Eiichi Chosa

Spleen plays an important role in maintaining tolerance after removal of the vascularized heart graft.

Background. This study addresses the question of the mechanism for maintaining tolerance to donor alloantigen in the absence of antigen and the role of secondary lymphoid tissues. Methods. Depleting anti-CD4 antibody administration in conjunction with allogeneic heart transplantation generates donor-specific operational tolerance. Primary C57BL/6 heart grafts were transplanted into the neck cavity of the anti-CD4 antibody pretreated C3H/He mice. At day 50, functioning heart grafts were removed from tolerant mice. At day 100, a secondary C57BL/6 or a third-party heart was transplanted into the abdomen. Results. Anti-CD4 antibody therapy induced CD4+CD25+ regulatory T cells by 50 days after transplantation, as depleting anti-CD25 treatment in tolerant mice abrogated graft prolongation when spleen leukocytes were adoptively transferred to syngeneic mice. Tolerance was maintained by CD4+CD25+ regulatory T cells via a CTLA-4 signal at 100 days, even after removal of the primary graft at day 50. Administration of anti-CD25 antibody immediately after removal of the primary graft did not break tolerance, as five out of six second allografts transplanted at day 100 were accepted. Anti-CD25 antibody therapy in conjunction with splenectomy, but not thymectomy, immediately after removal of primary heart grafts at day 50 broke tolerance at day 100; all allografts were rejected. Conclusion. The spleen is important in maintaining CD4+CD25+ regulatory T cells after primary allograft removal.

Combination of Adoptive Cell Transfer and Antibody Injection Can Eradicate Established Tumors in Mice–An in vivo study using anti-OX40mAb, anti-CD25mAb and anti-CTLA4mAb–

Boosting an effective immune response against established tumors remains a difficult challenge. This study shows the combination of 1) adoptive cell transfer using CD25 depleted splenocytes co-cultured with irradiated tumor cells, and 2) antibody injection therapy using CTLA4 blockade, the elimination of Treg and OX40, which together could eradicate an established MethA tumor in over 50% of the BALB/c mice. Each element of the protocol was shown to be necessary, as elimination of any factor except anti-CD25 antibody injection failed to eradicate the tumor.

Impact of smoking on outcome of resected lung adenocarcinoma

ObjectiveSmoking is a well-known causative factor of lung cancer and the association of smoking with adenocarcinoma is considered to be the weakest. We investigated the influence of smoking on postoperative prognosis in patients with lung adenocarcinoma.MethodsOne hundred and eighty-one consecutive patients of resected lung adenocarcinoma were studied retrospectively. The histologic subtype was subdivided into 2 groups: lepidic dominant histologic subtype, including adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic predominant invasive adenocarcinoma versus other subtypes.ResultsThe 5-year survival of ever smokers was significantly unfavorable than that of never smokers. Similarly, there was also a relationship between the patients’ survival and Brinkman index (BI), with unfavorable survival found in patients with greater smoking histories. Based on a multivariable analysis, pN status and BI were significant factors affecting the postoperative prognosis of patients undergoing surgery. However, gender, serum carcinoembryonic antigen (CEA) level, lepidic dominant histologic subtype and pure/mixed ground-glass opacity (GGO) were not prognostic factors although previous reports showed prognostic significance. These factors that we failed to find the prognostic significance were significantly associated with smoking.ConclusionThe smoking was significantly predictive of an unfavorable prognosis after surgery for lung adenocarcinoma. It is suggested that smoking is associated with serum CEA level, histologic subtype and GGO, resulting in unfavorable outcome.

Postoperative Serum CEA Level is a More Significant Prognostic Factor than Post/Preoperative Serum CEA Ratio in Non-small Cell Cancer Patients.

