[show abstract][hide abstract] ABSTRACT: Nedaplatin is a cisplatin derivative, which has similar activity to cisplatin in non-small-cell lung cancer (NSCLC) when combined with vindesine, and causes less nausea/vomiting and nephrotoxicity compared with cisplatin. The aim of this study was to evaluate the efficacy and safety of combination chemotherapy with docetaxel plus nedaplatin in patients with metastatic NSCLC.
Patients with metastatic stage IIIB excluding locally advanced diseases or stage IV NSCLC were enrolled between March 2004 and March 2006. They were treated with docetaxel (60 mg/m(2)) and nedaplatin (80 mg/m(2)) on day 1 every 3-4 weeks until progression or intolerable toxicity for up to 4 cycles.
Forty-four patients (mean age, 65 years; range, 40-79 years) received a total of 140 treatment cycles. Responses could be assessed in all patients (complete response, 0; partial response, 22; stable disease, 11; and progressive disease, 11). Response rate was 50.0 % (95 % confidence interval [CI], 35.2-64.8 %) with a disease control rate of 75.0 % (95 % CI, 62.2-87.8 %). A high response rate was achieved in patients with squamous cell carcinoma (66.7 %) compared with that in patients with adenocarcinoma (41.4 %). Median survival time from the start of the combination chemotherapy was 13.0 months, and the progression-free survival time was 7.4 months. Grade 3 or 4 hematologic toxicities included leukopenia (28.6 %) and neutropenia (61.4 %). Nonhematologic toxicities were mild.
The combination of docetaxel plus nedaplatin was well tolerated and demonstrated potent activity in patients with metastatic NSCLC, particularly squamous cell carcinoma of the lung.
Cancer Chemotherapy and Pharmacology 08/2012; 70(4):531-7. · 2.80 Impact Factor
[show abstract][hide abstract] ABSTRACT: In order to achieve sufficient therapeutic potency, it has been proposed that vaccine therapy with dendritic cells needs to be combined with manipulation of immunological checkpoints, such as inhibition of regulatory T cells and blockade of negative signals, and enhancement of T cell trafficking to tumor sites. In the combinatorial cancer immunotherapy, use of matured/activated dendritic cells (DCs) with more potent antigen presenting capacity seems to be essential for eliciting anti-tumor immune responses. We herein established an ex vivo induction strategy for activated DCs capable of eliciting efficient tumor antigen-specific cytotoxic T lymphocytes (CTLs) from patients with metastatic cancer as well as healthy donors. Immature DCs were matured by 48-h culture in the presence of anti-CD40 antibody and penicillin-killed streptococcus pyogenes (OK432). Supplementation with both anti-CD40 and OK432 resulted in induction of activated DCs with higher surface expression of CD80, CD83, CD86 and major histocompatibility complex class II antigens, compared with other mature DCs that were induced by the combination of anti-CD40 with tumor necrosis factor-alpha or lipopolysaccharide. In analysis of the produced cytokine profiles, the activated DCs produced the highest T-helper 1-type cytokines for at least 72 h. Furthermore, the activated DCs, pulsed with tumor-associated antigen peptide, elicited in vitro tumor-specific CTLs, but DCs activated with other combinations did not in cancer patients. Therefore, we suggest that the activated DCs studied here might be used as a basic element for the combinatorial cancer immunotherapy.
[show abstract][hide abstract] ABSTRACT: The aim of this study was to assess quantitatively the impairment of diaphragmatic motion after lung resection, with special reference to the location of the resected lobe, duration of the postoperative period, and patient posture. We used magnetic resonance imaging to make the assessments.
In 44 patients (29 men, 15 women; mean age 62.2 years) with lung cancer, diaphragmatic motion was measured during maximum deep, slow breathing using a spoiled gradient-recalled echo sequence before and after lung resection. The study group consisted of 34 patients who were examined using a 1.5-T unit in the supine position and 10 patients using a vertically open 0.5-T unit in both the sitting and supine positions. The influence of surgery site and patient posture on diaphragmatic motion after lung resection was investigated.
