Expression of ER stress markers (GRP78/BiP and PERK) in patients with tongue cancer.

The glucose-regulated protein (GRP78/BiP) and PKR-like endoplasmic reticulum kinase (PERK) plays a crucial role in the endoplasmic reticulum (ER) stress response. GRP78/BiP is highly elevated in various human cancers. Our study is to examine the clinicopathological significance of GRP78/BiP and PERK expression in patients with tongue cancer. A total of 85 tongue cancer patients were analyzed, and tumor specimens were stained by immunohistochemistry for GRP78/BiP, PERK, GLUT1, Ki-67 and microvessel density (MVD) determined by CD34.GRP78/BiP and PERK were highly expressed in 47% and 35% of all patients, respectively. GRP78/BiP disclosed a significant relationship with PERK expression, lymphatic permeation, vascular invasion, glucose metabolism and cell proliferation. The expression of GRP78/BiP was significantly higher in metastatic sites than in primary sites (79% vs. 47%, p=0.003). We found that the high expression of GRP78/BiP was proven to be an independent prognostic factor for predicting poor outcome in patients with tongue cancer. In the analysis of PFS, PERK was identified as an independent predictor. The increased GRP78/BiP expression was clarified as an independent prognostic marker for predicting worse outcome. Our study suggests that the expression of GRP78/BiP as ER stress marker is important in the pathogenesis and development of tongue cancer.

Prognostic significance of amino-acid transporter expression (LAT1, ASCT2, and xCT) in surgically resected tongue cancer.

BACKGROUND: Amino-acid transporters are necessary for the tumour cell growth and survival, and have a crucial role in the development and invasiveness of cancer cells. But, it remains unclear about the prognostic significance of L-type amino-acid transporter 1 (LAT1), system ASC amino-acid transporter-2 (ASCT2), and xCT expression in patients with tongue cancer. We conducted the clinicopathological study to investigate the protein expression of these amino-acid transporters in tongue cancer. METHODS: Eighty-five patients with surgically resected tongue cancer were evaluated. Tumour sections were stained by immunohistochemistry for LAT1, ASCT2, xCT, 4F2hc/CD98hc (4F2hc), Ki-67, and microvessel density (MVD) determined by CD34, and p53. RESULTS: L-type amino-acid transporter 1 and 4F2hc were highly expressed in 61% (52 out of 85) and 45% (38 out of 47), respectively. ASC amino-acid transporter-2 and xCT were positively expressed in 59% (50 out of 85) and 21% (18 out of 85), respectively. The expression of both LAT1 and ASCT2 was significantly associated with disease staging, lymph-node metastasis, lymphatic permeation, 4F2hc expression and cell proliferation (Ki-67). xCT expression indicated a significant association with advanced stage and tumour factor. By univariate analysis, disease staging, lymphatic permeation, vascular invasion, LAT1, ASCT2, 4F2hc, and Ki-67 had a significant relationship with overall survival. Multivariate analysis confirmed that LAT1 was an independent prognostic factor for predicting poor prognosis. CONCLUSIONS: L-type amino-acid transporter 1 and ASCT2 can serve as a significant prognostic factor for predicting worse outcome after surgical treatment and may have an important role in the development and aggressiveness of tongue cancer.

Functions of glutamate transporters in cerebellar Purkinje cell synapses.

