Incidence, clinicopathological features, and clinical outcomes of low HER2 expressed, inoperable, advanced, or recurrent gastric/gastroesophageal junction adenocarcinoma.

BACKGROUND: According to the DESTINY-Breast04 trial, treating patients with breast cancer and low human epidermal growth factor receptor 2 expressions (HER2-low) varies from that of those with no HER2 expression. However, it is interesting to know if HER2-low indicates for anti-HER2 therapy in the gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. Hence we conducted this study to assess the incidence, clinicopathological features, and treatment outcomes of patients with HER2-low G/GEJ adenocarcinoma. PATIENTS AND METHODS: This was a single-center, retrospective observational study. Patients with previously untreated G/GEJ adenocarcinoma were classified based on their HER2 status using immunohistochemistry (IHC) with or without in situ hybridization (ISH) as follows: HER2 negative (IHC 0), HER2-low (IHC 1+ or 2+/ISH-), and HER2-positive (IHC2+/ISH+ or 3+). RESULTS: In total, 734 patients with G/GEJ adenocarcinoma were divided into three groups (HER2-negative, n = 410; HER2-low, n = 154, and HER2-positive, n = 170). The intestinal-type histology, peritoneal metastasis, and higher serum carcinoembryonic antigen (CEA) levels differed significantly among patients with negative, low, and positive HER2 statuses: intestinal-type histology (21.0%, 44.2%, and 59.8%, respectively), peritoneal metastasis (56.3%, 44.8%, and 21.8%, respectively), and higher serum CEA level (32.2%, 41.6%, and 56.5%, respectively). Improved survival was observed in the HER2-positive group than in the HER2-negative G/GEJ adenocarcinoma group [hazard ratio (HR) = 0.73, 95% confidence interval (CI) 0.59-0.89; P = 0.002]. However, the prognoses of the HER2-low and HER2-negative groups were similar (HR = 1.01, 95% CI 0.82-1.23; P = 0.843). CONCLUSIONS: Patients with HER2-low G/GEJ adenocarcinoma exhibited intermediate and distinct characteristics than those in the HER2-negative group. Similarly, the HER2-low group's prognosis was worse than that of the HER2-positive group. Therefore developing novel therapeutic strategies targeting HER2-low G/GEJ adenocarcinoma is required.

[Three-dimensional demonstration of the spinal cord artery with 64-row computed tomography].

This is a report of 2 cases, in which preoperative 3-dimentional demonstration of the spinal cord artery with 64-row computed tomography was feasible, less invasive, less time-consuming, and helpful in making an interventional strategy for complex aortic disease, resulting in no postoperative paraplegia One was a 63-year-old man, who underwent total arch replacement and a long elephant trunk method for arch and descending aortic aneurysms. The length of the long elephant trunk was so determined that it ended between the descending aortic aneurysm and the origin of the spinal cord artery. The second case was a 59-year-old man, who underwent descending thoracic aorta replacement for type B aortic dissection. During the distal anastomosis, the dissection septa were trimmed in order to perfuse the blood into the true and 2 false channels, one of which was connected to the spinal cord artery. In this report, we are not suggesting that preservation of the demonstrated spinal cord artery is enough for spinal cord protection, because it is still controversial. Further study is needed to confirm the reliability and reproducibility of our methods.

[Aortic arch replacement placing priority on cardiac and cerebral reperfusion].

In this report, aortic arch replacement was performed successfully in 2 cases with our modified method placing priority on the cardiac and cerebral reperfusion, resulting in no postoperative cardiac or neurological complication. One was a 63-year-old man with old cerebral infarction and ischemic heart disease, and the other was a 72-year-old man with severe stenosis of the left common carotid arteries. Our method is similar to so-called "arch first technique". First, the ascending aorta is clamped and proximal anastomosis is accomplished during core cooling, followed by reconstruction of the brachiocephalic arteries under deep hypothermic circulatory arrest. Then perfusion of the heart and brain is restarted, while distal anastomosis is performed. It was proved that the method had several possible advantages such as minimized duration of brain ischemia and deep hypothermia, and elimination of direct cannulation to the branches of the aortic arch and a separate perfusion circuit for the brain.

Suppression of serum starvation-induced apoptosis by hepatitis C virus core protein.