In all cases after lung resection, diaphragmatic motion on the operated side was significantly decreased (P < 0.001), and that on the nonoperated side was significantly increased (P = 0.045). After left upper lobectomy and right bilobectomy, the diaphragmatic motion on the operated side was significantly decreased (P < 0.001), and that of the other side was significantly increased (P < 0.001). The diaphragmatic motion was not significantly changed after right middle lobectomy. The diaphragmatic motion on the operated side was impaired significantly more (P = 0.035) in the supine position than in the sitting position.
After lobe resection, diaphragmatic motion was impaired more significantly in the supine than in the sitting position; and it differed according to the location of the resected lobe. The improvement in diaphragmatic function after lobectomy was observed over a period of 3-24 months.
[show abstract][hide abstract] ABSTRACT: We reported previously that pigeon cytochrome c-derived peptides (Pan-IA), which bind broad ranges of MHC class II molecules efficiently, activate T helper (Th) function in mice. In an experimental model, Pan-IA DNA vaccines augmented antitumor immunity in tumor antigen-immunized mice. To elicit more potent antitumor immunity and to eradicate tumors in a therapeutic setting, Pan-IA-loaded dendritic cells (DCs) were inoculated in combination with vaccines including ovalbumin (OVA) antigen DNA in tumor-bearing mice. Seventy percent of the immunized mice survived tumor-free for at least 4 months after treatment. In contrast, mice vaccinated with OVA DNA, either with or without naïve DCs, did not eliminate the tumors and died within 5 weeks. Only in mice vaccinated with OVA DNA and Pan-IA-loaded DCs were both cytotoxic and helper responses specific for OVA induced at the spleen and tumor sites as well as at the vaccination sites. Furthermore, accumulation of OVA-specific CD4(+) and CD8(+) T lymphocytes and interferon-gamma-mediated anti-angiogenesis were observed in the tumors of these mice. Thus, the combined vaccination primed both tumor-specific cytotoxicity and helper immunity resulting in augmented tumor lysis ability and anti-angiogenic effects. This is the first report to show that most established tumors were successfully eradicated by collaboration of potent antitumor immunity and anti-angiogenic effects by vaccination with tumor antigens and helper-activating analogs. This novel vaccination strategy is broadly applicable, regardless of identifying helper epitopes in target molecules, and contributes to the development of therapeutic cancer vaccines.
Cancer Immunology and Immunotherapy 04/2007; 56(3):331-42. · 3.64 Impact Factor
[show abstract][hide abstract] ABSTRACT: Bullous lung disease is known to be a risk factor for developing a bronchogenic carcinoma. In this article, computed tomography appearances of 20 patients with histologically proven bronchogenic carcinoma were reviewed retrospectively. On the basis of the previous literatures and our findings, the computed tomography appearances of bronchogenic carcinoma associated with bullous lung disease could be classified into 3 types; nodule or mass extruding from the bullous wall, nodule or mass confined within the bullous lumen, and soft-tissue density extending along the bullous wall. Attention should be paid in the interpretations for mass or nodule in the wall of the bulla because they frequently lack the characteristic appearances of bronchogenic carcinoma.
[show abstract][hide abstract] ABSTRACT: We present herein a rare case of bilateral pulmonary sclerosing hemangioma, for which a differential diagnosis was made from metastatic lung tumors. A 32-year-old asymptomatic woman was referred to our hospital for further evaluation of abnormal chest shadows. A chest computed tomogram revealed two round, well-circumscribed masses in both sides of the lungs. Metastatic lung tumors were suspected, however, a primary lesion was not detected by several examinations. Thus, simultaneous video-assisted thoracic surgery for the bilateral tumors was performed. The tumors, measuring 16x13x12 mm in the left lung and 27x24x20 mm in the right lung, were resected, and then pathological examination confirmed the diagnosis of sclerosing hemangioma. Her postoperative course was uneventful and she has been doing well without any sign of recurrence.
The Japanese Journal of Thoracic and Cardiovascular Surgery 04/2005; 53(3):157-61.