Glutamate transporters play a critical role in the maintenance of low extracellular concentrations of glutamate, which prevents the overactivation of post-synaptic glutamate receptors. Four distinct glutamate transporters, GLAST/EAAT1, GLT-1/EAAT2, EAAC1/EAAT3 and EAAT4, are distributed in the molecular layer of the cerebellum, especially near glutamatergic synapses in Purkinje cells (PCs). This review summarizes the current knowledge about the differential roles of these transporters at excitatory synapses of PCs. Data come predominantly from electrophysiological experiments in mutant mice that are deficient in each of these transporter genes. GLAST expressed in Bergmann glia contributes to the clearing of the majority of glutamate that floods out of the synaptic cleft immediately after transmitter release from the climbing fibre (CF) and parallel fibre (PF) terminals. It is indispensable to maintain a one-to-one relationship in synaptic transmission at the CF synapses by preventing transcellular glutamate spillover. GLT-1 plays a similar but minor role in the uptake of glutamate as GLAST. Although the loss of neither GLAST nor GLT-1 affects cerebellar morphology, the deletion of both GLAST and GLT-1 genes causes the death of the mutant animal and hinders the folium formation of the cerebellum. EAAT4 removes the low concentrations of glutamate that escape from uptake by glial transporters, preventing the transmitter from spilling over into neighbouring synapses. It also regulates the activation of metabotropic glutamate receptor 1 (mGluR1) in perisynaptic regions at PF synapses, which in turn affects mGluR1-mediated events including slow EPSCs and long-term depression. No change in synaptic function is detected in mice that are deficient in EAAC1.

Glia-synapse interaction through Ca2+-permeable AMPA receptors in Bergmann glia.

Glial cells express a variety of neurotransmitter receptors. Notably, Bergmann glial cells in the cerebellum have Ca2+-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) assembled without the GluR2 subunit. To elucidate the role of these Ca2+-permeable AMPARs, we converted them into Ca2+-impermeable receptors by adenoviral-mediated delivery of the GluR2 gene. This conversion retracted the glial processes ensheathing synapses on Purkinje cell dendritic spines and retarded the removal of synaptically released glutamate. Furthermore, it caused multiple innervation of Purkinje cells by the climbing fibers. Thus, the glial Ca2+-permeable AMPARs are indispensable for proper structural and functional relations between Bergmann glia and glutamatergic synapses.

Phase I/II study of intravenous nedaplatin and intraarterial cisplatin with transcatheter arterial embolization for patients with locally advanced uterine cervical carcinoma.

BACKGROUND: Nedaplatin, a platinum analog with less renal toxicity and similar efficacy for cervical carcinoma, recently has been shown to have a synergistic effect on cervical carcinoma lines in combination with cisplatin. To determine the clinical efficacy of this combination in patients with cervical carcinoma, the authors conducted a Phase I/II study of intravenous nedaplatin and intraarterial cisplatin combined with transcatheter arterial embolization (TAE). METHODS: Eligibility criteria were as follows: cervical carcinoma (Stages IB2-IV; International Federation of Gynecology and Obstetrics), 16-70 years of age, performance status between 0 and 2, and adequate bone marrow, renal, and hepatic function. Nedaplatin (40-70 mg/m2) was administered intravenously on Day 1 followed by intraarterial administration of cisplatin (70 mg/m2) on Day 3 via both uterine arteries by using the Seldinger method. This then was followed by TAE. This course of treatment was repeated every 3 weeks for 3 cycles. RESULTS: Patient data were as follows: age 37-68 (median, 55 years) and Stages IB2:4, IIA:3, IIB:2, IIIA:1, IIIB:3, IVA:2 carcinoma. The response to therapy was defined by magnetic resonance imaging as follows: partial response in 60% (9 of 15) of patients, complete response in 40% (6 of 15) of patients, and an overall response rate of 100% (95% confidence interval, 78-100%). Myelosuppression was manageable. Grade 3/4 renal toxicity was observed in 2 patients who received 70 mg/m2 of nedaplatin. Thirteen patients received radical hysterectomy, 1 patient received lymph node sampling, and 11 patients received adjuvant radiotherapy or chemotherapy. CONCLUSIONS: The maximum tolerable dose was 70 mg/m2 nedaplatin, and the dose-limiting toxicity was renal toxicity. The recommended dose was 60 mg/m2 nedaplatin intravenously followed by 70 mg/m2 cisplatin intraarterially. Intravenous nedaplatin followed by intraarterial cisplatin with TAE appears to be very effective for locally advanced cervical carcinoma.

[Hepatic arterial infusion chemotherapy using totally implantable port system].

Because of low grade of response rate and high grade of toxicity, arterial infusion chemotherapy (AIC) is not the first choice therapy for hepatocellular carcinoma (HCC). Only far advanced HCC patients, who have no indication of surgical, transcatheter arterial embolization nor ablation therapy, are able to accept AIC. The AIC using totally implantable port system has an advantage for patient's quality of life in the long term. We recommend new intensive EEP regimen which has the response rate of 43% although its severe toxicity.

