Mihoko Doi

Circulating KL-6/MUC1 mucin carrying sialyl Lewisa oligosaccharide is an independent prognostic factor in patients with lung adenocarcinoma

MUC1 mucin is frequently observed in adenocarcinomas, and its association with metastasis has been postulated through the interaction between sialyl Lewis oligosaccharides present on this glycoprotein and selectins. Levels of soluble MUC1 recognized by anti‐KL‐6 monoclonal antibody were also frequently elevated in the sera of lung adenocarcinoma patients. The aim of this study was to demonstrate the presence of KL‐6/MUC1 carrying sialyl Lewisa oligosaccharide, designated as SLAK, and subsequently evaluate the clinical significance of circulating SLAK in patients with lung adenocarcinoma. We developed a sandwich ELISA system using anti‐sialyl Lewisa and anti‐KL‐6 antibodies to detect SLAK, and also measured circulating SLAK levels in 97 healthy controls and 103 patients with lung adenocarcinoma. Circulating SLAK levels were measured in the sera taken before treatment and then were evaluated to clarify whether such levels were related to the clinical outcomes. Levels of circulating SLAK were significantly higher in lung adenocarcinoma patients than in healthy subjects, and a higher serum SLAK level was correlated with the presence of distant metastasis. The overall survival rate for patients with high serum SLAK levels was significantly poorer than that of patients with low serum SLAK levels. The survival analysis restricted to the patients with distant metastasis also showed the same trend. In a multivariate survival analysis in lung adenocarcinoma patients, a high serum SLAK level was indicated as an independent prognostic factor. In conclusion, the circulating SLAK level at diagnosis is useful for predicting a poor prognosis in patients with lung adenocarcinoma.

Significance of pulmonary artery pressure in emphysema patients with mild-to-moderate hypoxemia

The guidelines of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) do not recommend the measurement of pulmonary artery pressure in patients with chronic obstructive pulmonary disease (COPD). This is on the basis that the mean pulmonary artery pressure (mPAP) does not provide more clinical information than measurement of the oxygen tension in arterial blood (PaO2). The mPAP correlates well with PaO2 in emphysema patients with severe hypoxemia (PaO2 < or = 7.3 kPa (55 mmHg)). However, the occurrence and significance of mPAP is unclear in patients without severe hypoxemia (PaO2 > 7.3 kPa (55 mmHg)). In order to evaluate the usefulness of measurement of mPAP in emphysema patients without severe hypoxemia, we performed right heart catheterization and investigated the pulmonary hemodynamics of 53 patients without severe hypoxemia. In addition, we identified long-term prognostic factors with a mean follow-up term of 77 months after right heart catheterization. Seventeen of 27 patients with mild-to-moderate hypoxemia exhibited pulmonary hypertension (mPAP > or = 2.7 kPa (20 mmHg)) and the classification according to severity in GOLD exhibited a greater correlation to mPAP than PaO2. Moreover, only mPAP was found to be a significant prognostic factor according to multivariate proportional hazards analysis (P = 0.01). We conclude that mPAP is more informative about the severity of emphysema than PaO2 in patients with mild-to-moderate hypoxemia.

Effect of Mustard Gas Exposure on Incidence of Lung Cancer: A Longitudinal Study

Sulfur mustard, an agent used in chemical warfare, is an alkylating substance with carcinogenic potential. However, the precise long-term carcinogenic effects of mustard gas are unclear. Since 1952, the authors have conducted health surveys of former workers who were employed from 1929 to 1945 in a poisonous gas factory in Okuno-jima, Hiroshima, Japan. This prospective study was undertaken from 1952 to 2005 to examine the incidence of lung cancer among the workers who were exposed to mustard gas (n=480), lewisite (n=55), and/or diphenylcyanarsine (n=178), as well as the incidence among unexposed workers (n=969). The stochastic relation between exposure and lung cancer was explored on the basis of multistage carcinogenesis by using an accelerated hazard model with a transformed age scale. Mustard gas exposure was found to transform the age scale for developing lung cancer. One year of exposure in subjects ≤18 or >18 years old at first exposure shifted the age scale down by 4.9 years and 3.3 years, respectively. On the basis of the long-term follow-up of former workers in the poisonous gas factory, the authors concluded that sulfur mustard decreased the age at which people were at risk of developing lung cancer and that the effect declined with aging.