Hepatitis C virus (HCV) core protein either enhances or inhibits apoptosis depending on the apoptosis-inducing stimuli and cell conditions. In this paper we studied possible effect of HCV core protein on apoptosis induced by serum starvation. NIH3T3 cells stably expressing HCV core protein were more resistant to serum starvation-induced apoptosis than were the non-expressing control. Neither p53, p21Waf1 nor Bax was detectably induced after serum starvation, irrespective of HCV core protein expression, suggesting that the observed apoptosis is p53-independent. Serum starvation-induced apoptosis was partially inhibited by SB203580, a specific inhibitor of p38 mitogen-activated protein (MAP) kinase, in the non-expressing control, but not in HCV core protein-expressing cells. Moreover, activation of p38 MAP kinase after serum starvation, as measured by the amount of its phosphorylated form, was inhibited in HCV core protein-expressing cells. Our results suggest that HCV core protein inhibits serum starvation-induced apoptosis through inhibition of p38 MAP kinase activation.

Effect of sodium thiosulfate on cisplatin removal with complete hepatic venous isolation and extracorporeal charcoal hemoperfusion: a pharmacokinetic evaluation.

BACKGROUND: Complete hepatic venous isolation and extracorporeal charcoal hemoperfusion (HVI.CHP) can limit systemic exposure to high-dose chemotherapeutic agents when given by hepatic arterial infusion (HAI). The purpose of this study was to determine if the concomitant use of sodium thiosulfate (STS) could further expand the advantages of pharmacologic delivery of HVI.CHP for cisplatin (CDDP) during HAI chemotherapy. METHODS: CDDP (4mg/kg) was administered over 20 minutes via HAI under conditions of HVI.CHP in 14 mongrel dogs. HVI.CHP was performed for 30 minutes after initiation of HAI. During CDDP infusion, 7 dogs each received 400 mg/kg STS (a 100-fold molar ratio to CDDP) over 20 minutes via the prefilter (STS group) circuit line, while the remaining 7 dogs (controls) received no STS. Blood samples were taken serially from the prefilter circuit line (hepatic venous blood), postfilter line, and the left carotid artery (systemic blood). The free and total CDDP concentrations in these samples were determined by flameless atomic absorption spectrophotometry. RESULTS: During 20 minutes HAI of CDDP, the mean CDDP extraction ratios (ER) by CHP filter were always higher in the STS group than in the control group, regardless of the form (free or total) of CDDP. The differences between the STS and control groups in the extraction ratios of free and total CDDP were significant at all time points measured (P < .05). Consequently, systemic exposure to CDDP, as assessed by area under the time-concentration curve of total CDDP, was significantly lower in the STS group than in the control group (P < .05). CONCLUSIONS: These results indicated that concomitant STS infusion could further increase the effect of HVI.CHP on CDDP removal after HAI.

Polymorphism of tumor necrosis factor-beta and alcohol dehydrogenase genes and alcoholic brain atrophy in Japanese patients.

BACKGROUND: Alcohol abuse can induce brain atrophy, but it only occurs in some alcoholics. Many inflammatory cytokines such as tumor necrosis factor (TNF) are produced rapidly in the brain by experimental or clinical injury. METHOD: To investigate whether genetic polymorphism of TNF was related to alcoholic brain atrophy, we determined restriction fragment-length polymorphisms of the TNF-beta genes in 72 male alcoholics. Computed tomography was used to determine the severity of brain atrophy. RESULTS: Digestion with NcoI and MspI after polymerase chain reaction amplification showed that the TNFB1 allele frequency was significantly higher in patients with brain atrophy than in those without brain atrophy (chi2 = 10.20, p = 0.0034). A multivariate analysis that included age, total alcohol intake, ADH2 genotype, and TNF-beta genotype showed that the ADH21/21 genotype and TNFB1/B1 genotype are independently associated with alcoholic brain atrophy. These findings suggest that the TNFB1 allele may be associated with alcoholic brain atrophy.

Mechanisms of alcoholic liver disease: cytokines.