[Regional differences of in vivo proton MR spectroscopy in developing human brain].

The purpose of this study was to clarify regional differences in proton MR spectroscopy (1H-MRS) in the developing human brain. Proton MR spectra were obtained from 24 infants aged 0 to 24 months old. Proton MR spectroscopy was performed on a 1.5 Tesla clinical MR unit using a 3D-chemical shift imaging sequence (3D-CSI). MR spectra obtained from voxels in frontal white matter and those in parietal white matter were compared. The NAA/Cho ratios of the frontal region were lower than those of the parietal region at birth but increased rapidly during the first six months of life. The rate of increase was reduced in the second year of life. In contrast, NAA/Cho ratios in paracentral areas were already high at birth but increased slowly through the first two years of life. Cho/Cr ratios of the frontal region were stable during the first year of life and started to decrease in the second year of life. In the parietal region, Cho/Cr ratios were decreased throughout infancy. Regional differences in 1H-MRS spectra were apparent during infancy, and these differences were suggested to reflect regional differences in the maturation of the developing human brain.

[Evaluation of hepatic toxicity following high-dose 5-FU arterial infusion chemotherapy: analysis of 42 cases of colorectal liver metastases].

The regional toxicity of an anticancer agent for normal liver tissue following hepatic arterial infusion chemotherapy (HAI) was evaluated in terms of morphology, function, and histopathology. Forty-two patients(M:F = 30:12; mean age, 59.9 years) with liver metastases from colorectal cancer were treated with HAI using a totally implantable vascular access port system from July 1994 to March 1999. The regimen used here was so-called weekly high-dose 5-fluorouracil(5-FU) infusion(5-FU, 1,000 mg/m2/week). Volume measurement of the liver demonstrated not only whole liver atrophy including the tumor but also volume reduction of the non-tumorous lobe. Atrophic change of the liver was seen in patients who were administered over 20 g/m2 of 5-FU(p < 0.01). The CT attenuation values of the liver were examined, and fatty infiltration was seen in six patients. Histologic examination of liver biopsies from the non-tumorous part revealed steatosis and infiltration of inflammatory cells in the portal triad, which were not seen in specimens prior to HAI. On clinical laboratory findings, enzymes representing bile duct, including alkaline phosphatase, leucine amino peptidase, and gamma-glutamyltranspeptidase, were increased in 22 patients. In terms of regional toxicity for long-term HAI, 20 g/m2 of 5-FU, is the key dose at which to consider temporary cessation or dose reduction.

[Radiation exposure to patient and radiologist during transcatheter arterial embolization for hepatocellular carcinoma].

PURPOSE: To evaluate radiation exposure to patients and radiologists during transcatheter arterial embolization(TAE) for hepatocellular carcinoma. MATERIALS AND METHODS: In 39 TAE procedures performed at eight institutes, skin doses were evaluated with thermoluminescence dosimeters at the patient's back(entrance surface) and lower abdomen, and at the radiologist's forehead and abdomen. Real-time dosimeters were also used to evaluate patient skin dose. RESULTS: The patients' mean entrance surface dose was 973 +/- 681 mGy(range, 185 to 3543 mGy) with the mean fluoroscopic time of 21 minutes and 6 digital subtraction angiography(DSA) acquisitions. The dose at the patients' lower abdomen was 0.98 +/- 0.77 mGy. Doses for the radiologists were 0.04 +/- 0.04 mGy at the forehead and 0.15 +/- 0.19 mGy and 0.005 +/- 0.01 mGy at the abdomen over and under the apron, respectively. Fifty-six percent of the patients' skin dose was from DSA and 44% from fluoroscopy. CONCLUSIONS: Patient skin dose may occasionally exceed the dose for transient erythema. Because a patient may have repeated TAEs, skin doses or X-ray conditions should be recorded. The exposed doses of radiologists were considered to be acceptable with proper techniques. Further efforts to reduce radiation should be directed toward both DSA and fluoroscopy.