Anti-tumor effect of the anti-KL-6/MUC1 monoclonal antibody through exposure of surface molecules by MUC1 capping.

Human polymorphic epithelial mucin (MUC1) is a heavily glycosylated large protein that is frequently overexpressed on the surface of many human adenocarcinomas. Studies using monoclonal antibodies (mAb) identified MUC1 as a tumor‐associated antigen that has been intensely studied as a target for cancer immunotherapy. We previously identified a mouse IgG1 mAb that recognizes a sialylated sugar chain, designated as KL‐6, classified in ‘Cluster 9 (MUC1)’. Using the anti‐KL‐6 mAb, we investigated antitumor effects of anti‐MUC1 mAb on breast cancer cell lines expressing MUC1 abundantly. We showed that anti‐KL‐6 mAb induced capping of MUC1 and facilitated E‐cadherin‐mediated cell–cell interaction in the breast cancer cell lines YMB‐S and ZR‐75‐1S, which proliferate in suspension culture without aggregation. Moreover, anti‐KL‐6 mAb enhanced the cytotoxic activity of lymphokine‐activated killer cells. These results indicate that the capping of MUC1 restores cell surface proteins, such as adhesion molecules and tumor antigens, to work in cell–cell interactions, leading to inhibition of tumor proliferation due to cell–cell adhesion and increased accessibility to effector cells that are needed to kill tumor cells. (Cancer Sci 2006)

Alternate‑day administration of S‑1 for elderly patients with advanced non‑small‑cell lung carcinoma: A prospective feasibility study

S-1 is an oral fluoropyrimidine agent used for the treatment of non-small-cell lung cancer (NSCLC). Although S-1 monotherapy has been reported to exhibit lesser hematotoxicity compared with other third-generation chemotherapeutics, digestive toxicity was also frequently observed. Alternate-day administration of S-1 has shown a lower rate of severe digestive toxicity than the daily standard administration in patients with NSCLC. However, the safety of alternate-day S-1 therapy in elderly patients aged 75 years or older has not been investigated. The present study was a multi-center and prospective feasibility study aimed to evaluate the safety of alternate-day S-1 therapy in elderly patients with NSCLC. The patients received S-1 orally twice daily for 4 days (Monday, Wednesday, Friday, and Sunday) every week until disease progression or unacceptable toxicity. The primary endpoint was safety, which was evaluated as the number of grade ≥3 adverse events, and the secondary endpoints were progression-free survival (PFS), 1-year survival, and disease control rate (DCR). A total of 10 patients were enrolled, but 2 patients failed to initiate the treatment protocol. Finally, 8 patients were treated with the study protocol regimen. No grade 3 or higher adverse events were observed. Four (50%) and 1 (12.5%) patient had grade 2 or lower digestive symptoms such as anorexia, diarrhea, or stomatitis and grade 1 lacrimation, respectively. Moreover, 2 (25%), 1 (12.5%), and 1 (12.5%) patients had grade 2 renal dysfunction, grade 2 ileus, and elevated blood bilirubin, respectively. The median PFS was 1.5 months (95% confidence interval: 0.9-1.8), and the 1-year survival rate was 42.9%. The DCR was 12.5%. In conclusion, alternate-day S-1 administration can be a safe treatment regimen for elderly patients with NSCLC, but its therapeutic efficacy and safety for elderly patients with NSCLC should be compared against the standard S-1 administration in a large-scale study.

