Yoshitomo Okumura

Circulating Tumor Cell as a Diagnostic Marker in Primary Lung Cancer

Purpose: To investigate the diagnostic performance of circulating tumor cells (CTC) in discrimination between primary lung cancer and nonmalignant diseases as well as in prediction of distant metastasis. Patients and Methods: We prospectively evaluated CTCs in 7.5-mL samples of peripheral blood sampled from patients with a suspicion or a diagnosis of primary lung cancer. A semiautomated system was used to capture CTCs with an antibody against epithelial cell adhesion molecule. Results: Of 150 eligible patients, 25 were finally diagnosed as having nonmalignant disease, and 125 were diagnosed as having primary lung cancer with (n = 31) or without (n = 94) distant metastasis. CTCs were detected in 30.6 of lung cancer patients and in 12.0 of nonmalignant patients. CTC count was significantly higher in lung cancer patients than in nonmalignant patients, but a receiver operating characteristic (ROC) curve analysis showed an insufficient capability of the CTC test in discrimination between lung cancer and nonmalignant diseases with an area under ROC curve of 0.598 (95 confidence interval, 0.488-0.708; P = 0.122). Among lung cancer patients, CTC count significantly increased along with tumor progression, especially with development of distant metastasis. The area under ROC curve for CTC count in prediction of distant metastasis was 0.783 (95 confidence interval, 0.679-0.886; P < 0.001). When patients with one or more CTCs were judged as having metastatic disease, sensitivity and specificity of the CTC test were 71.0 and 83.0, respectively. Conclusions: CTC is a useful surrogate marker of distant metastasis in primary lung cancer. (Clin Cancer Res 2009;15(22):69806)

Frequent inactivation of the BAP1 gene in epithelioid-type malignant mesothelioma.

In the present study, we analyzed genomic alterations of BRCA1‐associated protein 1 (BAP1) in 23 malignant mesotheliomas (MMs), 16 epithelioid and seven non‐epithelioid, consisting of 18 clinical specimens and five established cell lines. In examining these samples for homozygous deletions and sequence‐level mutations, we found biallelic BAP1 gene alterations in 14 of 23 MMs (61%). Seven of these 14 MMs had homozygous deletions of the partial or entire BAP1 gene, another five had sequence‐level mutations, including small deletions, a nonsense mutation, and missense mutations with additional monoallelic deletions, and the remaining two had homozygous mutations without allelic loss. All but one of the 14 BAP1 gene mutations were found in the epithelioid‐type MMs; BAP1 mutations were found in 13 of 16 epithelioid‐type MMs, but in only one of seven non‐epithelioid‐type MMs (13/16 vs 1/7; P = 0.005). There was no BAP1 mRNA expression in MMs with biallelic deletion and repressed expression was confirmed in MM specimens with deletion/mutation as compared with Met5a, SV40‐transformed normal mesothelial cells. Western blot showed that seven of eight epithelioid MMs analyzed were BAP1 negative. Immunostaining with anti‐BAP1 antibody in normal lung tissues revealed clear nuclear staining of normal mesothelial cells. No nuclear staining was observed among BAP1 mutation‐positive MM tumors, whereas nuclear staining was observed among BAP1 mutation‐negative MM tumors. These results suggest that the lack of the tumor suppressor BAP1 may be more specifically involved in the pathogenesis of epithelioid MM rather than non‐epithelioid MM, and would be useful for diagnosis of epithelioid‐type MM. (Cancer Sci 2012; 103: 868–874)

Serum carcinoembryonic antigen level in surgically resected clinical stage i patients with non-small cell lung cancer

BACKGROUND There is little general agreement concerning the effectiveness of serum carcinoembryonic antigen (CEA) as a prognostic indicator for non-small cell lung cancer (NSCLC) in clinical stage I patients. We conducted a retrospective study to investigate the relationship between serum CEA level and survival. METHODS We assessed 297 consecutive patients with clinical stage I NSCLC who underwent surgical resection at Toneyama National Hospital from 1985 to 1998. Serum CEA levels were measured with an enzyme-linked immunosorbent assay kit with the upper limit of normal defined as 7.0 ng/mL based on the 95% specificity level for benign lung disease, in our hospital. RESULTS There were 56 (19%) patients with serum CEA greater than 7.0 ng/mL. The high CEA group had a median survival time of 50 months and a 5-year survival rate of 49% compared with a 5-year survival rate of 72% (p < 0.0001) for the normal CEA group (n = 241). Patients with postoperatively high CEA levels (n = 15) had the worse prognosis (median survival time 35 months, and 5-year survival 18%) compared with patients whose levels returned to normal (n = 41, median survival time 8.8 months, and 5-year survival 68%; p = 0.01). These differences were also observed in patients with pathologic stage I or II tumors but not in those with pathologic stage III or IV tumors. CONCLUSIONS Serum CEA level is a useful predictor of survival for patients with clinical stage I NSCLC, and a persistently high CEA level after surgery is an especially strong indicator of a very poor prognosis.