[show abstract][hide abstract] ABSTRACT: We previously reported that 90K/Mac-2 binding protein (M2BP) is highly expressed in lung cancer and that M2BP-specific immunity was observed in many patients with lung cancer. These findings suggested the possibility of using M2BP as a target antigen in cancer immunotherapy. In this study, we selected 11 peptides derived from M2BP with an HLA-A24 binding motif and analyzed their ability to induce M2BP-specific cytotoxic T lymphocytes (CTL). CTLs were generated with the M2BP-derived peptides from peripheral blood CD8-positive T lymphocytes of HLA-A24-positive healthy donors in multiple in vitro stimulations. Two CTLs, one induced with M2BP(241-250) (GYCASLFAIL) and the other with M2BP(568-576) (GFRTVIRPF), produced interferon-gamma in response to HLA-A24-positive TISI cells pulsed with the same peptide used for the in vitro stimulation. Although the CTLs induced with M2BP(241-250) reacted with both peptide-pulsed TISI cells and BT20 cells expressing both M2BP and HLA-A24, the CTLs induced with M2BP(568-576) did not react with BT20 cells. The cytokine production was blocked by antibodies against HLA class I in CTLs induced using M2BP(241-250), but not in CTLs induced using M2BP(568-576). These findings suggest that M2BP(241-250) is naturally processed from the native M2BP molecule in cancer cells and recognized by M2BP-specific CTLs in an HLA-A24 restriction. An M2BP-derived CTL epitope with an HLA-A24 binding motif was identified for the first time in this study, and it is expected to be useful as a target antigenic epitope in clinical immunotherapy for lung cancer.
International Journal of Oncology 01/2005; 25(6):1537-42. · 2.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: 90K/Mac-2 Binding Protein (M2BP) plays a role in regulation of immune responses and cell adhesive ability in patients with cancer and infectious diseases. We previously reported that M2BP was highly expressed in lung cancer and that immune responses to M2BP were increased in many patients with lung cancer. To determine the involvement of M2BP in metastatic processes of cancer progression, we examined the ability of M2BP DNA-transduced lung carcinoma cell lines to adhere to extracellular matrices. Although expressions of cell-surface integrins were not modulated in the M2BP transfectants, they showed increased adhesiveness to fibronectin and collagen IV. We next analyzed the serum levels of M2BP in patients with lung cancer and normal donors and the relationships between M2BP expression and clinicopathological factors in the patients. The M2BP level was markedly elevated in the patients and was strongly correlated with nodal involvement and clinical staging. To determine whether expression of M2BP by cancer cells is modulated in the environment of tumor-bearing hosts, M2BP expression in M2BP-positive QG56 cells following exposure of the cells to pro-inflammatory cytokines was examined. The M2BP expression in QG56 cells was up-regulated by many of the cytokines that activate host protective immunity. The findings in this study suggest that M2BP plays a role in cancer metastasis by increased adhesiveness of cancer cells and that M2BP is increasingly produced even in a state of exposure to the host immune system. This molecule may be useful as a predictive factor of disease progression in lung cancer.
[show abstract][hide abstract] ABSTRACT: We have previously reported that 90K/Mac-2 binding protein (M2BP) was highly expressed in lung cancer and that M2BP-specific immunity was observed in many of cancer patients. In this study, we analyzed the ability of 11 M2BP-derived oligopeptides with an HLA-A*0201-binding motif to induce M2BP-specific cytotoxic T lymphocytes (CTL) from peripheral blood lymphocytes of normal donors by in vitro stimulation. One of the CTLs that were induced using M2BP216-224 (RIDITLSSV) produced interferon-gamma in response to HLA-A2-positive T2 cells pulsed with the same peptide and lysed MDA-MB-231 cells expressing both M2BP and HLA-A2. The cytolytic activities were blocked by antibodies against HLA class I or CD8. These findings suggest that M2BP216-224 is naturally processed from the native M2BP in cancer cells and recognized by M2BP-specific CTLs in an HLA-A2 restriction. We first identified M2BP-derived CTL epitopes that may be useful as a target antigenic epitope in clinical immunotherapy of cancer.