BACKGROUND In non-small cell lung cancer (NSCLC) patients with preoperative high serum carcinoembryonic antigen (CEA) level, patients with a persistently high serum CEA level after surgery have been reported to have a poor prognosis. In addition, in other cancers, the post/preoperative serum CEA ratio has been reported as a useful parameter. MATERIALS AND METHODS We enrolled 123 NSCLC patients with preoperative high CEA levels (≥ 5 ng/mL) who underwent curative surgery between 2004 and 2011. Prognostic significance of postoperative serum CEA level and the CEA ratio was examined. RESULTS The 5-year survival of patients with persistently high serum CEA level after surgery was poor. On the other hand, patients with normal postoperative serum CEA levels had significant favorable prognosis. The patients with CEA ratio>1 had poor prognosis, however the number was only 7 (5.7%). The 5-year survival rates of patients with other subgroup based on the CEA ratio (0.5 ≥ CEA ratio and 0.5 ≤ CEA ratio ≤ 1) was similar. Multivariate analysis revealed prognostic significance for the postoperative serum CEA level but not the CEA ratio. CONCLUSIONS For NSCLC patients with preoperative high serum CEA level, their postoperative serum CEA levels is a more significant prognostic factor than the post/preoperative serum CEA ratio.

Epidermal Growth Factor Receptor Mutations in Japanese Men with Lung Adenocarcinomas

BACKGROUND Epidermal growth factor receptor (EGFR) mutations play a vital role in the prognosis of patients with lung adenocarcinoma. Such somatic mutations are more common in women who are non-smokers with adenocarcinoma and are of Asian origin. However, to our knowledge, there are few studies that have focused on men. MATERIALS AND METHODS One hundred and eighty-four consecutive patients (90 men and 94 women) of resected lung adenocarcinoma were studied retrospectively. RESULTS EGFR mutations were positive in 48.9% and negative (wild type) in 51.1%. Overall mutation was significant in women (66.0% vs. 32.2%) compared with men (p<0.001). For overall patients, EGFR mutation status was associated with gender, pStage, pT status, lepidic dominant histologic subtype, pure or mixed ground-glass nodule type on computed tomography and smoking status. However, in men, EGFR mutation status was only associated with lepidic dominant histologic subtype and not the other variables. Interestingly, the Brinkman index of men with mutant EGFR also did not differ from that for the wild type (680.0±619.3 vs. 813.1±552.1 p=0.1077). CONCLUSIONS The clinical characteristics of men with lung adenocarcinoma related to EGFR mutation are not always similar to that of overall patients. Especially we failed to find the relationship between EGFR mutations and smoking status in men.

Prognostic Significance of a Tumor Marker Index Based on Preoperative Serum Carcinoembryonic Antigen and Krebs von den Lungen-6 Levels in Non-Small Cell Lung Cancer

Background: We retrospectively analysed the prognostic significance of a tumor marker index (TMI) based on preoperative serum carcinoembryonic antigen (CEA) and Krebs von den Lungen-6 (KL-6) levels in nonsmall cell lung cancer (NSCLC) patients. Materials and Methods: We enrolled 176 NSCLC patients who had preoperative serum CEA and KL-6 level measurements and had undergone curative surgery between 2009 and 2011. Results: The 5-year disease-specific survival of patients with high serum CEA levels was significantly poorer compared with that of patients with normal levels. The value for patients with high serum KL-6 levels was also poor. Patients with both normal serum CEA and KL-6 levels had a favourable prognosis, whereas those with both high serum CEA and KL-6 levels had a poor outcome. The5-year disease-specific survival rate was 82.9% for patients in the low TMI group compared to 47.5% in the high TMI group (p<0.01). Both univariate and multivariate analyses revealed prognostic significance for TMI. Conclusions: TMI based on preoperative serum CEA and KL-6 levels might be useful for the prediction of the prognosis of NSCLC patients.

