Kazu Shiomi

Novel ELISA system for detection of N‐ERC/mesothelin in the sera of mesothelioma patients

We have developed a novel enzyme‐linked immunosorbent assay (ELISA) system for the detection of N‐ERC/mesothelin in the serum of mesothelioma patients and have begun to examine its clinical usefulness. N‐ERC/mesothelin is a 31‐kDa protein that forms the N‐terminal fragment of the full‐length 71‐kDa ERC/mesothelin protein, and is physiologically secreted into the blood of mesothelioma patients where it can be detected using our sandwich ELISA containing two antibodies (rabbit polyclonal anti‐ERC/mesothelin antibody‐282 and mouse monoclonal antibody 7E7). Our ELISA system has thus far detected much higher serum levels of N‐ERC/mesothelin in mesothelioma patients than in healthy controls or patients with other lung or pleural diseases. In conclusion, N‐ERC/mesothelin is a promising candidate tumor marker for mesothelioma. (Cancer Sci 2006; 97: 928–932)

Effect of the introduction of minimum lesion size on interobserver reproducibility using RECIST guidelines in non-small cell lung cancer patients

We evaluated interobserver reproducibility for the response evaluation criteria in solid tumors (RECIST) guidelines and the influence of minimum lesion size (MLS) on reproducibility. The 110 consecutive patients with non‐small cell lung cancer were treated with platinum‐based chemotherapy. Five observers measured target lesions according to both the World Health Organization (WHO) criteria and RECIST. The percentage changes for unidimensional measurements (UD; RECIST type) and bidimensional measurements (BD; WHO type) were calculated for each patient. Interobserver reproducibility among five observers, that is 10 pairs, was expressed as the Spearmans correlation coefficient for the percentage changes, the proportion of agreement and the kappa statistics for response categories. The same analysis was carried out using MLS. BD was more reproducible than UD (Spearman rank correlation coefficient, 0.84 vs 0.81; proportion of agreement, 84.4% vs 82.5%; kappa value, 0.69 vs 0.61). When MLS was applied to UD, eligible cases decreased by 6.4% and the number of target lesions by 44.6%, whereas interobserver reproducibility for UD improved (Spearman rank correlation coefficient, 0.81–0.84; proportion of agreement, 82.5–84.2%; kappa value, 0.61–0.65). The introduction of MLS to UD could also improve intercriteria reproducibility between WHO and RECIST. It is important to apply the MLS when using RECIST for the comparable interobserver reproducibility attained with WHO. (Cancer Sci 2006; 97: 214–218)

Mesothelin (MSLN) promoter is hypomethylated in malignant mesothelioma, but its expression is not associated with methylation status of the promoter

Gene methylation leads to malignant progression in some tumors. The mechanism by which mesothelin is expressed in malignant mesothelioma (MM) is not well understood. MM is histologically divided into 3 subtypes, that is, the epithelioid, sarcomatoid, and biphasic types, and it was shown that mesothelin expression was restricted to the epithelioid type and the epithelioid component of the biphasic type of MM. However, its regulatory mechanism of expression has not been clarified. Here, we studied the expression of mesothelin by immunohistochemistry along with the methylation status of 20 CpG sites in the promoter of the mesothelin gene (MSLN) in 118 lung specimens, including 39 MM, 41 lung carcinoma, 26 nonneoplastic pulmonary lesions, and 12 normal lung tissue samples by the methylation-sensitive single nucleotide primer extension technique. We confirmed that mesothelin was expressed in the epithelioid type and epithelioid component of the biphasic type of MM but neither in the sarcomatoid type nor sarcomatous component of the biphasic type. Surprisingly, the MSLN promoter was significantly hypomethylated in the MM cases regardless of its subtype, compared with the other pulmonary lesions and normal lung tissue samples. These findings suggested that hypomethylation of the MSLN promoter may be specifically associated with the formation of MM, regardless of its expression status, and that the expression of mesothelin protein was lost in the sarcomatoid type by some unknown posttranscriptional regulatory mechanism. We also identified 4 CpG sites, among the 20 sites studied, to be more specifically hypomethylated in MM cases.

