[A case of carcinoma with sarcomatoid elements in the middle mediastinum].

We describe a 63-year-old man who, while under treatment as an outpatient for adult onset Still's disease (AOSD), developed edema of the extremities and mediastinal tumor was observed on a chest X-ray film and a chest CT scan. He was not pathologically diagnosed at first and received radiation therapy with a total dose of 30 Gy. Transbronchial biopsy was carried out because the tumor enlarged, and the tumor invasion was observed in the left lumen of the main bronchus. Histological findings suggested a diagnosis of carcinoma with sarcomatoid elements (CSE). Further radiation therapy with a dose of 20 Gy was unsuccessful; his condition gradually worsened and the patient died. The autopsy findings demonstrated that CSE developed in the middle mediastinum, and the other organs were not involved. From an embryologic standpoint, there seemed to be some possible differential diagnoses, such as a pleomorphic carcinoma as a subtype of lung cancer, and CEA as a metastatic mediastinal lymph node cancer of unknown origin or a primary mediastinal lymph node cancer. Like the present case, tumors developed in the middle mediastinum with rapid progression are rare. We report a case, that was difficult to diagnose and treat.

Immunological evaluation of CTL precursor-oriented vaccines for advanced lung cancer patients.

Recent clinical trials of peptide vaccine for cancer patients have rarely resulted in tumor regression. One of the reasons for this failure could be an insufficient induction of anti-tumor responses in these regimens, in which peptide-specific memory cytotoxic T lymphocytes (CTLs) were not measured prior to vaccination. We investigated in this study whether pre-vaccination measurement of peptide-specific CTLs can provide any advantages in lung cancer patients receiving peptide vaccination with regard to safety and immunological responses. Ten patients with advanced lung cancer received vaccination with peptides under a regimen of CTL precursor-oriented vaccination, in which pre-vaccination peripheral blood mononuclear cells (PBMCs) were at first screened for reactivity in vitro to each of 14 peptides, followed by in vivo administration of only the reactive peptides. Profiles of the vaccinated peptides varied markedly among the 10 patients. This regimen was generally well-tolerated, although local skin reactions, diarrhea, and colitis were observed in 8, 2, and 1 patient, respectively. Increased CTL responses against the immunized peptides and tumor cells were observed in the post-vaccination PBMCs from 4 of 8 and 3 of 10 patients tested, respectively. Peptide-specific IgG became detectable in post-vaccination sera in 4 of 10 patients tested, and these 4 patients had a long progression-free survival. Furthermore, the median survival time of 9 patients with non-small cell lung cancer was 668.0 +/- 164.2 days. These results encourage further development of CTL precursor-oriented peptide vaccination for lung cancer patients.

Phase 1 clinical study of cyclophilin B peptide vaccine for patients with lung cancer.

Cyclophilin B (CypB) possesses two antigenic epitopes (CypB(84-92) and CypB(91-99) ) recognized by HLA-A24-restricted and tumor-specific cytotoxic T lymphocytes (CTLs). To determine the safety of CypB-derived peptides and its ability to generate antitumor immune responses, patients with advanced lung cancer received subcutaneous vaccinations of these peptides or their modified peptides. All 16 patients were vaccinated with CypB(91-99) or its modified peptide, whereas only two patients were vaccinated with the modified CypB(84-92), as immediate-type hypersensitivity to CypB(84-92) or its modified peptide was observed in the remaining patients. No severe adverse events were associated with the vaccination. No significant increase in cellular responses to either peptides or tumor cells was observed in the postvaccination PBMCs by the conventional CTL assays in any patients tested. These results suggest that the vaccination of CypB(91-99) peptide was safe, but failed to induce objective immune responses at this regimen.

Elevation of serum MAGE-4 protein levels and prediction of hepatocellular carcinogenesis in patients with liver cirrhosis.

Early detection of hepatocellular carcinoma (HCC) is clinically important because advanced HCC limits treatment modalities for the cancer. We have previously reported that serum levels of MAGE-4 protein are strongly associated with the development of HCC. The present study was designed to determine whether elevated serum MAGE-4 protein levels can predict hepatocellular carcinogenesis in patients with liver cirrhosis before clinical diagnosis. Among 62 cirrhotic patients, 28 patients were diagnosed with HCC during the follow-up period. The levels of MAGE-4 protein and alpha-fetoprotein (AFP) were significantly elevated in cirrhotic patients with HCC. Univariate and multivariate analyses suggest that elevated serum MAGE-4 protein is more significant than AFP. Importantly, retrospective analysis of prefrozen sera of cirrhotic patients revealed a transient or continuous elevation of serum MAGE-4 protein levels in 14 of 28 cirrhotic patients with HCC (50%) before clinical diagnosis. In contrast, elevated serum MAGE-4 protein levels were observed in 3 of 33 cirrhotic patients without HCC (9%), and in 2 of 34 hepatitic patients (6%). These results indicate that elevated serum MAGE-4 protein levels can be a predictive marker of hepatocellular carcinogenesis in cirrhotic patients, thereby enabling us to treat patients at an earlier stage.

Cleavage and polyadenylation specificity factor (CPSF)-derived peptides can induce HLA-A2-restricted and tumor-specific CTLs in the majority of gastrointestinal cancer patients.

To identify CTL-directed antigens in gastrointestinal cancer, we have investigated antigens recognized by the HLA-A2-restricted CTL line established from T cells infiltrating into colon cancer and report herein cleavage and polyadenylation specificity factor (CPSF) as a potent antigen holding peptides capable of inducing CTLs. Five peptides at amino acid positions 250-258, 392-400, 534-542, 1296-1304 and 1359-1368 of CPSF, which were recognized by the CTL line, were found to have the ability to induce HLA-A2-restricted and tumor-specific CTLs in peripheral blood mononuclear cells of the majority (69%, 11/16) of gastrointestinal cancer patients with different HLA-A2 subtypes. Thus, these peptides might be appropriate molecules for use in the peptide-based specific immunotherapy of HLA-A2(+) patients with gastrointestinal cancers.

Serine proteinase inhibitor 9 can be recognized by cytotoxic T lymphocytes of epithelial cancer patients.

Serine proteinase inhibitor 9 (PI-9) inhibits granzyme B-mediated apoptosis and interleukin-1beta-converting enzyme activity. In this study, we report that the PI-9 gene encodes antigenic epitopes recognized by the HLA-A24-restricted and tumor-reactive cytotoxic T lymphocytes (CTLs) of epithelial cancer patients. Screening of an autologous cDNA library using a CTL line recognizing HLA-A24+ tumor cells resulted in the isolation of a cDNA, which had an identical coding region to the previously described PI-9 genes. PI-9 gene was expressed in approximately three-fourths of epithelial cancer cell lines and all leukemic cell lines tested. It was also expressed in normal peripheral blood mononuclear cells (PBMCs), but not in a normal fibroblast cell line. CTL sublines contained T cells capable of recognizing the PI-9(292-300) and PI-9(348-356) peptides among 13 different peptides having the HLA-A24 binding motifs. These two peptides were recognized by the CTL line in a dose-dependent and HLA class-I-restricted manner, and also possessed the ability to induce HLA class I-restricted and tumor-reactive CTLs in PBMCs from HLA-A24+ cancer patients. These results demonstrate that PI-9 is recognized by HLA class I-restricted and tumor-reactive CTLs of epithelial cancer patients.