Usefulness of intraoperative diagnosis of hepatic tumors located at the liver surface and hepatic segmental visualization using indocyanine green-photodynamic eye imaging.

BACKGROUND: To improve the diagnostic accuracy for hepatic tumors on the liver surface, we investigated the usefulness of an indocyanine green-photodynamic eye (ICG-PDE) system by comparison with Sonazoid intraoperative ultrasonography (IOUS) in 117 patients. Hepatic segmentation by ICG-PDE was also evaluated. METHODS: ICG was administered preoperatively for functional testing and images of the tumor were observed during hepatectomy using a PDE camera. ICG was injected into portal veins to determine hepatic segmentation. RESULTS: Accurate diagnosis of liver tumors was achieved with ICG-PDE in 75% of patients, lower than with IOUS (94%). False-positive and false-negative diagnosis rates for ICG-PDE were 24% and 9%, respectively. New small HCCs were detected in 3 patients. The ICG fluorescent pattern in tumors was strong staining in 41%, weak staining in 13%, rim staining in 20% and no staining in 26%. Hepatocellular carcinoma predominantly showed strong staining (61%), while rim staining predominated in cholangiocellular carcinoma (60%) and liver metastasis (55%). Hepatic segmental staining was performed in 28 patients, proving successful in 89%. CONCLUSION: ICG-PDE is a useful tool for detecting the precise tumor location at the liver surface, identifying new small tumors, and determining liver segmentation for liver resection.

Relationship between period of survival and clinicopathological characteristics in patients with colorectal liver metastasis.

AIM: Cancer death in the early period after hepatectomy still occurs in patients with colorectal liver metastasis (CLM). We examined the relationship between clinicopathological parameters and survival periods in 130 CLM patients who underwent hepatectomy. PATIENTS/METHODS: Patients were divided into four groups: Group 1 (5-year survivors without tumor relapse), Group 2 (survivors at 2-5 years), Group 3 (cancer death at 2-5 years), and Group 4 (cancer death within 2 years). RESULTS: A short surgical margin was frequent in Group 4 compared to Group 1 (31 vs. 78%, P<0.05). Primary node-positive status, absence of fibrous pseudo-capsular formation, higher Clinical Risk Score, and tumor recurrence within 12 months were frequent in Group 4 (P<0.05). Multivariate analysis revealed a short surgical margin (HR; 3.5) and early tumor relapse (HR; 5.9) as independently significant related parameters (P<0.05). CONCLUSIONS: Sufficient surgical margins and careful follow-up for early tumor relapse may be important for improving postoperative outcomes for CLM patients.

Comparison of survival between anatomic and non-anatomic liver resection in patients with hepatocellular carcinoma: significance of surgical margin in non-anatomic resection.

AIMS: Anatomic resection, i.e., systematic removal of a liver segment confined by portal branches, is theoretically effective in eradicating intrahepatic metastasis of hepatocellular carcinoma (HCC). The procedure may reduce tumour recurrence and enhance survival of HCC patients. To determine the significance of anatomic resection for HCC patients, we retrospectively conducted a comparative analysis between anatomic (AR) and non-anatomic liver resection (NAR) in 113 Japanese HCC patients with a solitary tumour, a tumour located within one segment, absence or invasion of distal to second order branches of the portal vein, and absence or invasion of peripheral branches of the hepatic vein. METHODS: Patients were divided into two groups, AR group (n = 49) and NAR group (n = 64). RESULTS: The prevalence of liver damage Grade B in the NAR group was significantly greater than in the AR group (p < 0.05). Tumour-free and overall survival following liver resection was not significantly different between AR and NAR groups. In the NAR group, tumour-free and overall survival in patients with tumour exposure at the surgical margin was significantly lower than with a surgical margin greater than 0 mm (not exposed) (p < 0.05). Survival between the AR and NAR groups without tumour exposure at the surgical margin was similar. CONCLUSIONS: Anatomic resection is the theoretical aim. In HCC patients with impaired liver functions, limited liver resection without tumour exposure may provide longer tumour-free and overall survival.

Postoperative changes in protein-induced vitamin K absence or antagonist II levels after hepatectomy in patients with hepatocellular carcinoma: relationship to prognosis.

