-guided percutaneous needle biopsy revealed that the lesions were morphologically comparable to IPT. After cholangiography and microscopic analysis of the tumor, the final diagnosis was determined to be IPT of the liver with PSC. A number of previous reports have suggested a possible relationship between IPT and PSC, based on pathological findings. This report confirmed, based on clinical findings, that PSC is one of the causes of hepatic IPT.

Nutritional pharmacotherapy of chronic liver disease: from support of liver failure to prevention of liver cancer.

Many patients with liver cirrhosis are in a state of protein and energy malnutrition and require careful nutritional support. Our research has revealed that approximately 30% of the patients have protein-energy malnutrition, 40% protein malnutrition, and 10% energy malnutrition; 20% are in a normal nutritional state. Supplementation with branched-chain amino acids alleviates chronic liver failure, improves the protein nutritional state, and subsequently prolongs survival. In contrast, therapeutic modalities for energy malnutrition have not yet been fully elucidated and await further studies. Improved survival of the cirrhotic patients essentially brings a higher incidence of hepatocellular carcinoma (HCC). A synthetic analogue of vitamin A (acyclic retinoid or 4,5-dehydrogeranyl geranoic acid) prevents at least the development of second primary tumors after curative treatment of preceding HCC. The mechanism of this cancer chemo-prevention is clonal deletion of premalignant and latent malignant cells by the retinoid. We describe our clinical experiences with these two nutritional pharmacotherapies of chronic liver diseases and review their basic mechanisms.

Involvement of a cis-acting element in the suppression of carbamoyl phosphate synthetase I gene expression in the liver of carnitine-deficient mice.

The expression of carbamoyl phosphate synthetase I (CPS) gene is suppressed in the liver of carnitine-deficient juvenile visceral steatosis (JVS) mice at weaning and under starvation at adult age. To clarify the suppression mechanism, we produced CPSL transgenic JVS mice carrying a transgene composed of the chloramphenicol acetyltransferase (CAT) gene with the upstream region (-12 kb to +138) of the rat CPS gene and CPSE transgenic JVS mice carrying a transgene composed of the luciferase gene with minimal promoter (299 bp from -161 to +138) and enhancer (469 bp around -6.3 kb) fragments of the rat gene. The expression of the CAT gene as well as the endogenous CPS was suppressed in CPSL transgenic JVS mice, but luciferase gene expression was not suppressed in CPSE transgenic JVS mice. We isolated the 5'-upstream region of the mouse CPS gene and identified an activator protein-1 (AP-1) site downstream of the minimum enhancer region of both rat and mouse CPS genes. In conjunction with the 313-bp mouse promoter region, the 714-bp mouse enhancer fragment conferred a cell-type-dependent hormone responsiveness. In rat primary cultured hepatocytes, the addition of oleic acid suppressed reporter gene expression induced by dexamethasone in the construct containing the enhancer fragment of 714 bp with the AP-1 site, but not in its AP-1 site mutants or in 519 bp without the AP-1 site. These results strongly suggest that direct protein-protein interaction between AP-1 and glucocorticoid receptor is not involved in the suppression of the CPS gene in JVS mice and that the AP-1 element is the cis-element which is responsible for the suppression.

[Aristolochic acids in herbal medicines].

Aristolochic acids are nitrophenanthrenes with a carboxylic acid fanction which have been found only among the Aristolochiaceae. In 1993, rapidly progressive interstitial renal fibrosis has been reported in women have been on a slimming regimen including Chinese herbal medicines in Belgium. In Japan, at the Kansai district, several cases of Chinese herbs nephropathy have been reported quite recently. In both cases, aristolochic acids was detected in the Chinese herbal medicines taken by the patients. We have Asiasarum Root, a species of Aristolochiaceae, in Japanese Pharmacopoeia. Therefore, we quantitatively analysed aristolochic acids in these herbal medicines and related plants.

Usefulness of novel imaging modalities in diagnosis of focal nodular hyperplasia of the liver.