This article represents the proceedings of a workshop at the 2000 ISBRA Meeting in Yokohama, Japan. The chair was Manuela G. Neuman. The presentations were (1) New aspects of hepatic fibrosis, by D. A. Brenner; (2) Cellular immune response in hepatitis C models, by B. Rehermann; (3) The role of interleukin-10 in acute alcoholic hepatitis, by J. Taieb, S. Chollet-Martin, M. Cohard, J. J. Garaud, and T. Poynard; (4) Cytokine-mediated apoptosis in vitro, by M. G. Neuman; (5) Signaling for apoptosis and repair in vitro, by G. G. Katz, R. G. Cameron, N. H. Shear, and M. G. Neuman; (6) Interferons activate the P42/44 mitogen-activated protein kinase and Janus Kinase signal transducers and activation of transcription (JAK-STAT) signaling pathways in hepatocytes: Differential regulation by acute ethanol via a protein kinase C-dependent mechanism, by B. Gao; (7) Genetic polymorphisms of interleukin-1 in association with the development of Japanese alcoholic liver disease, by M. Takamatsu, M. Yamauchi, M. Ohata, S. Saito, S. Maeyama, T. Uchikoshi, and G. Toda; and (8) Increased levels of macrophage migration inhibitory factor in sera from patients with alcoholic liver diseases, by T. Kumagi, S. M. F. Akbar, M. Abe, K. Michitaka, N. Horiike, and M. Onji.

Competitive incorporation of arachidonic acid analogs by cultured rat keratinocytes.

Arachidonic acid (20:4 n-6) and its metabolic products, such as prostaglandins and leukotrienes, have been known to be associated with skin inflammatory reactions. However, the mechanism of the competitive incorporation of 20:4 n-6 into keratinocytes among polyunsaturated fatty acids (PUFAs) remains uncertain. To investigate the relationship between the molecular structure of PUFAs and the rate of incorporation of PUFAs into cells, a fetal rat skin keratinocyte (FRSK) cell line was used. The cells were incubated for 24 h with any two of the following arachidonic acid analogs: mead acid (20:3 n-9), dihomo-gamma-linolenic acid (20:3 n-6), 11,14,17-cis-eicosatrienoic acid (20:3 n-3), arachidonic acid (20:4 n-6), eicosapentaenoic acid (20:5 n-3) and 5,8,11,14-cis-nonadecatetraenoic acid (19:4 n-5), at the ratio of 1:0, 0.5:0.5, or 0:1; and their incorporation into lipid was measured by capillary gas-liquid chromatography. The experiments indicated that 20:3 n-6 was preferentially incorporated into phospholipids of FRSK rather than 20:3 n-9 or 20:3 n-3, and 19:4 n-5 as well as 20:4 n-6 was preferentially incorporated into total cellular lipid and phospholipids rather than 20:3 n-9 or 20:5 n-3. When two PUFAs were added simultaneously to the medium, 19:4 n-5 most effectively reduced the competitive incorporation of 20:4 n-6 into phospholipids. These results suggest that keratinocytes discriminate 20:4 n-6 from other arachidonic acid analogs by its double bond positions from the carboxyl group.

[Phase I study of super high-dose chemotherapy for liver cancer with percutaneous isolated hepatic perfusion (PIHP) and peripheral blood stem cell transplantation (PBSCT)].

The aim of this study was to evaluate the phase I aspects of super high-dose chemotherapy for advanced liver cancer with combined use of PIHP and PBSCT. In 4 patients with HCC and 1 patient with colonic liver metastases, peripheral blood stem cells (PBSC) were mobilized by either i.v. infusion of ETP (180 mg/m2/day for 3 days) or i.a. infusion of doxorubicin (100-120 mg/m2). In 3 (60%) of 5 patients, PBSC for PBSCT were harvested in effective quantities (CFU-GM > or = 2 x 10(5)/kg or CD 34 positive cells > or = 2 x 10(6)/kg). In these 3 patients, a repeated PIHP with either doxorubicin, 5-fluorouracil, or CDDP was carried out 4 weeks after the 1st PIHP. Thereafter, auto-PBSCT was intravenously administered 2 days after PIHP. In the repeated PIHP treatments, although anti-cancer drugs were administered at doses equivalent to or even higher than those administered at the 1st PIHP, bone marrow suppressions were transient and well tolerated. Fatal complications were not observed in any patients. These results indicate that with the combined use of PIHP and PBSCT, high-dose regional chemotherapy of the liver can be safely repeated without systemic toxicities.

Results of filtering surgery in young patients with aniridia.

To evaluate whether filtering surgery is effective in controlling the intraocular pressure of young aniridic patients with glaucoma, we retrospectively reviewed the charts of aniridic patients with glaucoma under the age of 40 years. We defined a good intraocular pressure control period as the time from surgery until IOP exceeded 20 mm Hg, with or without glaucoma medication. Twenty filtering surgeries (17 trabeculectomies and 3 trabeculectomies with mitomycin C) were performed on 10 eyes in 6 patients for more than 20 years. The mean good intraocular pressure control period after the filtering surgery was 14.6 months (range, 2 to 54 months). Aside from mild choroidal detachment, no other serious complications were encountered. We believe that filtering surgery is efficacious for control of intraocular pressure of young aniridic patients with glaucoma.