BACKGROUND: alpha-Fetoprotein (AFP) has been used as a marker for hepatocellular carcinoma (HCC). However, AFP levels are often high in patients with chronic hepatitis or cirrhosis. Protein-induced vitamin K absence or antagonist II (PIVKA-II) is more sensitive for the diagnosis of HCC and prediction of patient survival. Changes in these markers after treatment may reflect treatment curability and patient outcome. METHODS: We conducted a retrospective analysis of prognosis of 63 HCC patients with high preoperative levels of AFP and PIVKA-II who underwent hepatectomy and examined the relationship between postoperative changes in both markers at 1 month and patient survival. Subjects were divided into three groups according to changes in these tumour markers after hepatectomy: normalization (N) group, decreased but still above the normal level (D) group and unchanged (U) group. RESULTS: There were no significant differences in the numbers of patients who developed tumour recurrence between changes in AFP and PIVKA-II. Survival analysis showed no significant differences in tumour-free and overall survivals between groups with respect to AFP level. The PIVKA-II-N group showed significantly better tumour-free and overall survival compared with the D and U groups (p<0.01). Multivariate analysis that included other prognostic factors identified changes in PIVKA-II level as a significant and independent prognostic factor associated with overall survival. DISCUSSION: Although changes in AFP did not correlate with patient prognosis, normalization of PIVKA-II was significantly associated with good patient survival after hepatectomy. Normalization of PIVKA-II after hepatectomy reflected the efficacy of treatment and is a suitable predictor of prognosis in HCC patients.

Comparative study of survival of patients with hepatocellular carcinoma predicted by different staging systems using multivariate analysis.

AIMS: In a previous pilot study, we reported the usefulness of the modified the Cancer of the Liver Italian Program (CLIP) score for patients with hepatocellular carcinoma (HCC). To determine the best staging system for predicting the survival of HCC patients, we conducted a comparative analysis of prognosis using multivariate analysis in 210 Japanese HCC patients who underwent hepatic resection. METHODS: We compared the survival as predicted by various staging systems, including tumour node metastasis (TNM) stage of the American Joint Commission on Cancer (AJCC) and the Liver Cancer Study Group of Japan, the Japan Integrated Staging (JIS) score (Japanese TNM and Child-Pugh classification), CLIP score and our modified CLIP score using protein induced by vitamin K absence or antagonist II (PIVKA-II). RESULTS: Univariate analysis showed that discrimination of disease-free survival in the early and advanced stages by the JIS score and modified CLIP score was clearer than by the Japanese or AJCC TNM or the original CLIP score. Discrimination between stages of overall survival by all staging systems was significant. Multivariate analysis showed that the JIS, CLIP and modified CLIP scores were better staging systems for predicting survival than the Japanese and AJCC TNM. The modified CLIP score showed the lowest Akaike information criteria statistical value for disease-free and overall survival, which means the best discrimination ability for patient survival compared with the JIS score and CLIP score. CONCLUSIONS: A staging system that combines tumour factors, sensitive tumour marker(s) and hepatic function is the best predictor of prognosis of HCC patients.

Unruptured aneurysm of the right coronary sinus of Valsalva with type B aortic dissection.

A seventy-two year-old man, who complained of severe back pain, was referred to our hospital. Digital subtraction angiogram (DSA) delineated an extracardiac unruptured aneurysm of the right coronary sinus of Valsalva and acute type B aortic dissection. Patch plasty of the right coronary sinus with reimplantation of the right coronary artery using a Dacron graft was performed. Postoperative DSA confirmed successful reconstruction of the aortic root and the patent right coronary artery.

Synthesis of anacardic acids, 6-[8(Z),11(Z)-pentadecadienyl]salicylic acid and 6-[8(Z),11(Z),14-pentadecatrienyl]salicylic acid.

