Yasuhiro Mizushima

Phase I clinical study of anti-apoptosis protein, survivin-derived peptide vaccine therapy for patients with advanced or recurrent colorectal cancer.

Survivin is a member of the inhibitor of apoptosis protein (IAP) family containing a single baculovirus IAP repeat domain. It is expressed during fetal development but becomes undetectable in terminally differentiated normal adult tissues. We previously reported that survivin and its splicing variant survivin-2B was expressed abundantly in various types of tumor tissues as well as tumor cell lines and was suitable as a target antigen for active-specific anti-cancer immunization. Subsequently, we identified an HLA-A24-restricted antigenic peptide, survivin-2B80-88 (AYACNTSTL) recognized by CD8+ cytotoxic T lymphocytes (CTLs). We, therefore, started a phase I clinical study assessing the efficacy of survivin-2B peptide vaccination in patients with advanced or recurrent colorectal cancer expressing survivin. Vaccinations with survivin-2B peptide were given subcutaneously six times at 14-day intervals. Of 15 patients who finished receiving the vaccination schedule, three suffered slight toxicities, including anemia (grade 2), general malaise (grade 1), and fever (grade 1). No severe adverse events were observed in any patient. In 6 patients, tumor marker levels (CEA and CA19-9) decreased transiently during the period of vaccination. Slight reduction of the tumor volume was observed in one patient, which was considered a minor responder. No changes were noted in three patients while the remaining eleven patients experienced tumor progression. Analysis of peripheral blood lymphocytes of one patient using HLA-A24/peptide tetramers revealed an increase in peptide-specific CTL frequency from 0.09% to 0.35% of CD8+ T cells after 4 vaccinations. This phase I clinical study indicates that survivin-2B peptide-based vaccination is safe and should be further considered for potential immune and clinical efficacy in HLA-A24-expression patients with colorectal cancer.

Clinical and immunological evaluation of anti-apoptosis protein, survivin-derived peptide vaccine in phase I clinical study for patients with advanced or recurrent breast cancer

BackgroundWe previously reported that survivin-2B, a splicing variant of survivin, was expressed in various types of tumors and that survivin-2B peptide might serve as a potent immunogenic cancer vaccine. The objective of this study was to examine the toxicity of and to c linically and immunologically evaluate survivin-2B peptide in a phase I clinical study for patients with advanced or recurrent breast cancer.MethodsWe set up two protocols. In the first protocol, 10 patients were vaccinated with escalating doses (0.1–1.0 mg) of survivin-2B peptide alone 4 times every 2 weeks. In the second protocol, 4 patients were vaccinated with the peptide at a dose of 1.0 mg mixed with IFA 4 times every 2 weeks.ResultsIn the first protocol, no adverse events were observed during or after vaccination. In the second protocol, two patients had induration at the injection site. One patient had general malaise (grade 1), and another had general malaise (grade 1) and fever (grade 1). Peptide vaccination was well tolerated in all patients. In the first protocol, tumor marker levels increased in 8 patients, slightly decreased in 1 patient and were within the normal range during this clinical trial in 1 patient. With regard to tumor size, two patients were considered to have stable disease (SD). Immunologically, in 3 of the 10 patients (30%), an increase of the peptide-specific CTL frequency was detected. In the second protocol, an increase of the peptide-specific CTL frequency was detected in all 4 patients (100%), although there were no significant beneficial clinical responses. ELISPOT assay showed peptide-specific IFN-γ responses in 2 patients in whom the peptide-specific CTL frequency in tetramer staining also was increased in both protocols.ConclusionThis phase I clinical study revealed that survivin-2B peptide vaccination was well tolerated. The vaccination with survivin-2B peptide mixed with IFA increased the frequency of peptide-specific CTL more effectively than vaccination with the peptide alone, although neither vaccination could induce efficient clinical responses. Considering the above, the addition of another effectual adjuvant such as a cytokine, heat shock protein, etc. to the vaccination with survivin-2B peptide mixed with IFA might induce improved immunological and clinical responses.

Malignant carcinoid tumor in the papilla of Vater: case report and review of 25 cases reported in Japan

Carcinoid tumors in the papilla of Vater are rare. We describe a 48-year-old male who was diagnosed with a tumor consisting of atypical cells in the papilla of Vater. He underwent curative resection of the tumor by pancreatico-duodenectomy (PD), with dissection of the regional lymph nodes. Microscopic examination revealed a metastatic lymph node in the pancreatic region. Characteristic findings on histopathological and electron microscopic studies led to the final diagnosis of malignant carcinoid tumor. It is clear from the literature that carcinoid tumors in the papilla of Vater metastasize to the regional lymph nodes and the liver. However, it has been difficult to preoperatively diagnose carcinoid tumor in the papilla of Vater. Therefore, if we observe atypical cells in the papilla of Vater, malignant carcinoid tumor should be considered. If this tumor is suspected, PD or pylorus-preserving PD, together with dissection of the regional lymph nodes, at least along the hepatoduodenal ligament, should be considered as the treatment of first choice.

A Case of Pan-peritonitis due to Perforation of the Pyometra as a Result of Invasion of Rectal Cancer to the Uterus

症例は88歳の女性で, 発熱・食欲低下を主訴に受診し, 腹部CTにて虫垂周囲膿瘍と触診にて腹膜刺激症状を認めた. 血液検査上, WBC27,600mm3, CRP34.8mg/dlと高度の炎症所見を伴っていたため虫垂穿孔による汎発性腹膜炎と診断し手術を行った. 術中所見では子宮底部に穿孔を認め, 直腸癌が子宮に浸潤し左尿管・左卵巣を巻き込んでいた. 膀胱への浸潤を認めなかったため直腸・子宮・左卵巣合併切除および人工肛門造設術を施行した. 病理組織学的には, 直腸癌が子宮筋層に浸潤しているのを確認した. 本症例は癌の浸潤により子宮内腔が汚染され, 癌の進行とともに子宮に機械的閉塞を生じ子宮留膿腫を引き起こし穿孔したまれな症例であった. 高齢女性の汎発性腹膜炎に遭遇した場合, 子宮・付属器の疾患も十分に考慮しつつ骨盤腔を精査し手術に望むべきであると思われた.

Amino acid metabolism in the cases of fatty liver.

乙型肝硬変症 (以下乙型n=25) とその起因症である脂肪肝 (n=10), 肝線維症 (n=23) の血漿遊離アミノ酸の相互関連性を検討することによって脂肪肝のアミノ酸代謝から程度を知ることを目的とし, 成人 (n=566) の正常値を1として比較検討した. 総アミノ酸濃度は3群間に差はなく正常域値内の変動である. 必須アミノ酸の総和は脂肪肝は0.80, 肝線維症は0.79で, 乙型の0.90より低い. 分岐鎖アミノ酸総和はいずれの群も正常値の70%程度である. 芳香族アミノ酸は脂肪肝1.22, 肝線維症1.31, 乙型1.59であり, Gln/Gluは脂肪肝0.55, 肝線維症0.46, 乙型0.42でこれらは肝障害の悪化に比例している. したがって, アミノ酸代謝の検討から肝障害の程度を知ることが可能である.