Advanced glycation end-products increase IL-6 and ICAM-1 expression via RAGE, MAPK and NF-κB pathways in human gingival fibroblasts.

BACKGROUND AND OBJECTIVES: Diabetes mellitus (DM) is a risk factor for periodontal diseases and may exacerbate the progression of the pathogenesis of periodontitis. Advanced glycation end-products (AGEs) cause DM complications relative to levels of glycemic control and larger amounts accumulate in the periodontal tissues of patients with periodontitis and DM. In the present study, we investigated the effects of AGEs on the expression of inflammation-related factors in human gingival fibroblasts (HGFs) to elucidate the impact of AGEs on DM-associated periodontitis. MATERIAL AND METHODS: HGFs were cultured with or without AGEs. Cell viability was examined, and RNA and protein fractions were isolated from AGE-treated cells. The expression of interleukin (IL)-6, intercellular adhesion molecule-1 (ICAM-1), and the receptor for AGE (RAGE) was investigated using reverse transcription-polymerase chain reaction, quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay, and reactive oxygen species activity was measured using a kit with 2',7'-dichlorofluorescin diacetate. Human monocytic cells (THP-1) labeled with a fluorescent reagent were co-cultured with HGFs treated with AGEs and IL-6 siRNA, and the adhesive activity of THP-1 cells to HGFs was assessed. The expression of IL-6 and ICAM-1 was examined when HGFs were pretreated with recombinant human IL-6, the siRNAs of RAGE and IL-6, and inhibitors of MAPK and NF-κB, and then cultured with and without AGEs. The phosphorylation of MAPK and NF-κB was assessed using western blotting. RESULTS: AGEs increased the mRNA and protein expressions of RAGE, IL-6, ICAM-1 and reactive oxygen species activity in HGFs, and promoted the adhesion of THP-1 cells to HGFs, but had no effect on cell viability until 72 hours. Recombinant human IL-6 increased ICAM-1 expression in HGFs, while the siRNAs of RAGE and IL-6 inhibited AGE-induced IL6 and ICAM1 mRNA expression, and IL-6 siRNA depressed AGE-induced THP-1 cell adhesion. AGEs increased the phosphorylation of p38 and ERK MAPKs, p65 NF-κB and IκBα, while inhibitors of p38, ERK MAPKs and NF-κB significantly decreased AGE-induced IL-6 and ICAM-1 expression. CONCLUSION: AGEs increase IL-6 and ICAM-1 expression via the RAGE, MAPK and NF-κB pathways in HGFs and may exacerbate the progression of the pathogenesis of periodontal diseases.

YKL-40 level in gingival crevicular fluid from patients with periodontitis and type 2 diabetes.

OBJECTIVE: YKL-40 is a chitin-binding glycoprotein, the level of which increases in inflammatory diseases, diabetes mellitus (DM), cardiovascular diseases, and tumors. Gingival crevicular fluid (GCF) contains many proteins and markers of periodontitis. The purpose of this study was to investigate YKL-40 level in GCF from patients with periodontitis and DM and the association between YKL-40 level and chronic periodontitis (CP) or DM. SUBJECTS AND METHODS: The subjects were 121 patients with DM, CP, DM and periodontitis (DM-P), and healthy subjects (H). GCF was collected using paper strips after the sites for GCF collection were clinically evaluated for probing depth (PD), gingival index (GI), and bleeding on probing (BOP). YKL-40 in GCF was identified by Western blotting, and its level was determined by ELISA. RESULTS: YKL-40 was contained in GCF samples from H, DM, CP, and DM-P sites, and its levels (amount and concentration) in CP and DM-P were significantly higher than those in H and DM. GCF YKL-40 level significantly correlated with PD and GI, and its level in BOP-positive sites was significantly higher than that in BOP-negative ones. CONCLUSIONS: GCF YKL-40 level was elevated in periodontitis, but not DM. YKL-40 in GCF may be an inflammatory marker for periodontitis.

Radiation therapy for advanced gastric cancer.