Significance of lung biopsy for the definitive diagnosis of lung nodules in breast cancer patients

The aim of the present study was to evaluate the significance of lung biopsy for the modification of the treatment strategy in breast cancer patients who develop lung nodules during follow-up after breast surgery. Of 53 consecutive patients who underwent lung biopsies in two institutions (Hiroshima University Hospital and Hiroshima Prefectural Hospital, Hiroshima, Japan) between 1997 and 2014, 45 underwent lung surgery and 8 underwent percutaneous or transbronchial tumor biopsy for lung nodules developing after curative surgery for breast cancer. The indications for lung biopsy included lung nodules for which a definitive diagnosis was difficult to achieve, and those for which the treatment strategy depended on the pathological diagnosis. The lung nodules were pathologically diagnosed as primary breast cancer metastases to the lungs in 25 (47%), primary malignant lung tumors in 21 (40%) and benign disease in 7 (13%) patients. Among the 25 metastatic patients confirmed by lung biopsy, phenotype discordance was observed in 6 patients (24%). A total of 3 patients with lung metastasis proven to have estrogen or progesterone receptor upregulation by lung biopsy received endocrine therapy. Univariate analysis revealed that patients with metastatic breast cancer confirmed by lung biopsy were significantly younger and had more locally advanced primary cancers diagnosed via clinical and pathological assessment compared with patients with other diseases. Therefore, mastectomy and axillary lymph node dissection were performed more frequently in the metastasis group compared with the others group. Multivariate analysis revealed that mastectomy (P<0.001) and axillary dissection (P<0.001) were independent factors predicting that the lung nodules would be metastases from breast cancer. Lung biopsy in breast cancer patients who developed lung nodules during the follow-up period after breast cancer surgery was crucial for making a definitive diagnosis and modifying the treatment strategy, which may improve the prognosis of breast cancer patients.

A Case of Stage IA Lung Cancer with Elevated Level of Serum Carcinoembryonic Antigen Prior to Surgery.

症例は65歳, 男性. 交通外傷のため近医に入院した時の胸部単純レントゲン検査で偶然右上肺野に直径6mmの淡い陰影を指摘された. 経過観察されていたが, 約1年後の胸部単純レントゲン検査で腫瘤陰影が17mm大に増大したため気管支鏡検査を施行された. 擦過細胞診でClass IVが得られ, 肺癌が疑われたため手術目的にて当院紹介となった. 術前血清CEA値が11.1ng/mlと高値を示したため消化器系などの重複癌を念頭に置き検査を進めたが, 肺以外には病変が認められず, 原発性肺癌の診断のもと右肺上葉切除術を施行した. 腫瘍は右S2に存在し大きさは13×12×8mm大で, p-T1N0M0, IA病期であった. 術後2週問目の血清CEA値は1.8ng/mlまで低下した. 術後化学療法, 放射線療法は施行せず, 第18病日に退院した. 術前血清CEA値が上昇している肺癌症例は進行期癌であることが多く, IA期肺癌では比較的まれであるので報告する.

Concurrent high-dose thoracic irradiation plus daily low-dose cisplatin and vindesine in locally advanced unresectable stage III non-small cell lung cancer.

Patients with unresectable non small-cell lung cancer were treated to evaluate the toxicity and efficacy of high-dose thoracic irradiation (RT) combined with concurrent daily cisplatin plus vindesine. Fourteen evaluable patients with unresectable stage III non small-cell lung cancer treated with continuous-course RT (70 Gy in 35 fractions of 2 Gy once daily) and concurrent daily intravenous cisplatin (6 mg/m2) plus vindesine (3 mg/m2 on day 1 and day 8). The objective response rate was 86%, and two patients achieved a radiographic complete response. Leukocytopenia was the severe toxicity, but there were no episodes of discontinuation of treatment. Only one patient had grade 3 acute radiation esophagitis. Ten patients experienced late radiation pneumonitis and nine of those had grade 1 or grade 2. There was only one life-threatening case of toxicity (grade 5 pneumonitis). We concluded that the regimen of high-dose thoracic RT combined with concurrent daily cisplatin plus vindesine obtained a high response rate. Further testing on late toxicities and survival time is required.