11-Chloro-3-methoxy-2-undecenal was synthesized from 8-bromooctanol, and an annelation reaction with this aldehyde and ethyl acetoacetate proceeded to give the ethyl 6-(8-chlorooctyl)salicylate. Ethyl 6-(8-chlorooctyl)salicylate was converted to ethyl 6-(7-formylheptyl)-2-methoxybenzoate through the iodide after protection of the phenolic hydroxyl group. Finally, the Wittig reaction with the aldehyde and triphenylphosphonium iodides in the presence of BuLi gave the methoxybenzoates, and then treatments of these methoxybenzoates with BBr3 in CH2Cl2 and 10% NaOH in ethanol gave 6-18(Z),11(Z)-pentadecadienyllsalicylic acid (anacardic acid 3) and 6-[8(Z),11(Z),14-pentadecatrienyl]salicylic acid (anacardic acid 4) which were isolated from plants of the anacardiaceae.

Spinal cord protection: effect of N-methyl-D-aspartate receptor antagonist MK-801 for spinal cord ischemia in a rabbit model.

Excitatory amino acids (glutamate, aspartate) play an important role in the ischemic cascade leading to cell death. The N-methyl-D-aspartate (NMDA) receptor is an excitatory amino acid (EAA) receptor, and NMDA receptor antagonists have been shown to exert a neuroprotective effect in central nervous system ischemia. The purpose of this study was to investigate the effects of noncompetitive NMDA receptor antagonists MK-801 and to observe the changes in EAAs after spinal cord ischemia in a rabbit model. Spinal cord ischemia was induced by clamping the infrarenal abdominal aorta for 24 min. Group 1 (n = 6) received no pharmacologic infusion. Group 2 (n = 5) was administered an intra-aortic hypothermic MK-801 (1 mg/kg) solution and group 3 (n = 6) was administered an intra-aortic normothermic MK-801 (2 mg/kg) solution immediately after clamping of the abdominal aorta. We evaluated the neurological function at 12, 24 and 48 hrs after spinal cord ischemia. A histopathologic study was carried out 72 hrs after spinal cord ischemia, and the results for groups 1 and 3 were compared. The glutamate and aspartate levels in the blood plasma were compared at pre-ischemia and at 12, 24, and 48 hrs among the groups. The perfusion of a normothermic MK-801 (2 mg/kg) solution significantly reduced the neurological dysfunction and the neuronal damage. There was a significant increase in aspartate at 24 and 48 hrs in group 1, but no such increase in glutamate occurred in groups 1 and 3. In conclusion, these data provide the evidence that therapeutic intervention with MK-801 (2 mg/kg) in the early period of spinal cord ischemia is beneficial in reducing neurological dysfunction and neuronal damage.

A new concise synthesis of arcyriacyanin A and its unique inhibitory activity against a panel of human cancer cell line.

The nucleophilic addition reaction of N-tosyl-4-oxo-4,5,6,7-tetrahydroindole (12) with the lithium salt of 1-methoxyindole (5), followed by dehydration with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) gave the derivative of 2,4'-bi-1H-indole (9) which provides a new concise synthetic method of an indole pigment of the slime mould, arcyriacyanin A. The compound was first demonstrated here to have unique inhibitory activity to a panel of human cancer cell lines and to inhibit protein kinase C and protein tyrosine kinase.

Synthesis of 2-substituted 3-nitro-1,2-dihydropyridines by heterocyclic annulation reactions of a sec-nitrodienamine with aldehyde compounds.

The reaction of a sec-nitrodienamine 3 with aldehyde compounds afforded 2-substituted 3-nitro-1,2-dihydropyridines 5, providing a heterocyclic annulation reaction.

A new synthesis of indoloquinolizines by Pictet-Spengler reaction of tryptamine type 1,2-dihydropyridines utilizing sec-nitrodienamine.

The Pictet-Spengler reaction of tryptamine type 1,2-dihydropyridine 5c derived from the cycloaddition of the sec-nitrodienamine 3c with acetaldehyde afforded the indoloquinolizine derivatives 6 and 7.

Cerebral protection selection in aortic arch surgery for patients with preoperative complications of cerebrovascular disease.