A retrospective study of 75 patients with advanced inoperable gastric cancers, referred to the National Cancer Center Hospital between 1962 and 1982, was performed. According to the Borrmann classification based on X ray findings, Type 1 was found in 3 patients, Type 2 in 5, Type 3 in 40, and Type 4 in 15. Twelve patients could not be classified. The histological type was papillary adenocarcinoma in 7 patients, tubular adenocarcinoma in 23, mucinous carcinoma in 6, poorly differentiated adenocarcinoma in 14, signet ring cell carcinoma in 12 and others in 13. The site of remote metastasis in 19 patients was Virchow's lymph node in 8 patients, Douglas pouch in 3, liver and lung in 2 each and others in 4. All patients were treated by a either telecobalt 60 unit or a linear accelerator using 6 Mv photon and the total dose to primary lesion was 4000 cGy in 5 weeks to 7000 cGy in 8-9 weeks. Complete response (CR) was achieved in 6 patients or 8.0%, partial response (PR) in 46 or 61.3%, and no change (NC) in 23 or 30.7%. The response rate based on the sum of CR and PR was about 70%. The 50% survival period in months was 26.5, 7.3, and 3.2, respectively for patients with CR, PR, and NC. For the response of advanced gastric cancer to chemotherapy in the National Cancer Center Hospital, the combined use of UFT and Mitomycin C gave the highest rate, 46%. As for as local response is concerned, the response rate to radiation was 70%, a better result than that of chemotherapy alone.

Hyperthermic therapy of deep seated tumors: comparison of the heating efficiencies of an annular array applicator and a capacitively coupled radiofrequency system.

Among 82 cases of deep seated tumors treated by hyperthermia with an annular array applicator (AA) and/or a capacitively coupled 8 mHz system (CCS) combined with radiation therapy, 13 cases were treated by both devices. The efficiencies of tumor heating were compared in terms of the time required to attain 42 degrees C, the duration of heating time and the thermal dose as determined by a biological iso-effect formula for equivalent minutes at 42.5 degrees C. Temperature profiles and percent of temperature levels greater than 42 degrees C were better in the cases treated by the AA, but higher thermal doses were obtained with the CCS because longer treatment times were tolerated with the CCS than with the AA. Methods are necessary to prevent excess elevation of body temperature in the case of the AA, and to reduce superficial pain where the applicators contact the skin in the case of the CCS.

Radiotherapy of brain metastases.

The effect of radiotherapy in 254 cases of brain metastases, treated between 1977 and 1984, were studied. The cases included 141 of lung cancer, 28 of mammary cancer, and 85 of other primary sites. The percentages of patients with improvement in clinical symptoms were 8, 39, and 66, respectively. These were groups of patients irradiated with less than 30 Gy, 30 Gy to 50 Gy, and more than 50 Gy. The 50% survival periods from the start of irradiation for the last group were as follows: for radiotherapy only, 4.1 months, radiotherapy and surgery, 4.2 months, radiotherapy and chemotherapy combined, 6.9 months, radiotherapy, surgery and chemotherapy combined, 12.1 months. The intervals between the initial diagnosis and brain metastases were different in lung cancer and mammary cancer, but the prognosis after brain metastases showed little difference between them.

Dose equivalence for high-dose-rate to low-dose-rate intracavitary irradiation in the treatment of cancer of the uterine cervix.

By comparing the incidence of major radiation injury, we estimated doses clinically equivalent for high-dose-rate (HDR) to conventional low-dose-rate (LDR) intracavitary irradiation in patients with Stages IIb and IIIb cancer of the uterine cervix. We reviewed a total of 300 patients who were treated with external beam therapy to the pelvis (50 Gy in 5 weeks) followed either by low-dose-rate (253 patients) or high-dose-rate (47 patients) intracavitary treatment. The high-dose-rate intracavitary treatment was given 5 Gy per session to point A, 4 fractions in 2 weeks, with a total dose of 20 Gy. The low-dose-rate treatment was given with one or two application(s) delivering 11-52 Gy to the point A. The local control rates were similar in both groups. The incidence of major radiation injury requiring surgical intervention were 5.1% (13/253) and 4.3% (2/47) for low-dose-rate and high-dose-rate groups, respectively. The 4.3% incidence corresponded to 29.8 Gy with low-dose-rate irradiation, thus, it was concluded that the clinically equivalent dose for high-dose-rate irradiation was approximately 2/3 (20/29.8) of the dose used in low-dose-rate therapy.

Carcinoma of the uterine cervix treated with external irradiation alone.

One hundred and four out of 2701 patients with carcinoma of the uterine cervix were treated with a curative intent by external irradiation alone at the National Cancer Center Hospital from 1962 to 1979. All patients were judged inappropriate for the combined treatment of intracavitary and external irradiation, which was the treatment of choice for patients with advanced carcinoma of the uterine cervix in the hospital. The 5-year survival rate was 17% overall and 36, 17, and 5% for patients with Stage II, III, and IV disease, respectively. The local control rate was 20%, at 2 years, for all patients. Major complications were observed in five patients. There were no major complications in patients given a total dose of less than 115 in the Time Dose Fractionation factor (TDF). External irradiation combined with interstitial irradiation and/or hyperthermia is being considered to improve the results.

