Teruhisa Takuwa

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)

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.

Low-fat diet management strategy for chylothorax after pulmonary resection and lymph node dissection for primary lung cancer.

OBJECTIVE We reviewed our experience of iatrogenic chylothorax after pulmonary resection for primary lung cancer to evaluate a low-fat diet management strategy. METHODS From October 2003 to March 2010, 1580 patients underwent lobectomy or greater resection and systematic mediastinal lymph node dissection for primary lung cancer at our institution. Chylothorax was diagnosed on the basis of chylous leakage from the chest tube and was confirmed by presence of triglycerides (>110 mg/dL) in the drainage fluid. We initially treated the patients with chylothorax conservatively with a low-fat diet (fat intake <10 g/day). If chest tube drainage produced >500 mL of chylous fluid during the first 24 hours after the initiation of the low-fat diet, surgical intervention was performed. If chest tube drainage produced >300 mL/day of chylous fluid after 3 days of a low-fat diet, we performed pleurodesis by injecting a preparation of OK-432, a penicillin-treated lyophilized preparation of a Streptococcus strain into the thoracic cavity through a chest tube. RESULTS Postoperative chylothorax developed in 37 patients (2.3%), 33 men and 4 women, with a median age of 69 years (range, 44-84). The initial procedures were pneumonectomy in 1 patient and lobectomy in 36 patients. In 23 patients (62%), their condition resolved with the low-fat diet only. A total of 10 patients underwent OK-432 pleurodesis, and 8 of these were cured with continuation of the low-fat diet. These 31 patients who responded to conservative treatment (84%) resumed a normal diet at a median of 10 days (range, 5-27) after the chylothorax diagnosis. The remaining 6 patients (16%) underwent reoperation and were discharged at a median of 18 days (range, 14-33) after the initial surgery. CONCLUSIONS A low-fat diet and OK-432 pleurodesis achieved positive results in >80% of patients with chylothorax after pulmonary resection with systematic mediastinal lymph node dissection within 4 weeks after the initial surgery. More than 500 mL of chylous fluid during the first 24 hours after the initiation of the low-fat diet was valid as an indication of the need for surgical intervention.

Perivascular epithelioid cell tumor of the rib

We present a rare case of perivascular epithelioid cell tumor (PEComa) in the right 6th rib of a 28-year-old man. A plain computed tomography scan showed a round osteolytic lesion in the right 6th rib. The resected tissue contained a globular-shaped, soft tumor. Histologically, the tumor was rich in vasculature and exclusively composed of perivascular epithelioid cells with clear cytoplasm. Immunohistochemically, the tumor expressed diffusely a melanocyte marker, human melanoma black-45, and focally a myogenic marker, α-smooth muscle actin, but not an epithelial marker, AE1/AE3. Fontana–Masson-positive melanin pigments were present and c-kit receptor tyrosine kinase (CD117), involved in the development of melanocytes but not myogenic cells, was expressed in tumor cells. These findings indicate that the tumor is PEComa with some differentiation into melanocytes. Notably, owing to the unique location of the occurrence, the tumor occupied bone marrow tissues of the rib, resulting that the tumor has the potential for hematogenous metastasis. In spite of the lack of cells with severe atypia, necrosis, and numerous mitoses, tumor cells invaded into surrounding tissues and overexpressed cyclin D1. To the best of our knowledge, this is the first case report of PEComa arising from the rib with the signs of malignant potential.

Prognostic significance of metabolic response by positron emission tomography after neoadjuvant chemotherapy for resectable malignant pleural mesothelioma

BACKGROUND To select optimal candidates for extrapleural pneumonectomy (EPP), we retrospectively evaluated the usefulness of metabolic response by fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) after neoadjuvant chemotherapy to predict prognosis for patients with resectable malignant pleural mesothelioma (MPM) who underwent EPP in a multicenter study. PATIENTS AND METHODS We carried out high-resolution CT (HRCT) and FDG-PET/CT before and after neoadjuvant platinum-based chemotherapy on 50 patients with clinical T1-3 N0-2 M0 MPM who underwent EPP ± postoperative hemithoracic radiotherapy. A decrease of ≥30% in the tumor maximum standardized uptake value (SUVmax) was defined as a metabolic responder. The radiologic response using the modified RECIST or metabolic response and surgical results were analyzed. RESULTS The median overall survival (OS) from diagnosis was 20.5 months. Metabolic responders significantly correlated to OS with median OS for metabolic responders not reached versus 18.7 months for non-responders. No correlation was observed between OS and radiologic response with median OS for radiologic responders and non-responders. Based on the multivariate Cox analyses, decreased SUVmax and epithelioid subtype were significantly independent factors for OS. CONCLUSIONS The metabolic response after neoadjuvant chemotherapy is an independent prognostic factor for patients with resectable MPM. Patients with metabolic responder or epithelioid subtype may be good candidates for EPP.