OBJECTIVE: Retrograde perfusion is gaining acceptance as a means of cerebral protection, but it remains unclear how long the brain is protected and whether it is effective in patients with preoperative cerebrovascular disease. METHODS: From January 1989 to August 1999, 205 patients--118 male and 87 female patients who ranged 12 to 86 years old, mean: 65.5 years old--underwent surgery at our hospital for aortic arch aneurysm using cerebral protection. We focused on mortality, stroke incidence and perioperative risk factor between 2 groups--selective cerebral and retrograde cerebral perfusion--also studying patients with preoperative cerebrovascular disease that influenced postoperative stroke. RESULTS: The hospital mortality was 11.7% (selective cerebral perfusion group: 12%, retrograde group: 10.9%). Stroke occurred in 11 patients (5.3%), 4.7% in the selective cerebral perfusion group and 7.3% in the retrograde group. Preoperative cerebrovascular disease does not appear to be a risk factor for postoperative brain damage in aortic arch surgery. Regarding total replacement of the aortic arch, the incidence of postoperative brain damage in the retrograde group with preoperative cerebrovascular disease was higher than that in another group (p = 0.072). Cardiopulmonary bypass time and selective cerebral perfusion time in the patients with postoperative stroke were significantly longer than that in non-stroke group. CONCLUSIONS: Preoperative cerebrovascular disease did not appear to be a risk factor in postoperative neurological deficit in the selective cerebral perfusion group. Prolonged selective cerebral perfusion time and cardiopulmonary bypass time may, however, lead to brain edema and cause neurological deficit.

Simultaneous repair of cardiovascular disorders and pectus deformity in a patient with Sprintzen-Goldberg syndrome: A case report.

We report a 12-year-old girl with Sprintzen-Goldberg syndrome (SGS) who was complicated with annuloaortic ectasia with aortic regurgitation, mitral valve prolapse with mitral regurgitation, and a severe pectus excavatum. In this patient, aortic root replacement, mitral valve replacement, and sternal elevation were simultaneously performed, and a version of Ravitch's procedure that was technically modified to support the sternum was used for sternal elevation. This modified sternal elevation technique gave excellent operative exposure, and maintained chest wall stability after the operation.

Effects of chroman derivatives on platelet aggregation induced by some aggregating agents in rabbits.

1. We synthesized 10 chroman derivatives (CD-1 to CD-10) derived from khellactone, including praeruptorin A and praeruptorin B and examined the effects of these compounds on rabbit platelet aggregation. 2. These compounds exhibited an inhibitory effect on platelet-activating factor (PAF)-induced platelet aggregation and their effects were more potent on PAF-induced platelet aggregation than on adenosine triphosphate (ADP)-, arachidonate (AA)- or collagen-induced platelet aggregation. In particular, (+/-)-cis-5-methoxy-6-methoxycarbonyl-2,2-dimethyl-3,4-ditiglyloxychr oman (CD-6), (+/-)-cis-5-methoxy-6-(2-methoxycarbonylethenyl)-2,2-dimethyl- 3,4-ditiglyloxychroman (CD-8), (+/-)-cis-3,4-diacetoxy-5-methoxy-2,2-dimethyl-6-propylchroman (CD-9) and (+/-)-cis-5-methoxy-2,2-dimethyl-6-propyl-3,4-ditiglyloxychroman (CD-10) showed a moderate inhibition of PAF-induced platelet aggregation. 3. From these findings, it is suggested that compounds with potent PAF antagonist activities have the following features: (i) a tiglyloxy moiety is required at the 3 and 4 positions; and (ii) the methoxy moiety is also required at the 5 position of chroman skeleton in khellactone.

Pharmacological activities of khellactones, compounds isolated from Peucedanum japonicum THUNB. and Peucedanum praeruptorium DUNN.