Complex formation between hepatitis C virus core protein and p21Waf1/Cip1/Sdi1.

The core protein (Core) of hepatitis C virus (HCV) has been known to play an important role in hepatocarcinogenesis. By using glutathione S-transferase (GST) pull-down assay, we show here that Core formed a complex with p21Waf1/Cip1/Sdi1 (p21) cell cycle regulator. The deletion-mapping analysis revealed that a portion near the N-terminus of Core (amino acids 24-52) and a C-terminal portion of p21 (amino acids 139-164) were involved in the complex formation. The complex formation was not impaired by point mutations of p21 at residues 147, 149, and 150, which have been reported to abrogate interaction of p21 with proliferating cell nuclear antigen (PCNA), discriminating the Core-binding sequence from the PCNA-binding sequence. Due to the close vicinity of the binding sites, however, Core and PCNA competed with each other when interacting with p21. The distinct interaction between Core and p21 may provide a new aspect to the studies of HCV pathogenesis.

Localization of prostaglandin E receptor subtypes in the ciliary body of mouse eye.

Prostaglandin E2 (PGE2) markedly reduces intraocular pressure (IOP) when applied topically and induces strong relaxation of pre-contracted isolated ciliary muscle through PGE2 receptor. Because the ciliary muscle relaxation reduces IOP by enhancing uveoscleral aqueous outflow, the ciliary muscle where the existence of PGE2 receptors has been demonstrated is thought to be one of the target tissues for PGE2-induced IOP reduction. To investigate the subtypes of PGE2 receptors in the ciliary muscle, the regional distribution of four PGE2 receptor subtypes (EP1, EP2, EP3 and EP4) in the mouse ciliary body was investigated by in situ hybridization using specific probes. Consistent messenger RNA signals for EP1 and EP4 receptors were expressed in the ciliary muscle, although signal levels for these subtypes were less potent as compared with the kidney, which was used as a reference organ. EP2 and EP3 signals were not detected. Stimulation of the EP4 receptor activates adenylate cyclase, which should induce ciliary muscle relaxation. Therefore, the IOP reduction induced by PGE2 analogs may be mediated by the EP4 receptor. In contrast, stimulation of the EP1 receptor is believed to promote intracellular Ca2+ mobilization, and hence should cause ciliary muscle contraction. Thus, the coexistence of EP1 and EP4 receptors in the ciliary muscle suggests that the regulation of ciliary muscle tone by PGE2 is based on a complex mechanism involving multiple receptor subtypes.

Genetic polymorphisms of interleukin-1beta in association with the development of alcoholic liver disease in Japanese patients.

OBJECTIVE: Cytokine interleukin-1beta plays a central role in the inflammation process. Serum levels of IL-1beta are elevated in patients with alcoholic liver disease (ALD), especially in those with cirrhosis and alcoholic hepatitis. Recently, the presence of genetic polymorphisms of this cytokine was confirmed. The aim of this study was to determine whether IL-1beta polymorphisms are associated with the development of ALD. METHODS: We examined the frequency of two polymorphisms in the IL-1beta gene located in promoter -511 and exon 5 +3953 locus by restriction fragment length polymorphisms in 142 male patients with ALD, 30 heavy drinkers without ALD, and 218 healthy controls. RESULTS: The carriers of -511 IL-1beta allele 2 were present significantly more often in patients with alcoholic cirrhosis than in those with noncirrhotic ALD (p = 0.026), heavy drinkers without ALD (p = 0.001), and healthy controls (p = 0.032). The frequencies of allele 2 and heterozygotes of +3953 polymorphism were both significantly higher in heavy drinkers without ALD than in patients with ALD (allele, p = 0.030; genotype, p = 0.027) and healthy controls (allele, p = 0.047; genotype, p = 0.043). The haplotype, IL-1beta -511 allele 2/+3953 allele 1 was associated with the development of alcoholic cirrhosis (p < 0.05). CONCLUSIONS: These results suggest that IL-1beta polymorphisms may be related to the development of ALD in Japanese alcoholics.

[Preliminary clinical evaluation of low-dose CDDP and continuous 5-FU therapy for advanced gallbladder cancer].

