Hyperthermia enhances tumor necrosis factor alpha-induced apoptosis of a human gastric cancer cell line

We have investigated the effects of hyperthermia on the apoptosis induced by tumor necrosis factor alpha (TNF-alpha). Confluent monolayers of human gastric cancer cell line MKN45 were either treated or untreated with hyperthermia for 1 h. The cells were subsequently stimulated with TNF-alpha. A 24-h incubation with TNF-alpha did not affect cell viabilities; however, pretreatment with hyperthermia significantly enhanced the level of apoptosis induced by TNF-alpha. Pretreating MKN45 cells with hyperthermia (42.0 degrees C) significantly inhibited the TNF-alpha-induced increase in the binding activity of NF-kappaB to DNA. This study suggests that hyperthermia can inhibit the TNF-alpha-induced NF-kappaB activation and that hyperthermia renders human gastric cancer cells susceptible to the TNF-alpha-induced apoptosis, possibly via inhibition of the NF-kappaB pathway.     

Nonoperative assessment of nodal status for locally advanced cervical squamous cell carcinoma treated by radiotherapy with regard to patterns of treatment failure

PURPOSE: Lymph node metastasis is a major prognostic factor in the treatment of cervical cancer, but its nonsurgical assessment is not necessarily accurate, particularly in small nodes. We evaluated whether node-negative status could be accurately assessed using a low cutoff measure. METHODS AND MATERIALS: The subjects were 84 patients with Stage IIB-IVA cervical squamous cell carcinoma treated by definitive radiotherapy. Nodal status was assessed by CT as negative (<5 mm), possibly positive (5-10 mm), or probably positive (>10 mm). Cause-specific survival and the disease-free rate, including the pelvic recurrence-free and distant metastasis-free rates, were estimated. RESULTS: The cause-specific survival, disease-free rate, and pelvic recurrence-free rate at 5 years were significantly higher for the 32 patients with node-negative disease (83.5%, 86.1%, and 86.1%) and the 17 patients with possibly node-positive disease (59.2%, 93.8%, and 93.8%) than for the 35 patients with probably node-positive disease (32.6%, 22.0%, and 46.8%), respectively. No significant difference was found between negative and possibly node-positive status. In contrast, the distant metastasis-free rate differed significantly among node-negative (96.4%), possibly node-positive (59.3%), and probably node-positive (35.1%) status. CONCLUSION: Node-negative status assessed using a strict cutoff measure may be useful as a strong predictor of cervical cancer being confined to the pelvis.     

Paclitaxel and carboplatin with or without pirarubicin (THP-ADR) as first line chemotherapy in elderly patients

To evaluate the validity of administration of paclitaxel and carboplatin with or without pirarubicin (THP-ADR) as first line chemotherapy in elderly patients with gynecologic cancer, we explored the efficacy and safety of these regimens. From October 1, 1998 to September 30, 2001, we administered paclitaxel and carboplatin with or without THP-ADR pursuant to the chart we prepared originally as first line chemotherapy in patients with gynecologic cancer. Eleven elderly patients (age > 70 years) and 62 younger patients (age < 70 years) were entered into the present study. Paclitaxel was administered as a 3-hour intravenous (i.v.) infusion at dosages of 135 to 180 mg/m2 immediately followed by carboplatin over 60 minutes at dosages of area under the curve (AUC) 3 to 5, administered intravenously or intraperitoneally. We observed grade 3/4 anemia more frequently in elderly patients receiving the regimen including paclitaxel and carboplatin without THP-ADR (9% v.s. 47%, p < 0.0001). Grade 3/4 anemia (10% v.s. 22%, p = 0.02) and grade 3/4 thrombocytopenia (7% v.s. 22%, p = 0.007), febrile neutropenia (14% v.s. 44%, p = 0.02) also occurred more frequently in elderly patients receiving the regimen including paclitaxel and carboplatin with THP-ADR. The overall response rates were equivalent among elderly and younger patients (69% and 78%), respectively. The regimen consisting of paclitaxel and carboplatin without THP-ADR was applied safely to elderly patients.     

Successful treatment with chemotherapy of vinorelbine and gemcitabine for an elderly patient with advanced non-small cell lung cancer

A 74-year-old man with non-small cell lung cancer was referred to our hospital for chemotherapy. On admission, he suffered from high fever and left upper back pain. Laboratory data showed marked leukocytosis and increased CRP. He was treated with chemotherapy of weekly vinorelbine and gemcitabine. After the second cycle, the levels of leukocytes and CRP were remarkably decreased, and the severe back pain was also alleviated. He has been given an additional 4 cycles as an outpatient. He is now doing well. This regimen seems to be effective in alleviating symptoms and improving QOL.     