The spasmolytic and antiallergic effects of AA and BB, compounds isolated from Peucedanum japonicum THUNB. (P. japonicum THUNB.) and Peucedanum praeruptorium DUNN. (P. praeruptorium DUNN.), were investigated in isolated smooth muscle and rat PCA. AA and BB showed noncompetitive antagonistic effects on Ach- and histamine-induced contraction in the isolated guinea pig ileum. Both AA and BB at 10(-6) g/ml caused a slight shift to the right of the dose-response curve for Ca2+ in isolated guinea pig ileum, and a concentration up to 3 x 10(-6) g/ml displayed noncompetitive antagonistic effects. The Ba2+ (3 x 10(-4) g/ml)-induced contraction in ileum and the histamine (10(-3) g/ml)-induced contraction in trachea were obtained to relaxation by AA and BB in a concentration-dependent fashion. AA and BB showed noncompetitive antagonist action on serotonin-induced contraction of the rat uterus excised 24-48 h after subcutaneous injection of female rats with estradiol. But, AA and BB were found to have hardly any inhibitory effect on rabbit thoracic aorta contractions induced by epinephrine (3 x 10(-6) g/ml). When the effect of oral administration of 40 mg/kg dose of BB was tested on the rat homologous PCA using anti-egg albumin mouse serum dilutions (1:100, 1:250, 1:500 and 1:750), it inhibited the 1:750 serum reaction 42.6%, but the inhibition rates for the other dilutions were 12-20%. Thus, based on the results of testing AA and BB, compounds isolated from P. japonicum THUNB. and P. praeruptorium DUNN. were confirmed to possess a spasmolytic effect on different types of smooth muscle and a mild antiallergic effect. These findings are of interest in regard to the medical uses of P. japonicum THUNB. and P. praeruptorium DUNN. as a herbal drug for bronchial asthma, spasmolytic effect, etc.

Oxygenation reaction of methyl valproate with a mono-oxygenase model reagent: implication for stereochemical identification of the mammalian metabolites of valproic acid.

Non-enzymic oxygenation reaction of methyl valproate (2) utilizing a simple model system for mono-oxygenases, Fe(MeCN)2(6+)-H2O2-Ac2O in MeCN, was investigated in connection with stereochemical analyses of the mammalian metabolites of 1. This oxygenation reaction of methyl valproate (2) gave a 92:8 mixture of the anti-isomer 4a and the syn-isomer 4b, together with 5a, and 5b corresponding to the mammalian metabolites of 1. The stereochemistry of 4a, 5a, and 5b was elucidated by spectral analyses of the corresponding beta-lactone 6a, gamma-lactone 7a and 7b prepared from the oxygenation products. The asymmetric synthesis of (+)-7a was also achieved.

[Weitz' aminium salt initiated electron transfer reactions and application to the synthesis of natural products].

A stable cation radical Weitz' aminium salt, tris(4-bromophenyl)aminium hexachloroantimonate (BAHA) initiated electron transfer has been found to efficiently promote a great variety of reactions on electron-rich substrates: e.g. the cation radical pericyclic reactions, the chain-induced cation radical oxygenation of strained olefines and dienes, and several other intriguing reactions on a great variety of electron-rich substrate. The discovery of the Weitz' aminium salt catalysed Diels-Alder reaction has stimulated interest in cation radical chemistry and facilitated the development of a wide range of cation radical pericyclic chemistry. Applications of the method to the synthesis of natural products utilizing BAHA are also presented. Reaction of a lignan precursor, cinnamyl alcohols with BAHA in tetrahydrofuran (THF) gave a furofuran lignan, (+/-)-sesamin in one step. Podophyllum lignans, (+/-)-isopodophyllotoxin and (+/-)-isopicropodophyllin were synthesized by a biomimetic procedure from the doubly unsaturated esters by means of the BAHA induced cation-radical cycloaddition reaction. A new general synthesis for (+/-)-dibenzocyclooctadiene lignans was established utilizing novel synthetic method for quinone derivatives by oxidation with BAHA. Reactions of phenol derivatives using BAHA gave the corresponding quinone derivatives, which may be useful synthon for obtaining quassinoids such as quassin.

Effects of methyl 9(or 10)-hydroxy-10(or 9)-mercaptostearate and hexadecanethioic S-acid on cupric ion- or 2,2-azo-bis(2-amidinopropane) dihydrochloride (AAPH)-induced oxidation of low density lipoprotein.