5-fluorouracil (5-FU) has been widely used for the treatment of gastrointestinal cancers. Low-dose cisplatin (CDDP) and continuous venous infusion of 5-FU have recently shown additive or synergistic antitumor effects in experimental models. In this study, we evaluated the clinical effects of low-dose CDDP and 5-FU (low-dose FP therapy) in patients with advanced gallbladder cancer. From December, 1993 to June, 1998, 13 patients with advanced gallbladder cancer were treated with low-dose FP therapy. Patients were eligible for this study if they had a bidimensionally measurable tumor. 5-FU (160 mg/m2/day) was continuously infused over 24 hours using an implantable port, and CDDP (3 mg/m2/day) was infused for one hour. The administration schedule consisted of 5-FU for 7 consecutive days and CDDP for 5 days followed by a 2-day rest, each for four weeks according to response and tolerance. Low-dose FP therapy was given to 12 patients (92.3%). The response rate was 66.7% and the median survival time was 151 days. The regimen was tolerable, with the most common toxicity being nausea (38.5%). There were no severe side effects except for one patient who suffered from grade 3 nausea. We conclude that low-dose FP therapy may be useful as a palliative chemotherapy for cases of advanced gallbladder cancer.

[Effect of stellate ganglion block on human retinal blood flow].

PURPOSE: The effect of stellate ganglion block (SGB) on human retinal blood flow was evaluated. METHODS: We measured the diameter of the retinal artery and vein, and retinal venous flow rate by laser speckle retinal blood flow meter simultaneously in 11 eyes of 11 normal volunteers. RESULTS: The reliable data from 9 eyes of 9 person were used for analysis. SGB did not change the blood pressure, heart rate, retinal arterial diameter, or venous diameter. However SGB increased retinal blood velocity significantly from 9.9 +/- 1.6 (mean +/- standard deviation) mm/s to 11.1 +/- 1.5 mm/s (p < 0.01). Intraocular pressure decreased from 12.3 +/- 2.1 (mean +/- standard deviation)mmHg to 9.4 +/- 2.2 mmHg after SGB (p < 0.01). There was no relationship between the change of ocular perfusion pressure and that of retinal venous blood velocity. CONCLUSION: SGB increased the retinal venous blood velocity without changing the retinal vessel diameter.

[Low-dose CDDP and continuous 5-FU treatment of advanced gastric cancer with peritoneal dissemination: a case with long disease-free survival].

The patient was diagnosed to have gastric cancer (T3 N3 M0 P3, Stage IV b). We conducted LcFP therapy. CDDP, 7 mg/m2/day, day 1-5 i.v. drip for 2 hours, and 5-FU, 170 mg/m2/day, day 1-7, i.v. continuously for 24 hours. After 3 courses (one course: 4 LcFPs followed by one rest week), down staging (T3 N2 M0 P1. Stage IV a) and improvement of performance status were obtained, and then surgical resection was undertaken. After operation one course of LcFP therapy served as adjuvant chemotherapy. The patient has survived over one year and 8 months to date in a tumor-free condition. LcFP therapy promises to be useful in the clinical management of advanced gastric cancer.

Correlation of a polymorphism in the interleukin-1 receptor antagonist gene with hepatic fibrosis in Japanese alcoholics.

The aim of this study was to determine whether there is any association between interleukin-1 receptor antagonist (IL1-Ra) genotype and alcoholic liver disease. The IL1-Ra genotype was assessed in 102 Japanese male alcoholic liver disease patients and 46 healthy subjects by polymerase chain reaction with leukocyte DNA. The distribution of IL1-Ra genotype and the allelic frequencies in Japanese healthy subjects are both significantly different from that previously reported in Caucasians (A1/A1 genotype: 95.7% in Japanese vs. 54.0% in Caucasians, p < 0.001; A1 allele: 97.8% vs. 73.4%, p < 0.001). The frequency of A1 heterozygotes tended to be higher in Japanese alcoholics with fibrosis, compared with those without fibrosis (14.9% vs. 2.9%). Furthermore, within the fibrotic groups, cumulative alcohol intake was significantly lower in A1 heterozygotes than in the A1 homozygotes (877 +/- 118 kg vs. 1369 +/- 90 kg,p < 0.05). In conclusion, a genetic polymorphism in the IL1-Ra gene may influence the risk of developing hepatic fibrosis in Japanese alcoholics. The same study should be conducted in Caucasian patients having more frequency of IL1-Ra A1 heterozygotes.