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.     

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.     

ABCE1, a member of ATP-binding cassette transporter gene, encodes peptides capable of inducing HLA-A2-restricted and tumor-reactive cytotoxic T lymphocytes in colon cancer patients

To provide a scientific basis for specific immunotherapy of colon cancer, this study focused on the identification of tumor-associated antigens recognized by HLA-A2-restricted and cancer-reactive cytotoxic T lymphocytes (CTLs) from tumor-infiltrating lymphocytes (TIL) of a colon cancer patient. We identified a gene coding a member of the ATP-binding cassette transporter (ABCE1), which is known as an inhibitor to the 2-5A/RNase L system, a central pathway of interferon action, and its gene expression is amplified in drug-resistant cells. The ABCE1 mRNA was ubiquitously expressed in tumor cell lines, as well as normal cells or tissues. Among 21 peptides with the HLA-A2 binding motifs, 2 ABCE1-derived peptides were recognized by the colon cancer-reactive CTLs in a dose-dependent manner. CTL precursors reactive to these 2 ABCE1 peptides were detected in the peripheral blood mononuclear cells (PBMCs) of the colon cancer patient, from whom the TILs had been obtained. In addition, these ABCE1 peptides had the potential to generate HLA-A2-restricted and colon cancer-reactive CTLs from the PBMCs of colon cancer patients, but not from those of healthy donors. Their cytotoxicity against colon cancer was mainly ascribed to peptide-specific and CD8+ CTLs. No definite cytotoxicity was observed against normal T cell blasts, irrespective of the expression of the ABCE1 mRNA. These results indicate that the ABCE1 and its peptides could be target molecules in specific immunotherapy for HLA-A2(+) colon cancer patients.     

Usefulness of Radio-guided Surgery Using Technetium-99m Methoxyisobutylisonitrile for Primary and Secondary Hyperparathyroidism

The efficacy of technetium-99m methoxyisobutylisonitrile (^99mTc-MIBI)-guided surgery for detecting abnormal parathyroid glands in patients with secondary hyperparathyroidism (2-HPT) was evaluated and compared with the results from the same examination in patients with primary hyperparathyroidism (1-HPT). The results were also compared with those found by ultrasonography (US) and preoperative ^99mTc-MIBI scintigraphy was also made. At operation ^99mTc-MIBI accumulated in 64 nodules of 15 cases of 2-HPT, and all of 60 parathyroid swellings were detected (true-positives 60, sensitivity 100%, accuracy 94%). In the cases of 1-HPT, ^99mTc-MIBI revealed 11 hot nodules in 10 cases, and the evaluation was true-positive 10, sensitivity 100%, and accuracy 91%. US and preoperative ^99mTc-MIBI scintigraphy in patients with 2-HPT had a sensitivity of 75% and 67% and an accuracy of 70% and 66%, respectively. The usefulness of ^99mTc-MIBI-guided surgery for detecting abnormal parathyroid tissue in 2-HPT patients was similar to that in 1-HPT patients but was superior to US and preoperative ^99mTc-MIBI scintigraphy. Intraoperative ^9mTc-MIBI for patients with 2-HPT is effective and makes the surgery easier, especially when the parathyroid glands are ectopic or when a few glands are markedly enlarged but the other glands are atrophied.     

Present state of guidelines for perioperative management of deep vein thrombosis and pulmonary embolism in Japan

To clarify the present state of local institutional guideline for perioperative deep thrombosis and pulmonary embolism in individual hospitals, a questionnaire was sent to anesthesia departments in Japan. According to the replies, 82 hospitals have original guidelines. Forty of them reported the contents of their guidelines. However, 37 hospitals have some problems regarding their guidelines. Cost for these perioperative managements and application of spinal or epidural anesthesia for heparinized patients appears to be commonly recognized as pending questions in their guideline. It seems to be difficult to make a stereotyped standard guideline in Japan because each local guideline has a specific strategy according to their situations. However, it is needless to say that a further nationwide survey and collaboration, and governmental support for these diseases would be required.