Well-differentiated papillary mesothelioma with invasion to the chest wall.

Well-differentiated papillary mesothelioma (WDPM) is an uncommon tumor with a papillary architecture, bland cytologic features, a tendency toward superficial spread without invasion, and good prognosis with prolonged survival. WDPM occurs primarily in the peritoneum of women, but also rarely in the pleura. We here report a case of 48-year-old woman who developed WDPM in the pleura with no history of asbestos exposure. Tumors were multifocal and widespread with a velvety appearance on the surface of parietal and visceral pleurae resected by extrapleural pneumonectomy (EPP). Tumors showed papillary structures with fibrovascular cores and lined by epithelioid cells. Immunohistochemically, these epithelioid tumor cells were positive for epithelial membrane antigen (EMA), a marker of malignant mesothelioma, with more than 50% positive for p53. Tumor cells microinvaded into subpleural parenchyma of the lung and minimally spread to adipose tissues of the mediastinal lesion. In addition, tumor cells invaded into the chest wall with a trabecular or glandular architecture. Based on these findings, this case is pathologically considered as WDPM of the pleura with malignant potential.

Diagnosis of synchronous primary lung adenocarcinomas based on epidermal growth factor (EGFR) gene status: A case report.

The diagnosis of multiple primary lung cancer is sometimes difficult when multiple lung tumors with the same histologic type are identified. We now present a case of synchronous double primary lung adenocarcinomas (one in the right upper lobe and another in the right middle lobe) diagnosed based on mutational analysis of the epidermal growth factor receptor (EGFR) gene, although clinico-pathological findings suggested the diagnosis of intrapulmonary metastasis. After complete resection, pathological sections revealed the similar pathological features of two adenocarcinomas and unexpected subcarinal nodal metastasis. As the L858R mutation within exon 21 of the EGFR gene was identified in the middle-lobe tumor and the subcarinal node but not in the upper-lobe tumor, we diagnosed as double primary cancers. Local mediastinal recurrence after operation has been well-controlled with administration of gefitinib, a EGFR-tyrosine kinase inhibitor, and mutational analysis of the EGFR gene provided important information not only in the diagnosis of double primary cancers but also in decision-making of selection of chemotherapeutic agent.

Current surgical strategies for malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is associated with a poor prognosis. The main components of multimodality treatment include surgery, chemotherapy, and radiation therapy. Surgery remains controversial. Two procedures are currently offered: extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D). The recent scientific literature suggests that P/D is a well-tolerated procedure, with the potential of becoming a default procedure in multimodality regimens. However, the precise treatment schemes and surgical procedures are yet to be established. In our study, we review the advantages and disadvantages of EPP and P/D, summarize the post-EPP and post-P/D observations (including mortality, morbidity, and median survival time), and discuss the choice of surgical technique (EPP vs. P/D). Moreover, we highlight the aspects of the multimodality treatments that are offered to MPM patients, including chemotherapy, radiotherapy, intensity-modulated radiation therapy, and other types of therapy.

Circulating tumor cells as a potential biomarker in selecting patients for pulmonary metastasectomy from colorectal cancer: report of a case.

Pulmonary metastasectomy is indicated for selected patients with metastatic colorectal cancer. A 43-year-old woman presented with solitary pulmonary metastasis from descending colon cancer and pulmonary metastasectomy was performed because of absence of any other active metastasis as well as normal serum carcinoembryonic antigen value. However, she died due to early development of nodal and bone metastases within 6 months after thoracotomy. The presence of circulating tumor cells (CTCs) in the peripheral blood (6 CTCs/7.5 ml) was the only factor to predict such a poor prognosis, suggesting that the CTC test is useful in selecting patients for pulmonary metastasectomy.