High-dose-rate intracavitary irradiation in the treatment of carcinoma of the uterine cervix: early experience with 84 patients.

Eighty-four patients with previously untreated invasive carcinoma of the uterine cervix were treated by high-dose-rate intracavitary irradiation using a remotely controlled afterloading system (Ralstron) with or without external irradiation at the National Cancer Center Hospital, Tokyo, between 1977 and 1981. Survival rates and local control rates were comparable to those for 372 patients treated by low-dose-rate intracavitary irradiation with or without external irradiation from 1972 to 1981 at the hospital. The incidence of major complications was 5.1 and 2.4% for the patients treated by low-dose-rate intracavitary irradiation and by high-dose-rate irradiation, respectively. The results are comparable to those reported by other institutions. We have abandoned the conventional low-dose-rate intracavitary irradiation with the impression that the high-dose-rate remotely controlled afterloading system is a good alternative to the conventional one.

Multi-fractionated wide-field radiation therapy for palliation of multiple symptomatic bone metastases from solid tumors.

PURPOSE: This was a pilot study to explore the toxicity and response of multi-fractionated wide-field radiation therapy (MF-WFRT) in patients with multiple symptomatic osseous metastases. PATIENTS AND METHODS: From February 1997 to April 1998, a total of nine patients (5 lung cancer, 3 breast cancer, 1 prostate cancer) were treated with MF-WFRT. The patients received 1.5 Gy per fraction (twice a day) to a total dose of 7 Gy in 3 days for the upper body and a total dose of 9 Gy in 3 days for the lower body. Ten treatments in nine patients were carried out with this technique (2 upper half-body, 5 lower half-body, 3 mid-body; one patient had both upper mid-body and lower-half body treatments). RESULTS: Pain relief was complete in two patients (20%) and eight (80%) achieved better than 50% pain relief. Seventy-five percent of pain responders achieved pain relief within one week of MF-WFRT. The pain relief was long-lasting and continued without need of reirradiation for 45% of the remainder of the patients' lives. The incidence of gastrointestinal complications was low, basically Grade 1-2 toxicity. Four patients (40%) experienced Grade 3-4 hematological toxicity. Hematological toxicity was treated with blood transfusion or G-CSF. General tolerance was excellent, and no pneumonitis or radiation-related deaths occurred. CONCLUSION: This treatment modality appears to be well tolerated and effective. The optimal indications, dose, and fractionation for MF-WFRT should be further explored in randomized studies.

Ir-192 brachytherapy by an afterloading technique: initial experience at the National Cancer Center Hospital, Tokyo.

Twenty-nine patients with various tumors treated by 192Ir brachytherapy at the National Cancer Center Hospital from 1977 to 1984 were reviewed. Of 10 patients with carcinoma of the extrahepatic bile duct, three with carcinoma of the urinary bladder, and three others with various tumors, none showed locally controlled disease. Two of six patients with recurrent brain tumor, three of five with skin tumor and two with carcinoma of the female genital tract showed locally controlled disease. Although the effectiveness of this mode of treatment needs to be more clearly demonstrated, it is easily applied to clinical practice and is at least as effective as radium 262 implantation.

Suppression of bony growth of the orbit after radiotherapy for retinoblastoma.

Suppression of the growth of orbit and skull in 13 retinoblastoma patients treated by radiotherapy was investigated. The age of patients at the time of treatment ranged from 1 month to 6 years and 11 months. They were examined after three to 18 years. Suppression of the growth in involved areas and other parts of the skull within the beam of radiation were estimated by inspection, X-ray findings, and X-CT examinations. The involved orbit received more than 32 Gy, and the suppression of bone growth was prominent. At the opposite temporal bone, suppression of growth was prominent in eight cases out of 11, in these cases, the radiation dose was at least 14 Gy. Two cases, in whom the radiation dose was less than 12.6 Gy, have not shown any suppression of bony growth. Results were also obtained for a nominal single dose (ret). In all cases of more than 1,000 ret, suppression was prominent, but at less than 1,000 ret, four out of nine cases, and at less than 600 ret, two out of four cases showed suppression of bony growth. If the safety dose to avoid the suppression of bony growth is 400 ret, this is equivalent to three times the radiation dose of 200 cGy. In conclusion, the suppression of bony growth of the orbit and temporal area of the skull of young patients is caused by very small doses of radiation.