The preventive effects of two antioxidants, methyl 9(or 10)-hydroxy-10 (or 9)-mercaptostearate (SH-S) and hexadecanethioic S-acid (thiopalmitic acid, SH-Pal) against the oxidative modification of low density lipoproteins (LDL) induced by cupric ion or a water soluble initiator of peroxyl radicals, 2,2-azobis(2-amidinopropane) dihydrochloride (AAPH), were studied by measuring thiobarbituric acid-reactive substances (TBARS). SH-S acted as an effective antioxidant in the oxidative modification of LDL induced by either cupric ion or AAPH. Interestingly, SH-S completely inhibited the formation of fluorescence products and decreased both the fluorescence and alpha-tocopherol content in LDL induced by cupric ion, and reduced 1,1-diphenyl 2-picrylhydrazyl (DPPH) used as a stable free radical model. The antioxidative effect was effectively prevented by the addition of increasing amounts of N-ethylmalemide (NEM) to the system. SH-Pal also inhibited the cupric ion-induced LDL oxidation, but showed little inhibitory effect on the AAPH-induced LDL oxidation. Moreover, SH-Pal was reduced to palmitic acid during the AAPH-induced LDL oxidation. These findings indicate that SH-S protects against oxidative damage of LDL in vitro, and that it acts as a free radical in peroxidation. In addition, this study shows that SH-Pal doesn't act as an efficient antioxidant in AAPH-induced lipid peroxidation.

Induction of hepatic microsomal P450 by 4-phenylalkylpyridines in rat: chain length-dependent and sex-related differential induction of P450s.

The effects of 4-phenylalkylpyridines (chain length of 0-5, 7, 9 and 11 carbon atoms) on the induction of hepatic microsomal P450 and its multiple forms (1A1/2 (1A1, 1A2), 3A2, 2B1/2, 2C6 and 2E1) in the male and female rat have been investigated. P450 induction gradually declined with increasing chain length of the 4-phenylalkylpyridines. Immunoblot analysis revealed that three pyridine compounds having methylene units of 0, 1 and 2 only induced P4501A2, whereas those having 4, 5 or 7 methylene units only induced 1A1 in the male rat. In the female rat, however, we could not observe such a chain length-dependent differential induction of the P4501A subfamily. Induced levels of P4503A2 and 2E1 were dependent on total P450 specific content, but 2C6 was increased in a chain length-dependent manner in both sexes. These results provide new information on the differential effects of pyridine-containing compounds on P450 induction in the rat.

The antagonistic effects of khellactones on platelet-activating factor, histamine, and leukotriene D4.

Khellactones of Peucedanum praeruptorum DUUN., including praeruptorins A (= Pd-Ia, 2) and B (= Pd-II,11), had an antagonistic effect specifically on platelet aggregation induced by platelet activating factor (PAF) among various aggregating agents examined, and represent a new class of PAF antagonists. We examined the effects of twenty compounds on PAF-induced platelet aggregation and on histamine- and leukotriene D4 (LTD4)-induced contractions in isolated guinea pig ileum. Compounds 2, (+/-)-cis-3',4'-diacetylkhellactone (3), (+/-)-cis-4'-acetyl-3'-crotonoylkhellactone (5), (+/-)-cis-4'-acetyl-3'-tetrolylkhellactone (6), (+/-)-cis-4'-acetyl-3'-tigloylkhellactone (7), (+/-)-cis-4'-acetyl-3'-(2"-methylbutyryl)khellactone (8), (+/-)-cis-3',4'-ditigloylkhellactone (10), and 11 all strongly inhibited PAF-induced platelet aggregation. (+/-)-cis-4'-Acetyl-3'-(2"-methyl-2"-dodecenoyl)khellactone (9), (+/-)-cis-4'-ethyl-3'-tigloylkhellactone (13), (+/-)-cis-4'-ethyl-3'-[N-(2"-triethylammonio)ethylcarbamoyl] khellactone iodide (16), (+/-)-trans-3',4'-diacetylkhellactone (18), (+/-)-trans-4'-acetyl-3'-crotonoylkhellactone (19), (+/-)-trans-4'-acetyl-3'-valerylkhellactone (20), (+/-)-trans-4'-acetyl-3'-isovalerylkhellactone (21), and (+/-)-trans-4'-acetyl-3'-tigloylkhellactone (22) were weakly inhibitory. Most of the compounds exhibited noncompetitive antagonist actions on histamine- and LTD4-induced contractions.(ABSTRACT TRUNCATED AT 250 WORDS)