Fas ligand-expressing tumors induce tumor-specific protective immunity in the inoculated hosts but vaccination with the apoptotic tumors suppresses antitumor immunity

The interaction between Fas and Fas ligand (FasL) is involved in the apoptotic death of a number of cells including lymphocytes. Forced expression of FasL in tumors can induce apoptosis of infiltrating Fas-positive T cells; accordingly, tumors can survive in the milieu of systemic immune responses. However, FasL-expressing murine lung carcinoma (A11) and melanoma (B16) cells did not develop subcutaneous tumors and FasL-expressing A11 (A11/FasL) cells produced few spontaneous lung metastatic foci in syngeneic mice. The mice that rejected A11/FasL cells were resistant to subsequent challenge of parent A11 but not irrelevant B16 cells. Vaccination of mice with UV-treated A11/FasL, but not UV-treated A11 cells, however, augmented the growth rate of A11 but not B16 tumors, both of which were subsequently inoculated. The number of lung metastatic foci of A11 cells was also increased in the mice that received UV-treated A11/FasL but not UV-treated A11 cells. Intraperitoneal injection of UV-treated A11/FasL cells resulted in the production of larger amounts of immunosuppressive TGF-beta in peritoneal exudate than that of UV-treated A11 cells. Expression of the CD80 costimulatory molecule in tissues where UV-treated A11/FasL cells were inoculated was lower than the expression at an untreated A11/FasL-injected site. Our results indicated that apoptotic FasL-expressing tumor cells could impair host immune responses against the tumors, in contrast to potent antitumor immunity generated by viable FasL-expressing tumors.     

Identification of the human IAI.3B promoter element and its use in the construction of a replication-selective adenovirus for ovarian cancer therapy

Little is known concerning promoters or gene therapy specific for ovarian cancer. To explore the potential use of IAI.3B isolated from ovarian cancer cells in gene therapy for ovarian cancer, we identified the promoter region of the IAI.3B gene and created a replication-selective adenovirus, AdE3-IAI.3B, driven by the promoter. Transient transfection experiments showed that the DNA segment located between -1816 and -1 bp resulted in preferential expression in ovarian cancer cells with negligible expression in squamous cell carcinoma and normal cells. The promoter activity of IAI.3B was almost the same as that of cytomegalovirus and an order of magnitude higher than those of midkine and cyclooxygenase-2 in ovarian cancer cells. AdE3-IAI.3B replicated as efficiently as the wild-type adenovirus and caused extensive cell killing in a panel of ovarian cancer cells in vitro. In contrast, squamous cell carcinoma and normal cells were not able to support AdE3-IAI.3B replication. In animal studies, AdE3-IAI.3B administered to flank and i.p. xenografts of ovarian cancer cells led to a significant therapeutic effect. These results demonstrate the usefulness of the IAI.3B promoter for generation of ovarian cancer-specific adenoviral vectors and provide a potential for the development of ovarian cancer-specific oncolytic viral therapies.     

Melanoma differentiation-associated gene 7/interleukin (IL)-24 is a novel ligand that regulates angiogenesis via the IL-22 receptor

The melanoma differentiation-associated gene 7 (mda-7), also called interleukin (IL)-24, suppresses the growth of some cancers in vitro and in vivo as a result of the ectopic expression of its protein. However, the function of the secreted form of the protein in cancer has not been previously studied. The purpose of this study was to determine the antiangiogenic function of a secreted form of the MDA-7/IL-24 protein (sMDA-7/IL-24). In vitro, sMDA-7/IL-24 inhibited both endothelial cell differentiation and migration of endothelial cells induced by vascular endothelial growth factor and basic fibroblast growth factor. The sMDA-7/IL-24-mediated inhibitory effect was 10-50 times more potent than endostatin, IFN-gamma, and IFN-inducible protein 10 in vitro. Furthermore, the inhibitory effect was not mediated by IFN or IFN-inducible protein 10. IL-22 receptor mediated the antiangiogenic activity of sMDA-7/IL-24. Administration of a blocking antibody to IL-22 receptor in conjunction with sMDA-7/IL-24 led to abrogation of inhibition of endothelial differentiation. sMDA-7/IL-24 inhibited vascular endothelial growth factor-induced angiogenesis as evidenced by reduced vascularization and hemoglobin content in in vivo Matrigel plug assays. In vivo, the growth of human lung tumor cells was significantly inhibited, and vascularization was reduced when the cells were mixed with 293 cells stably expressing sMDA-7/IL-24. Systemic administration of sMDA-7/IL-24 inhibited lung tumor growth in a mouse xenograft model. Associated with tumor growth inhibition was decreased tumor microvessel density and hemoglobin content, indicating the presence of antiangiogenic activity. These data demonstrate that sMDA-7/IL-24 is a novel and potent antiangiogenic effector and support the development of MDA-7/IL-24-based therapeutics.     