Local effect of hyperthermia for superficial and shallow-seated tumors.

In approximately seven years, 134 patients with 161 tumors were treated by hyperthermia combined with radiation or chemotherapy at our department. The primary tumors were breast cancer, head and neck cancer, and soft tissue tumors in most patients. Adenocarcinoma was the most frequent, followed by squamous cell carcinoma and soft tissue sarcoma. The local response rates for primary inoperable advanced, metastatic, and local recurrence of breast cancer were 88% (7/8), 50% (10/15), and 86% (18/21), respectively. The local response rate of 39 tumors of neck lymph nodes was 49% (19/39). A total of 26 tumors of bone and soft tissue were treated. Five tumors showed CR and six PR, for a total response rate of 42%. Among 20 patients with malignant melanoma, CR and PR were 25% (5/20) and 30% (6/20), respectively. The local response rate for all patients with superficial and shallow-seated tumors was 58% (94/161). In some tumors classified as showing NR, complete disappearance of tumor cells was demonstrated by a post-treatment histological examination. The efficacy of hyperthermia, when evaluated solely on the basis of tumor size, is likely to be underestimated.

A comparison of swine abdominal temperature distribution after heating with BSD-1000, an annular phased array system (APAS), and Thermotron RF-8.

External hyperthermia for deep-seated tumors is still a difficult problem. We compared the abdominal temperature distribution in a pig after heating with BSD-1000, an annular phased array system (APAS), and Thermotron RF-8. Thirty elastic tubes were inserted into the upper abdomen of the pig and a thermocouple was inserted into each of the tubes. After heating, these thermocouples were moved at 1-cm intervals and the three-dimensional temperature distribution was obtained. The temperature distribution after heating with APAS and Thermotron RF-8 was compared by using the distribution on the longitudinal center line of each sagittal plane at 1-cm intervals from the center. The temperature was much higher and its distribution more homogeneous with APAS than Thermotron RF-8.

Classification of the 16,471 patients treated by radiation therapy from 1962 to 1986, and crude five-year survival rates of patients in each category of radiotherapy treatment from 1962 to 1978 in the National Cancer Center Hospital.

The summation and classification of patients registered for planned radiation therapy in the 24-year period from 1962 to 1986, in the Department of Radiation Therapy, National Cancer Center Hospital, are reported. Patients numbered 16,471, and total sessions of treatment were 26,175. The ratio of the two figures, 1.58, is the average number of treatment sessions per patient. Peak age was 61-65 years' old and 56-60 years old, respectively for males and females. The most frequent primary site of disease for radiation therapy was the head and neck, followed by trachea, bronchus and lung, crevix uteri, breast, and esophagus. Frequency of squamous cell carcinoma was 38.0%; that of adenocarcinoma was 20.9%. Radical treatment was performed in 32.0% of patients in the first session, but this figure decreased to 24.7% for all sessions. There were many cases of secondary and primary palliative treatment, i.e., 31.8%. Radiotherapy was done in 70% of patients by megavoltage X-ray, with 9.4% treated by electron beam. Crude 5-year survival rates for each classification of malignant disease respective to the category of treatment policy from 1962 to 1978 were obtained. Among the radical treatment group, head and neck tumors, skin cancer, and Hodgkin's disease showed 5-year survival rates greater than 50%.

[Alteration of gamma-aminobutyric acid in streptozotocin-induced diabetic rat retina].

To elucidate possible alteration of gamma-aminobutyric acid (GABA) in the diabetic retina, the distribution and determination of GABA was analyzed in streptozotocin-induced diabetic and normal rats after electroretinogram (ERG) recording. Immunoreactivity of GABA was found in the inner nuclear layer, inner plexiform layer, and ganglion cell layer in normal and diabetic rats. In the inner nuclear layer, strong immunoreactivity of GABA was found in amacrine-like cells. In diabetic retinas, GABA immunoreactivity was higher than in normal retinas. The contents of GABA increased began 1 week after occurrence of diabetes mellitus, attained a maximum at 2 months, and maintained this amount for 5 months. The latencies of oscillatory potentials of ERG were prolonged beginning 1 month after occurrence. These results suggest that increase of GABA in the amacrine cells of diabetic retinas may be related with the abnormality of oscillatory potentials.

[Stage IV renal cell carcinoma producing alpha-fetoprotein treated with multimodal treatment. A case report].