The N-ERC index is a novel monitoring and prognostic marker for advanced malignant pleural mesothelioma

BACKGROUND Although N-ERC/mesothelin (N-ERC) is an attractive diagnostic and treatment monitoring biomarker for malignant pleural mesothelioma (MPM), its clinical utility for predicting the prognosis has not yet been clarified. The aim of this study is to investigate whether the serum N-ERC level can accurately predict the outcome in patients with MPM. METHODS Twenty-six patients with MPM were enrolled. Serum N-ERC level was measured before and after chemotherapy. The N-ERC index was determined by the logarithm of the division of the N-ERC level after two courses of chemotherapy by the prior level. RESULTS The median N-ERC index in the partial response (PR) group was significantly lower than that in patients with the stable disease (SD) plus the progressive disease (PD) group. The overall survival in the group whose median N-ERC index was lower than its median value was significantly longer than the group whose median N-ERC index was higher than its median value. CONCLUSIONS The N-ERC index is therefore considered to be a useful biomarker for predicting not only the chemotherapeutic response, but also the prognosis in patients with advanced MPM.

MESOMARK kit detects C-ERC/mesothelin, but not SMRP with C-terminus.

ERC/mesothelin is expressed on the normal mesothelium and some cancers such as mesothelioma or ovarian carcinoma. A splicing isoform of ERC/mesothelin (known as SMRP), which has an 82-bp insertion and codes for a C-terminus with a hydrophilic, presumably soluble, tail instead of a GPI-anchoring signal, has been reported as a useful marker for the diagnosis of mesothelioma. However, the existence of SMRP has not yet been demonstrated in the serum of mesothelioma patients. To elucidate the existence of SMRP, we have established a new enzyme-linked immunosorbent assay (ELISA) system for SMRP. The ELISA study revealed that N- and C-ERC/mesothelin were detected in sera from mesothelioma patients, but not SMRP, even in these samples. This result showed that the SMRP detected with MESOMARK kit should be lack of soluble C-terminus and indistinguishable from C-ERC/mesothelin. Further study might be necessary to demonstrate the relationship between SMRP and mesothelin.

Pulmonary torsion after open esophagectomy for esophageal cancer: a case report and review

Pulmonary torsion (PT) is an extremely uncommon event (1-4). Although PT is known to occur only rarely after lung resection, we now know that it can also occur after other thoracic procedures such as cardiac, esophageal, and chest trauma surgery and, spontaneously, after chest trauma itself (3-11). A delay in diagnosis and/or an improper treatment strategy can lead to serious complications (3,4,10-15). In this report, we describe a case of PT, discuss what we learned about methods of early diagnosis and appropriate treatment strategies from our experience, and review the literature.

Feasible and promising modified trans-subxiphoid thoracoscopic extended thymectomy for patients with myasthenia gravis

Background We have used a promising, minimally invasive thoracoscopic technique of extended thymectomy for patients with myasthenia gravis (MG). The aim of this study was to report our promising technique, a modified single-port trans-subxiphoid approach (MTXA) and to compare perioperative outcomes and effects on MG between our approach and sternotomy. Methods We retrospectively reviewed records of all patients undergoing extended thymectomy for MG and/or thymoma between January 1, 2010 and December 31, 2016. The patients were divided into the MTXA group and Sternotomy group. Results Of the 50 consecutive patients undergoing extended thymectomy for MG, finally, 13 patients undergoing our MTXA extended thymectomy technique were compared with 20 patients undergoing extended thymectomy via sternotomy. Intraoperative blood loss, postoperative length of stay, and C-reactive protein value on postoperative day 1 were significantly more favorable in the MTXA group than the Sternotomy group (P<0.0001, P=0.0040 and P=0.0073, respectively). Furthermore, no significant differences in the frequency of patients with improvement of their Quantitative Myasthenia Gravis score and/or MG-Activities of Daily Living scale, decrease in the serum level of acetylcholine receptor antibody, and dose reduction of oral prednisone were seen between the two groups. Conclusions Our approach to extended thymectomy might be more favorable than sternotomy in patients with MG.