Circulating Tumor Cells in Pulmonary Venous Blood of Primary Lung Cancer Patients

BACKGROUND Circulating tumor cells in peripheral blood (CTC) is a potential surrogate of distant metastasis, which is the critical factor influencing decision making regarding therapy and prognosis of primary lung cancer patients. After our preliminary study showing that CTCs were detected in peripheral blood in 29.4% of resectable lung cancer patients, we conducted a prospective study on CTC in pulmonary vein (PV) blood because tumor cells apart from the primary tumor may circulate after passing through the drainage PV. METHODS A total of 30 consecutive lung cancer patients who underwent thoracotomy were included. The CTCs in peripheral blood and in PV blood from the primary tumor site were quantitatively examined with the CellSearch system, and the numbers of CTCs per 7.5 mL peripheral and PV blood in each patient were represented as periCTC count and pvCTC count, respectively. RESULTS Circulating tumor cell was detected in peripheral blood in 5 patients (16.7%; the periCTC count was 1 in 2 patients; and 2, 3, and 16 in 1 patient each), and the incidence of positive periCTC was higher in squamous carcinoma patients than in adenocarcinoma patients (p = 0.028). Circulating tumor cell was detected in PV blood in most patients (29 of 30, 96.7%), and the mean and median pvCTC counts were 1,195 and 81, respectively (range, 0 to 10,034). There was no significant correlation between pvCTC count and any other patient characteristic, including periCTC count. CONCLUSIONS In resectable lung cancer, CTC was positive in peripheral blood of some patients and in PV blood of most patients. A long-term follow-up study to clarify the clinical significance of pvCTC status is warranted.

Significant increase in circulating tumour cells in pulmonary venous blood during surgical manipulation in patients with primary lung cancer

OBJECTIVES Circulating tumour cells (CTCs) are tumour cells shed from a primary tumour and circulate in the peripheral blood after passing through the drainage vein. In previous studies, we showed that high numbers of CTCs were detected in the drainage pulmonary venous blood of most patients with resectable primary lung cancer, whereas only low numbers of CTCs were detected in the peripheral blood of some patients. Accordingly, this prospective study was conducted to assess changes in CTCs in the drainage pulmonary vein (PV) during lung cancer surgery. METHODS A total of 30 consecutive peripheral-type primary lung cancer patients who underwent lobectomy (or right upper and middle bilobectomy) through open thoracotomy were included. For each patient, 2.5 ml of blood was sampled from the lobar PV of the primary tumour site before and after surgical manipulation for lobectomy. The CTCs were evaluated quantitatively with the CellSearch® system. RESULTS Before surgical manipulation, CTCs were detected in PV blood in the majority of patients (22 of 30, 73.3%), although CTCs were detected in peripheral blood in only two patients (6.7%). The median number of CTCs in the PV (pvCTC-count) before surgical manipulation was 4.0 cells/2.5 ml, and there was no significant correlation between pvPV-count and any clinicopathological characteristic, including tumour size, progression and histological type. After surgical manipulation, at the time of completion of the lobectomy, the pvCTC-count significantly increased (median, 60.0 cells/2.5 ml; P = 0.001). The increase in pvCTC-count was significantly associated with microscopic lymphatic tumour invasion (ly); pvCTC-count significantly increased in ly-positive patients (pvCTC-count before and after surgical manipulation, 4.0 and 90.5 cells/2.5 ml, respectively; P = 0.006), but not in ly-negative patients (3.5 and 7.0 cells/2.5 ml, respectively; P = 0.153). The increase in pvCTC-count was not significantly associated with any other clinicopathological factor or with any surgical procedure, including the sequence of vessel interruption. CONCLUSIONS We documented a significant increase in CTC count in drainage PV blood after surgical manipulation, especially in tumours with lymphatic invasion. We are awaiting survival data at 5 year follow-up examination, which may provide clinical significance of the pvCTC-count.

Pulmonary Benign Metastasizing Leiomyoma from the Uterus in a Postmenopausal Woman: Report of a Case

We report a case of pulmonary benign metastasizing leiomyoma (BML) from the uterus in a 77-year-old woman. The patient presented for investigation of multiple pulmonary nodules on a routine chest roentgenogram. Because a preoperative diagnosis could not be made, the largest tumor, 3.5 cm in diameter, was resected from the right lower lobe, and histological examination confirmed BML. She had undergone hysterectomy with oophorectomy for uterine leiomyomas 12 years earlier, at the age of 65. The microscopic findings of the lung tumor were similar to those of the uterine leiomyoma, and both lesions were histologically benign. Although this disease is considered to be hormone-dependent, metastasis was found in this elderly postmenopausal woman whose tumor was negative for estrogen receptor.

Localized pleural malignant mesothelioma.