A 63 year old man, having right renal cell carcinoma which was found after initial symptoms of left supraclavicular tumor and gross hematuria, is presented. The points to note with this case are; (1) An unusual production of alpha-fetoprotein (AFP), (2) Being discovered at a very advanced stage and that the disease progressed rapidly (at initial presentation the patient had lymph nodes metastases from the paraaorta, mediastinum to the left supraclavicular region. Later the patient had a recurrent tumor in the left supraclavicular area and multiple cutaneous metastases), (3) Various modalities of treatment were given (right nephrectomy, abdominal lymph nodes dissection, resection of the supraclavicular and mediastinal lymph nodes metastases, hyperthermia combined with irradiation for the recurrent tumor in the supraclavicular region and systemically adoptive immunotherapy with tumor infiltrating lymphocytes). During this treatment course, the drift of serum AFP showed a good correlation. The possibility of AFP as a tumor marker of renal cell carcinoma in selected cases was presented and the suitability of the treatments performed to this patient was discussed.

[Surgery for thymomas and thymic carcinomas; treatment results in terms of WHO histologic typing, Masaoka staging system, and p53 expression].

Forty thymomas and thymic carcinomas were classified in terms of WHO histologic typing, Masaoka staging system, and p53 expression. In WHO histologic typing, type A, AB, B1, B2, B3, and C were 1, 10, 16, 5, 4, and 4 cases, respectively. In Masaoka staging system, I, II, III, and IV were 15, 9, 10, and 6 cases, respectively. Thirteen thymomas exhibited positive p53 expression and 27 did not. Type A and AB thymomas had more favorite prognosis than type B3 and C thymomas, and prognosis of type B1 and B2 was middle. Staging by the Masaoka system also correlated with survival rates. Patients who had p53-negative thymomas survived longer than those who had p53-positive thymomas. A treatment strategy for thymomas and thymic carcinomas should be made on the basis of WHO histologic typing, Masaoka staging system, and p53 expression.

[Hyperthermia in bone and soft tissue tumors].

Local response of hyperthermia for soft tissue and bone tumors was investigated. Ten tumors were superficial tumors and 16 were deep seated tumors; 9 tumors were malignant fibrous histiocytoma, 5 were liposarcoma, 4 were neurogenic and 3 were myogenic sarcoma. The other five tumors were an angiosarcoma, a malignant mesenchymoma, an Ewing's sarcoma, a chordoma and an osteosarcoma. Some 23 tumors were heated in combination with radiation therapy, and 3 were combined with arterial infusion of ADR. Four of 10 superficial tumors disappeared (CR), and, 2 of 10 signified PR. Only one of 16 deep seated tumors showed CR, 3 were PR and 12 showed no response. But 4 of 12 tumors without regression in tumor volume indicated coagulation necrosis owing to histological examinations, and 5 of 12 were regarded as the same response from hypodensity area with CT examination after hyperthermia. Local response rate of of superficial tumors was 60% and that of deep-seated tumors was 81.4%.

[A case of advanced gastric cancer with liver metastasis with no recurrence and long survival].

A 61-year-old male was admitted after detecting gastric lesion by gastrography in a medical health examination. The patient was diagnosed as Borrmann 2 advanced gastric cancer with remarkable intraperitoneal lymph node metastasis and liver tumor of lateral segment. Relative non-curative gastrectomy was performed with combined partial hepatectomy. The liver tumor measured 1.5 x 1.5 cm and was intraoperatively diagnosed as metastasis of gastric cancer. Mitomycin C 26 mg was given intravenously on the day of operation and 5-fluorouracil (5-FU) 150 mg/day orally since postoperative 14th day as adjuvant chemotherapy. The administration of 5-FU was continued for 5 years. As a result of such combination therapy, the patient still has had no recurrence 8 years following operation.

[Effect of intraperitoneal therapy in gastric cancer with peritoneal dissemination].

Eighty gastric cancer patients with peritoneal dissemination were analyzed to evaluate the effect of intraperitoneal chemo- and/or immunotherapy on abdominal ascites. Among them, 19 were treated with intraperitoneal chemo- and/or immunotherapy, and 21.1% of them showed decreased ascites and better QOL. Patients treated with intraperitoneal administration with OK-432 showed good survival. Among patients with OK-432 administration, those receiving postoperative chemotherapy showed better survival than those given immunochemotherapy. Conversely, among patients with chemotherapy, those given postoperative immunochemotherapy showed better survival than those on chemotherapy. Patients with HLA-type I and III, and those with preoperative normal immune status showed good response when they received intraperitoneal therapy.