Katsuichi Matsuo

Is preoperative hepatic arterial chemoembolization safe and effective for hepatocellular carcinoma

OBJECTIVE The value of preoperative transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) has not been duly appreciated. The authors assessed the advantages and disadvantages of preoperative TACE by reviewing their experience with the procedure. METHODS A total of 140 patients who underwent hepatectomy for HCC were entered into the study (105 received preoperative TACE and 35 did not). The authors investigated the reduction of tumor size and the complications after TACE, as well as the relationship between the interval from TACE to resection and the occurrence of complications. They compared postoperative morbidity and mortality between the TACE and non-TACE groups. They also compared survival and disease-free survival between the two groups, as well as between subgroups, defined by the extent of tumor necrosis achieved with TACE. RESULTS A distinct reduction of tumor size was observed in approximately half of the TACE group. However, there were 68 appreciable complications of TACE in 56 patients (53.3%), and the interval between TACE and resection was significantly prolonged in the patients with complications. The postoperative morbidity and mortality rates of the TACE group were not different from those of the non-TACE group. Preoperative TACE did not improve the survival or disease-free survival of the whole patient group after hepatectomy. In addition, the survival and disease-free survival rates of the three TACE subgroups were not different from those of the non-TACE group. CONCLUSIONS Preoperative TACE should only be performed to reduce tumor bulk in patients with HCC with borderline resectability. In such patients, increased tumor resectability appears to improve the survival rate. Preoperative TACE does not promote tumor recurrence.

ATP release and contraction mediated by different P2‐receptor subtypes in guinea‐pig ileal smooth muscle

1 The present study was addressed to clarify the subtypes of P2‐purinoceptor involved in ATP release and contraction evoked by α,β‐methylene ATP (α,β‐mATP) and other P2‐agonists in guinea‐pig ileum. 2 α,β‐mATP 100 μM produced a transient and steep contraction followed by ATP release from tissue segments. These maximum responses appeared with different time‐courses and their ED50 values were 5 and 25 μM, respectively. The maximum release of ATP by α,β‐mATP was markedly reduced by 250 μM suramin, 30 μM pyridoxal‐phosphate‐6‐azophenyl‐2′,5′‐disulphonic acid (PPADS) and 30 μM reactive blue 2 (RB‐2), P2‐receptor antagonists. However, the contractile response was inhibited by suramin, tetrodotoxin and atropine, but not by PPADS and RB‐2. 3 Although the contraction caused by α,β‐mATP was strongly diminished by Ca2+‐removal and nifedipine, and also by tetrodotoxin and atropine at 0.3 μM, the release of ATP was virtually unaffected by these procedures. 4 UTP, β,γ‐methylene ATP (β,γ‐mATP) and ADP at 100 μM elicited a moderate release of ATP. The release caused by UTP was virtually unaffected by RB‐2. However, these P2‐agonists failed to elicit a contraction of the segment. 5 The potency order of all the agonists tested for the release of ATP was α,β‐mATP>UTP>β,γ‐mATP>ADP. 6 In superfusion experiments with cultured smooth muscle cells from the ileum, α,β‐mATP (100 μM) enhanced the release of ATP 5 fold above the basal value. This evoked release was inhibited by RB‐2. 7 These findings suggest that ATP release and contraction induced by P2‐agonists such as α,β‐mATP in the guinea‐pig ileum result mainly from stimulation of different P2‐purinoceptors, P2Y‐like purinoceptors on the smooth muscles and, probably, P2X‐purinoceptors on cholinergic nerve terminals, respectively. However, the ATP release may also be mediated, in part, by P2U‐receptors, because UTP caused RB‐2‐insensitive ATP release.

Possible transsynaptic cholinergic neuromodulation by ATP released from ileal longitudinal muscles of guinea pigs

The effects of alpha, beta-methylene ATP (alpha, beta-mATP) and beta, gamma-methylene ATP (beta, gamma-mATP) on endogenous acetylcholine (ACh) release evoked by electrical nerve stimulation were evaluated in guinea-pig ileal longitudinal muscles. Release of ACh was measured with an HPLC-electrochemical detector system and release of ATP by luciferin-luciferase assay. Electrically evoked endogenous ACh release was reduced by both alpha, beta-mATP and beta, gamma-mATP at concentrations of 3 and 30 microM. The inhibitory effect of alpha, beta-mATP (30 microM) on ACh release was not detectable in the presence of theophylline (100 microM), a P1-purinoceptor antagonist, that itself enhanced ATP release. When exogenous ATP (0.1 microM) was added to the bath in which the ileal segment was suspended, it was rapidly metabolized, presumably by ecto-ATPase, and disappeared from the medium within 15 min. At 30 microM, alpha, beta-mATP induced ATP release in a suramin-sensitive but Ca(2+)- and atropine-insensitive manner, suggesting P2-receptor-mediated release of ATP from the smooth muscle. We conclude from these findings that alpha, beta-mATP and, probably, also beta, gamma-mATP, do not reduce ACh release by direct stimulation of presynaptic P1-purinoceptors, and that endogenous ATP released postjunctionally by these ATP analogs is decomposed metabolically to adenosine in the synapse and this adenosine triggers P1-purinoceptor sensitive neuromodulation of cholinergic transmission.

Protection of trocar sites from gallbladder cancer implantation by sodium hyaluronate shill carboxymethylcellulose–based bioresorbable membrane (Seprafilm) in a nurine model

Background: The risk of port site metastasis in laparoscopic surgery for cancer patients is a problem that has yet to be resolved. We examined the protective effect of a sodium hyaluronate–based bioresorbable membrane (Seprafilm) on tumor cell implantation at laparoscopic trocar sites. Methods: Four 2-mm trocar sites were created in nude mice, and the peritoneal wounds were covered with different-sized pieces of Seprafilm. The protective effect of Seprafilm on the implantation of GB-d1 (a human gallbladder cancer cell line) at the trocar sites was assessed after 7 days. In addition, the effects of sodium hyaluronate and Seprafilm on the growth and motility of GB-d1 were examined in vitro. Results: Seprafilm significantly decreased the incidence of implantation compared with the control group. Histologically, Seprafilm was observed on days 1 and 3, as a sheet of gel that covered the injured peritoneum and muscle layer. In an invasion assay using Seprafilm, no cells were found to infiltrate through the gel sheet. Conclusion: Seprafilm protects peritoneal wounds by physically covering the injured peritoneum. Therefore, if Seprafilm were attached to the injured peritoneum after laparoscopic surgery for cancer patients, it might reduce port site metastasis.

Inhibitory effect of okadaic acid on noradrenaline exocytosis from guinea-pig vas deferens

The effects of okadaic acid (30 microM), a protein phosphatase inhibitor, on noradrenaline (NA) release evoked by 70 mM KCl and 100 microM ouabain were evaluated in guinea-pig vas deferens. Release of NA evoked by high KCl was inhibited by okadaic acid but this inhibition was antagonized by Bay K 8644. Furthermore, okadaic acid, like Ca(2+)-channel blockers, reduced NA release by ouabain. However, ATP-release induced by alpha,beta-methylene ATP was virtually unaffected by okadaic acid or Ca(2+)-free medium. These findings suggest that phosphatases may play an important role in Ca(2+)-channel activation and consequent NA exocytosis from adrenergic nerves.