The occurrence of pleural malignant mesothelioma (MM) is unusual and the cases that appear as a localized tumor are extremely rare. A case of localized pleural MM including immunohistochemical findings is presented. A 70‐year‐old man had an abnormal shadow found during a routine roentgenogram at an annual health checkup and was admitted to Toneyama National Hospital (Toyonaka, Osaka, Japan) for detailed examinations. Chest X‐rays showed a 2 × 5 cm‐sized nodule with relatively smooth margins in the right segment three. Computed tomography (CT) showed an extrapleural mass with a smooth surface and a thickened parietal pleura, and results of a biopsy performed under CT scanning yielded MM. Systematic examinations did not show any metastasis and the patient underwent surgery for removal of the mass. The resected tumor, measuring 3.2 × 3.1 cm, was firm, partially encapsulated, and irregularly shaped. Pathological examinations revealed that it consisted of large polygonal cells, partially showing myxoid patterns, which led to a diagnosis of localized pleural MM. Tumor recurrence was seen, and the duration between initial symptoms and death was 29 months. This case suggests that localized pleural MM has a high proliferative potential and aggressive course, and is considered an early stage of diffuse pleural MM.

Long-term pulmonary function after lobectomy for primary lung cancer.

The aim of this study was to investigate the factors affecting long-term postoperative pulmonary function with a view to increasing the application of combined resection, bronchoplasty, and induction therapy. Results in 80 patients who underwent lobectomy for primary lung cancer were analyzed. Predicted postoperative pulmonary function was calculated using the formula: postoperative predicted function = preoperative function × [1 − (b − n) /(42 − n)], where n and b are the numbers of obstructed segments and total segments, respectively, in the resected lobe. Spirometry was performed serially on the preoperative day, and at 3, 6, 12, 18, and 24 months postoperatively. The difference between the predicted postoperative pulmonary function and the function measured at 12 months postoperatively was calculated, and clinical and therapeutic variables were analyzed. Univariate analysis revealed that the difference in vital capacity was significantly related to surgical approach, bronchoplasty, and induction therapy, while the difference in forced expiratory volume in one second (FEV1) correlated with surgical approach and induction therapy. Multiple regression analysis showed induction therapy to be the sole factor related to the differences in both vital capacity and FEV1. Lung resection after induction therapy may cause an additional loss of pulmonary function in the late phase.

Immunohistochemical analysis of resectedclinical stage i pulmonary adenocarcinomas withhigh preoperative levels of serumcarcinoembryonic antigen

Abstract Background Clinical stage I pulmonary adenocarcinoma (AD) patients with persistently high serum carcinoembryonic antigen (CEA) levels after surgery have a poor prognosis. Although CEA staining pattern is reported to be a prognostic indicator for patients with colorectal cancer, the relationship with lung cancer is unclear. Methods One hundred eighteen patients with clinical stage I AD underwent surgery from 1993 to 1997. Of them, 19 (16%) patients with a high preoperative serum level of CEA and 19 randomly selected control patients with preoperatively normal CEA were studied. CEA staining of tumor specimens from each of the 38 patients was performed, and the staining patterns were then classified into two types: apical and diffuse. Results Patients with normal postoperative serum CEA levels (group HN, n=13) had a 5-year survival rate higher than those with persistently high postoperative serum CEA (group HH, n=6). In a comparison between the two groups, apical patterns (n = 10) were only seen in group HN, and those who demonstrated an apical CEA staining pattern had a 5-year survival rate (5-YSR) of 80% as compared with 13% for those HN patients with only a diffuse pattern ( p = 0.01). In the control group, 16 (84%) patients had an apical staining pattern and the other 3 patients showed no staining. Conclusions Patients with normalized serum CEA levels had a high chance of showing an apical staining pattern, which may be a very good prognosis predictor for patients with high preoperative levels of CEA.

Bronchoscopically undiagnosed small peripheral lung tumors

Small peripheral lung cancers (2 cm or less maximum diameter) are often surgically resected, and the survival rate of those patients has been reported to be significantly higher than that of patients with tumors 2.1 cm or more in diameter. We evaluated the status of these small tumors diagnosed during surgery, following unsuccessful transbronchial biopsy procedures. In a retrospective study, 84 consecutive patients, with a maximum diameter of 2 cm or less on chest computed tomography, were enrolled. All underwent surgery for diagnosis. Video-assisted thoracoscopic surgery was performed in 49 cases (58%), Video-assisted thoracoscopic surgery+mini-thoracotomy in ten cases (12%), and an open lung biopsy in 25 cases (30%). Primary lung cancer was found in 40 cases (48%), metastatic lung tumors in three cases (3%), and benign lung tumors in 41 cases (49%). Among the 40 primary lung cancer cases, adenocarcinoma was in 38, squamous cell carcinoma was in one, and small cell carcinoma was in one. The rate of stage IA was 90%. Surgical excision of undiagnosed small peripheral nodules without waiting is necessary if transbronchial biopsy diagnosis is unsuccessful, because of the high rate of stage IA non-small cell lung cancer.