Phase II study of combined administration of 5-fluorouracil, epirubicin and mitomycin-C by hepatic artery infusion in patients with liver metastases of gastric cancer.

This multicenter phase II study evaluated the efficacy of the FEM regimen (5-fluorouracil 333 mg/m(2) each week, epirubicin 30 mg/m(2) once every 4 weeks and mitomycin-C 2.7 mg/m(2) once every 2 weeks) administered by hepatic artery infusion (HAI) for unresectable hepatic metastases of gastric cancer. The response rates were 55.6% (complete response: 3, partial response: 32, no change: 21, progressive disease: 7/63) and the mean 50% survival was 10.5 months. Most responders died due to the progression of extrahepatic lesions. HAI of the FEM regimen induced a high response rate in patients with hepatic metastases of gastric cancer, and the prognosis-determining factor was the existence of extrahepatic lesions in many patients.

[Clinical experiences of implantable vascular access device, "Vital Port" for arterial infusion chemotherapy].

We had the opportunity to use "Vital Port", a subcutaneous implantable vascular access port which was developed in the U.S. and has been used clinically in a multicenter study for clinical evaluation. To prevent the result from varying by facility, standardized criteria were made. The access port was implanted in 31 patients, and then intra-arterial infusion chemotherapy was performed. The follow-up period was 4 weeks. No complications were observed in any of the cases. Intra-arterial infusion chemotherapy was carried out without any problem. This port is lightweight and has good biocompatibility, and the clinical results were evaluated highly.

Intrahepatic interleukin-2 with chemotherapy for unresectable liver metastases: a randomized multicenter trial.

BACKGROUND/AIMS: A pilot study of Interleukin-2 (IL-2) with chemotherapy for unresectable colorectal liver metastases revealed a favorable response rate (76%). This prospective, randomized, multicenter study was conducted to evaluate the efficacy of this treatment protocol. METHODOLOGY: Over a period of 32 months, 46 patients with unresectable liver metastases were randomly assigned to 1 of 3 treatment groups: group A: chemotherapy alone, group B: chemotherapy plus high-dose, intermittent IL-2 (2.1 x 10(6) U twice weekly) or group C: chemotherapy plus low-dose, continuous IL-2 (7 x 10(5) U daily). Treatment continued for 4 weeks in the hospital and on an outpatient basis according to the clinical response. No crossover between treatment arms was permitted. RESULTS: IL-2 combined with chemotherapy produced a higher complete and partial response rate of 40% in group A, 60% in group B, and 78% in group C. Toxicity related to IL-2 included fever, chills, malaise, and eosinophilia. CONCLUSIONS: Hepatic arterial infusion of chemotherapy plus IL-2 resulted in an increased tumor response when compared with chemotherapy alone. To confirm the efficacy of this treatment protocol, we have started a large-scale, randomized, multi-institution trial.

[Evaluation by MR imaging of neoadjuvant intra-arterial infusion chemotherapy in uterine cervical cancer].

Eight patients with uterine cervical cancer received two or three courses of neoadjuvant chemotherapy, including 254-S i.v. and CDDP i.a. Transcatheter arterial embolization (TAE) was added for seven patients. The therapeutic efficacy was evaluated by MR imaging and postoperative histopathological examination. Three patients achieved a complete response (CR) and five others were evaluated as a partial response (PR) on MR imaging. On postoperative histology, three of eight showed CR or PR, which coincided with MR findings. Viable cancer cells were shown in five patients. To detect these viable tumors, dynamic MR imaging was indispensable. However, because of limited spatial resolution, the detection of small residual tumors was not easy using dynamic MR imaging.

[Arterial infusion of SMANCS-Lipiodol for advanced hepatocellular carcinoma].