Measurement of fractional anisotropy using diffusion tensor MRI in supratentorial astrocytic tumors

In vivo, water diffusion displays directionality due to presence of complex microstructural barriers in tissue. The extent of directionality of water diffusion can be expressed as a fractional anisotropy (FA) value, using diffusion tensor MR imaging (DTI). The aim of this study was to determine whether FA values indicate microstructures in astrocytic tumors. We performed DTI in 31 patients with astrocytic tumor, and measured the FA values of tumor and normal brain regions prior to CT-guided stereotactic biopsy. After biopsy, FA values were compared to assess the cellularity and vascularity of tumor tissue. Although mean FA values trended to differ among histological types, all mean tumor FA values were lower than those of normal brain regions. Positive correlation was observed between FA values and both cellularity (r = 0.65, p < 0.05) and vascularity (r = 0.45, p < 0.05). We had hypothesized that the FA value of an astrocytic tumor would be determined by a balance between factors increasing the directionality of water diffusion, such as high cellularity and/or vascularity, and factors decreasing the directionality of water diffusion, such as fiber destruction. However, our results suggest that the FA values of glioblastoma, anaplastic astrocytoma, diffuse astrocytoma and pilocytic astrocytoma are largely affected by cellularity and/or vascularity, whereas that of gliomatosis cerebri are largely affected by the preservation of nerve fibers. Measurement of FA value using DTI will allow prediction of histological characteristics such as cellularity, vascularity and/or fiber structure in astrocytic tumors.     

Is whole-brain irradiation necessary for primary central nervous system lymphoma? Patterns of recurrence after partial-brain irradiation

BACKGROUND: Neurotoxicity after whole-brain irradiation remains a major problem in the treatment of primary central nervous system lymphoma (PCNSL). To clarify whether whole-brain radiation is necessary for PCNSL, the authors retrospectively analyzed the outcome of patients treated with partial-brain irradiation. METHODS: A nationwide survey was performed regarding the treatment of PCNSL. Among 62 institutions surveyed, 7 were identified in which whole-brain irradiation was not necessarily employed. Questionnaires were sent to these institutions and 43 patients who had been treated using partial-brain fields since 1985 were collected. Thirty-two patients had solitary lesions and 11 had multiple lesions. Patterns of recurrence could be identified in 38 patients. RESULTS: The cumulative in-field and out-field recurrence rates at 5 years were 57% and 49%, respectively. Of 14 out-field recurrences, 2 occurred at the safety margin of the previous radiation field. The out-field recurrence rate was 45% in patients with a single lesion and 67% in those with multiple tumors (P = 0.79). The out-field recurrence rate was 22% for patients treated with safety margins of > or = 4 cm and 83% for those treated with safety margins of < 4 cm (P = 0.0079). The median survival time and the 5-year survival rate were 28.5 months and 20%, respectively, in the former group of patients and 15 months and 11%, respectively, in the latter group (P = 0.057). CONCLUSIONS: Focal radiotherapy with safety margins of < 4 cm appears to be associated with a very high rate of out-field recurrence, but the use of a radiation field with generous safety margins (> or = 4 cm) appears to be worth further investigation.     

Increased expression of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 is correlated with poor prognostic variables in patients with thymic epithelial tumors

BACKGROUND: A distinction between noninvasive, invasive, and metastatic thymoma on the basis of the cytologic features is difficult. The current study investigated whether the expression of MMP and TIMP was correlated with tumor invasiveness and prognosis in patients with thymoma. METHODS: Tumor tissue samples were obtained from 42 patients with thymic epithelial tumors between 1974 and 2001 at Tokushima University Hospital. Three-micrometer-thick, formalin-fixed, paraffin-embedded tissue sections were immunostained using specific antibodies against MMP-2, MMP-9, TIMP-1, and TIMP-2. RESULTS: MMP-2 expression was detected in 30 tumors (71%), and TIMP-2 expression was detected in 31 tumors (74%). MMP-9 expression was detected in 22 of 36 tumors (61%), and TIMP-1 expression was detected in only 7 tumors (19%). MMP-2 and TIMP-2 expression levels were very low (10% and 0%, respectively) in noninvasive tumors but were very high (91% and 97%, respectively) in invasive tumors. In thymic epithelial tumors, the more progressive the clinical stage of tumor, the higher the strongly positive rate of MMP-2 and TIMP-2 expression. There was no correlation between positivity for MMP-9 and stage. Twenty-five percent of Type AB thymomas and 50% of Type B1 thymomas expressed MMP-2 and TIMP-2. Most of Type A, Type B2, Type B3, and Type C thymomas expressed MMP-2 and TIMP-2. There were significant differences in disease-free survival at 5 years between patients without and with MMP-2 expression (91% vs. 55%, respectively) and patients without and with TIMP-2 expression (100% vs. 53%, respectively). CONCLUSIONS: MMP-2 and TIMP-2 are key enzymes for invasiveness of thymic epithelial tumors. The expression of these proteins can predict a poor outcome in patients with thymoma.