Prognostic significance of preoperative serum Krebs von den Lungen-6 level in non-small cell lung cancer

ObjectivesWe retrospectively analyzed the prognostic significance of preoperative serum Krebs von den Lungen-6 (KL-6) level in non-small cell lung cancer (NSCLC) patients.MethodsWe enrolled 175 NSCLC patients who underwent curative surgery between 2009 and 2011. We subdivided the patients into 2 groups: with and without interstitial lung disease (ILD). Prognostic significance of serum KL-6 level was examined.ResultsThe 5-year survival of patients with high serum KL-6 level was poor. Multivariate analysis also revealed the prognostic significance of serum KL-6 level. Serum KL-6 level was also a prognostic factor for patients without ILD. Although the number of patients with ILD was small, in patients with ILD, there was a trend towards an association between serum KL-6 level and patients’ prognosis but this did not reach statistical significance.ConclusionsSerum KL-6 level is a prognostic factor for resected NSCLC patients, especially patients without ILD. There is a possibility that serum KL-6 level is a prognostic marker regardless of the presence of ILD.

Correlation between Serum Carcinoembryonic Antigen Level and Histologic Subtype in Resected Lung Adenocarcinoma

BACKGROUND Recent studies revealed a relationship between ground-glass opacity (GGO) ratio on computed tomography (CT) and serum carcinoembryonic antigen (CEA) level in lung adenocarcinoma. Since an association between lepidic histologic pattern and GGO is well accepted, we investigated the link between histologic subtype and serum CEA level in resected lung adenocarcinoma. MATERIALS AND METHODS One hundred and eighty-one consecutive patients with resected lung adenocarcinoma were studied retrospectively. The histologic subtype was subdivided into 2 groups: lepidic dominant histologic subtype, including adenocarcinoma in situ, minimally invasive adenocarcinoma and lepidic predominant invasive adenocarcinoma versus other subtypes. RESULTS The 5-year survival of patients with s high serum CEA level was significantly more unfavorable than that with normal levels. Similarly, there was also a relationship between the patient survival and histologic subtype, with favorable survival found in patients with the lepidic dominant histologic subtype. There was a significant relationship between serum CEA level and lepidic dominant histologic subtype overall and in p-stage I patients. CONCLUSIONS Lung adenocarcinomas with non-lepidic dominant histologic subtype are associated with high serum CEA levels.

Port-site implantation of Type A Masaoka Stage I thymoma after video-assisted thoracic surgery: a case report.

A 60-year-old woman was referred to our hospital with an anterior mediastinal tumor measuring 3.5 cm in diameter on computed tomography (CT). We performed tumor resection by video-assisted thoracic surgery (VATS) with three ports. The final diagnosis was Type A Masaoka Stage I thymoma. On follow-up CT performed 36 months after the operation, two pleural tumors were detected at the port sites through which the forceps and ultrasonic scalpel had passed repeatedly during the operation. We therefore performed a second operation and enucleated the tumors while preserving the ribs. However, other tumor tissue was detected along the surgical marginal line during the pathological diagnosis after the operation. Surgeons should thus be aware that port-site recurrence can occur after VATS resection of Type A thymoma, despite its mild biological behavior. Wide resection of the chest wall is therefore recommended for operations of port-site recurrence after VATS thymectomy.

Unusual cystic hamartomatous lung lesion with clinical manifestation of subpleural bullae in a woman of reproductive age: A case report

Pulmonary hamartoma is a common benign lung disorder, and most cases show solid nodules. Here, we documented the clinicopathological features of a growing, bulla‐like, multilocular hamartomatous lung lesion in a woman of reproductive age. To the best of our knowledge, this disorder has not been reported in the literature to date. An asymptomatic 29‐year‐old Japanese woman with no significant past medical history was referred to our institution for surgical treatment of a bullous lesion in the right upper lobe because the pulmonary lesion had enlarged to multilocular cysts, including a giant bulla, within 1 year, leading to compression of the right lung. The bullous lesion, which was projected from the apex of the lung via a narrow stalk, showed nonemphysematous, multiloculated tissue. The wall mimicked a bronchiolar structure with ciliated, nonatypical epithelium and layers of nonatypical spindle cells that were positive for smooth muscle markers and sex steroid hormone receptors. No cartilage was included in the lesion. We believe that this may be a novel form of hamartoma. This disorder may be included in a differential diagnosis of subpleural bullous diseases in women of reproductive age.