Biochemical and Biophysical Research Communications 06/2004; 317(4):1089-95. · 2.41 Impact Factor
[show abstract][hide abstract] ABSTRACT: RB1-inducible Coiled-Coil 1 (RB1CC1) is a putative transcription factor that functions as a key regulator of retinoblastoma 1 (RB1). RB1CC1 mutations lacking this function are involved in the tumorigenesis of breast cancers. RB1CC1 is distributed in various tissues other than the breast, and is thought to play a biological role in controlling cell growth and progression of various cancers. The present study examined the correlation between RB1CC1 and cell cycle-related molecules in human neoplastic cells, and the ratios of cells at various phases of the cell cycle were verified in the RB1CC1-transduced human leukemic cell lines, K562 and Jurkat. The results showed that RB1CC1 was synchronously expressed with RB1 in various cell lines and that introducing RB1CC1 induced RB1 expression in human leukemic cell lines, although independently of the other molecules. Western blotting showed that underphosphorylated forms of RB1 were elicited by RB1CC1, whereas E2F1 was not affected. Cell cycle analysis demonstrated that G2-M phases were suppressed in RB1CC1-transduced cells. These data suggested that RB1CC1 induces the expression of RB1, especially of underphosphorylated forms, then suppresses cell cycle progression in human neoplastic cells.
International Journal of Molecular Medicine 12/2003; 12(5):767-9. · 1.96 Impact Factor
[show abstract][hide abstract] ABSTRACT: Vaccine immunotherapy must induce helper and cytotoxic cell-mediated immunity to generate the powerful antitumor immune responses needed to suppress cancer progression. We reported previously that a 16-amino acid peptide analogue derived from pigeon cytochrome c can bind broad ranges of MHC class II types and activate helper T cells in mice. To determine whether DNA encoding the Pan-MHC class II IA peptide (Pan-IA) can increase the efficacy of tumor suppression by DNA vaccine immunotherapy targeting tumor antigens, Pan-IA DNA was administered with ovalbumin (OVA) DNA to C57BL/6 mice bearing the OVA-expressing tumor cell line E.G7. Specific proliferative responses to and cytotoxic activities against OVA-expressing targets were induced in mice vaccinated with both OVA and Pan-IA DNA but not in those vaccinated with OVA DNA alone or control DNA plus Pan-IA DNA. Growth of E.G7 cells was suppressed only by combined vaccination with OVA and Pan-IA DNA, and tumors in five of the nine mice that received this combined vaccination were eradicated completely. In those mice, the frequency of CD8-positive T cells reactive with OVA(257-264) peptides in the context of H-2K(b) was significantly increased in the tumor site. Furthermore, immunofluorescent study of the inoculated tumors revealed increased accumulation of both CD4- and CD8-positive T cells producing IFN-gamma in the tumor only by this vaccine protocol. The data suggest that Pan-IA DNA can augment suppressive effects of DNA vaccines on tumor growth by increasing numbers of antigen-specific CTLs and helper T cells. This is the first study in which established tumors have been eradicated successfully by vaccination with DNA corresponding to CTL epitopes and helper T cell epitopes. Our animal model may contribute to the development of therapeutic DNA vaccines against cancer.
Cancer Research 12/2003; 63(22):7920-5. · 8.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: The use of dendritic cells (DCs) for cancer vaccination is effective in suppressing cancer progression. This is because the DCs play a crucial role in priming tumor-specific immunity efficiently as antigen-presenting cells. In this study, we analyzed the ability of DCs to elicit tumor-specific immunity and clinical effects of DC vaccine immunotherapy targeting MUC1 tumor antigens. DCs from 14 patients with advanced or metastatic breast or lung cancer (9 positive for MUC1 and 5 negative for MUC1) were loaded with MUC1 antigens or tumor lysate and used for therapeutic vaccination. After vaccination, all the MUC1-positive patients acquired antigen-specific immunity whereas only 1 case with MUC1-negative cancer showed the specific immunity. Clinically, marked effects such as reduction in tumor sizes or tumor marker levels or disappearance of malignant pleural effusion were observed in 7 of the 9 MUC1-positive cases. However, MUC1-negative patients did not respond to DC vaccines, with the exception of 1 case with MAGE3-positive lung cancer. Survival of MUC1-positive patients was significantly prolonged in comparison with MUC1-negative patients (mean survival: 16.75 versus 3.80 months, p=0.0101). These data suggest that MUC1 is sufficiently immunogenic to elicit strong anti-tumor immunity as a tumor antigen and that DC vaccines targeting MUC1 are useful for immunotherapy of cancer.
International Journal of Molecular Medicine 11/2003; 12(4):493-502. · 1.96 Impact Factor