A 17-year-old woman was admitted because of a liver tumor found incidentally by ultrasonography. Liver function was normal and there were no markers of hepatitis viruses or malignancy. Abdominal ultrasonography, computed tomography (CT), and magnetic resonance imaging revealed a mass (2 cm in diameter) in the lateral segment of the left lobe of the liver. The lesion was not detected by hepatic arteriography. However, dynamic CT with fast scanning and dynamic CO2-enhanced ultrasonography demonstrated initial central enhancement of the mass followed by centrifugal spread of enhancement to the periphery. Color Doppler flow imaging detected a central color spot, shown to be an artery by a pulsed Doppler spectrum analysis. Fine-needle biopsy confirmed a diagnosis of focal nodular hyperplasia. Dynamic CT with fast scanning, dynamic CO2-enhanced ultrasonography, and color Doppler flow imaging were useful in detecting the vascular pattern specific to focal nodular hyperplasia. Investigation of further cases with these novel imaging modalities should help to establish a comprehensive diagnostic procedure and thus avoid unnecessary surgery for focal nodular hyperplasia, which is a completely benign lesion.

Inhibitory effects of shouseiryu-to on two-stage carcinogenesis. II. Anti-tumor-promoting activities of lignans from Asiasarum heterotropoides var. mandshuricum.

Two lignans, asarinin (6) and xanthoxylol (7), were isolated from the radix of Asiasarum heterotropoides var. mandshuricum, which consist of a kampo prescription, Shouseiryu-to, as inhibitors of Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). These lignans also exhibited remarkable inhibitory effects on a two-stage carcinogenesis test of mouse skin and pulmonary tumors. Furthermore, it was confirmed that these hydrophobic lignans dissolved in the water decoction of Shouseiryu-to, and these lignans might be among the active constituents of this kampo prescription in terms of its anti-tumor-promoting activity.

Deletion of serum lectin-reactive alpha-fetoprotein by acyclic retinoid: a potent biomarker in the chemoprevention of second primary hepatoma.

A goal of cancer chemoprevention is the deletion of latent premalignant or malignant clones before they expand to a clinically detectable tumor. However, such clonal deletion has not been demonstrated in clinical studies. We have evaluated serum levels of lectin-reactive alpha-fetoprotein (AFP-L3), which suggests the presence of latent hepatoma cells, in a randomized controlled trial that used acyclic retinoid to prevent second primary hepatomas in patients who had received treatments that cured initial hepatomas. The trial involved 21 patients in each acyclic retinoid (600 mg daily) and placebo group and consisted of a 12-month period of drug administration and a subsequent follow-up period. Serum AFP-L3 was determined at entry and at the end of the 12-month treatment period using lectin-affinity electrophoresis and antibody-affinity blotting. Although neither treatment affected serum levels of total AFP, acyclic retinoid significantly reduced AFP-L3 levels after a 12-month administration (P < 0.01). Acyclic retinoid not only deleted AFP-L3 from patients who had been positive for AFP-L3 at entry but also prevented the appearance of AFP-L3 in patients who had been negative at entry (P < 0.01). In contrast, placebo significantly raised the incidence of AFP-L3-positive patients after a 12-month administration from that at entry (P < 0.05). Patients positive for AFP-L3 after a 12-month treatment had a significantly higher risk of second primary hepatomas in the subsequent follow-up period (P = 0.03). Acyclic retinoid may have deleted a clone of latent hepatoma cells producing AFP-L3 and thereby inhibited second primary hepatomas. Serum AFP-L3 may be a useful intermediate biomarker in the chemoprevention of second primary hepatomas by acyclic retinoid.

Ester-type cephalotaxus alkaloids from Cephalotaxus harringtonia var. drupacea.

Three alkaloids, neoharringtonine, homoneoharringtonine and 3'S-hydroxyneoharringtonine, were isolated from the leaves and stems of Cephalotaxus harringtonia var. drupacea. Their structures were established by spectroscopic methods, including two-dimensional NMR and CD spectra, and their antileukaemic activity was evaluated using P-388 leukaemia cells.