Twenty-four patients were treated with arterial infusion of SMANCS dissolved in Lipiodol. Twenty of these patients had HCC with the main trunks of portal vein occluded by tumor, and four patients had severe cirrhosis and multiple HCC. The actual dose of SMANCS administered each patient ranged from 4 to 6 mg. Side effects occurred in 50%. Severe side effects such as shock and shivering-chilliness were observed in 18%. The differences between the values of hepatic functional serum indexes obtained before and after treatment with SMANCS were small and transient. With regard to the therapeutic response of the arterial infusion of SMANCS, the mean survival time was approximately 2.8 months. It was suggested that the more effective administration of SMANCS was combination of the arterial infusion of SMANCS-Lipiodol with TAE at the level of the right hepatic artery of left hepatic artery for multiple HCC.

Combination chemotherapy using intravenous nedaplatin (254-S) and intraarterial cisplatin (CDDP) with transcatheter arterial embolization (TAE) for a patient with uterine cervical cancer: a case report.

A 45-year-old Japanese woman with a bulky (75 x 40 mm) stage 2a uterine cervical cancer was treated with 87 mg (50 mg/m2) of nedaplatin (254-S) intravenously and 120 mg (70 mg/m2) of cisplatin (CDDP) intraarterially with transcatheter arterial embolization (TAE). She received three courses of this combination chemotherapy and showed a complete response, as confirmed by magnetic resonance imaging. A radical hysterectomy was performed and the pathological findings revealed the absence of carcinoma cells. This type of combination chemotherapy seems to be effective for the treatment of locally advanced uterine cervical cancer.

Determination of the optimum dose level of lipiodol in transcatheter arterial embolization of primary hepatocellular carcinoma based on retrospective multivariate analysis.

PURPOSE: Multivariate analysis was used to study the effectiveness and optimum dose level of Lipiodol (LP) in transcatheter arterial embolization (TAE) of hepatocellular carcinoma (HCC). METHODS: A total of 219 cases of nodular type HCC, with a tumor diameter less than 7 cm, were studied. TAE was performed using both Gelfoam sponge (GS) and LP in 158 cases; in the remaining 61 cases only GS was used. RESULTS: Statistical stepwise variable selection revealed that only LP had a negative T-value, suggesting that LP is a useful factor for prognosis. The most favorable effect on patient prognosis was obtained with an LP dose level (expressed in mm) of 1-1.5 times the absolute value of the tumor diameter (expressed in cm). CONCLUSION: A significant difference (p < 0.01, log-rank test) in survival was found between the GS with LP group and the GS only group, using Cox's proportional hazard model.

Outcome of localized hepatocellular carcinoma treated with segmental arterioportal chemoembolization.

When lipiodol is injected into the hepatic artery at a dose exceeding a certain level, it flows into the portal vein. On the basis of this feature, an emulsion of Adriamycin with lipiodol was injected into a segmental or subsegmental artery such that it was delivered to the portal vein of the same segment, and the artery was then embolized with Gelfoam. This segmental arterioportal chemoembolization (cement therapy) was performed in 50 patients with localized hepatocellular carcinoma. A posttreatment CT scan showed that almost 100% of the lesions were occupied by lipiodol. The cumulative survival values determined for the 50 patients were very high: 83.4% after 1 year and 62.7% after 2 years.

Effectiveness of Lipiodol in transcatheter arterial embolization of hepatocellular carcinoma.

The effectiveness of Lipiodol (iodized oil) in transcatheter arterial embolization (TAE) of hepatocellular carcinoma (HCC) was retrospectively evaluated using statistical analysis. A total of 343 HCC patients who underwent TAE at 5 institutions between 1984 and 1989 were divided into 2 groups: the GS-TAE group underwent TAE with Gelfoam sponge alone, whereas the LP-TAE group was given Lipiodol (LP) immediately before GS-TAE. The statistical T value calculated for the LP-TAE group showed that the administration of LP, the tumor size, intrahepatic metastasis, portal vein infiltration, and serum total bilirubin and alpha-fetoprotein levels significantly (P < 0.01) affected the patients' survival. Both the cumulative survival determined using the Kaplan-Meier model and the cumulative hazard calculated using Cox's proportional hazard model differed significantly (P < 0.01) between the GS-TAE group and the LP-TAE group (log-rank test). These results confirmed the effectiveness of LP used in combination with Gelfoam sponge for TAE of HCC.