Phase III study of adjuvant gemcitabine compared with adjuvant uracil-tegafur in patients with completely resected pathological stage IB-IIIA non-small cell lung cancer (WJTOG0101).

BACKGROUND: Adjuvant oral uracil-tegafur (UFT) has led to significantly longer postoperative survival among patients with non-small-cell lung cancer (NSCLC). Gemcitabine (GEM) monotherapy is also reportedly effective for NSCLC and has minor adverse events (AEs). This study compared the efficacy of GEM- versus UFT-based adjuvant regimens in patients with completely resected pathological stage (p-stage) IB-IIIA NSCLC. PATIENTS AND METHODS: Patients with completely resected p-stage IB-IIIA NSCLC were randomly assigned to GEM or UFT. The primary endpoint was overall survival (OS); secondary endpoints were disease-free survival (DFS), and AEs. RESULTS: We assigned 305 patients to the GEM group and 303 to the UFT group. Baseline factors were balanced between the arms. Of the 608 patients, 293 (48.1%) had p-stage IB disease, 195 (32.0%) had p-stage II disease and 121 (19.9%) had p-stage IIIA disease. AEs were generally mild in both groups, and only one death occurred, in the GEM group. After a median follow-up of 6.8 years, the two groups did not significantly differ in survival: 5 year OS rates were GEM: 70.0%, UFT: 68.8% (hazard ratio 0.948; 95% confidence interval 0.73-1.23; P = 0.69). CONCLUSION: Although GEM-based adjuvant therapy for patients with completely resected stage IB-IIIA NSCLC was associated with acceptable toxicity, it did not provide longer OS than did UFT.

Minimally invasive surgical procedures for thymic disease in Asia.

Video-assisted thoracic surgery (VATS) procedures for thymic tumors and myasthenia gravis were introduced in Asia in the middle 1990s in at least two regions, Hong Kong and Japan. To overcome difficulties in obtaining a wide view of the anterior mediastinum, several methods for lifting the sternum or anterior chest wall have been presented, mainly by Japanese surgeons. More recently, single port VATS through a subxiphoid incision was also introduced in Japan. The long-term outcome of a VATS extended thymectomy for myasthenia gravis has been shown to be comparable to that of a trans-sternal extended thymectomy, while the long-term outcome of a VATS thymectomy for thymic epithelial tumors remains to be elucidated. Nevertheless, its indication for tumors in an early stage is now widely accepted, and the number of VATS procedures is steadily increasing in Japan and China. Single-port VATS through a subxiphoid incision was developed in Japan and might become accepted as a useful approach in the near future when combined with robot-assisted thoracoscopic surgery. In addition, robot-assisted thoracoscopic surgery for the thymus has also been introduced in some areas in Asia. Although few of those surgical procedures for the thymus have been performed, results obtained thus far indicate that it might be preferable to lung resection. Several novel minimally invasive thymectomy techniques have been invented and developed in Asia, and further advancements in this field by Asian surgeons are anticipated.

Surgical resection for advanced lung cancer using the hemi-clamshell approach.

OBJECTIVES: The hemi-clamshell (HCS) approach consists of partial sternotomy with antero-lateral thoracotomy. This study evaluated the utilities and outcomes of the HCS approach in advanced lung cancer patients. METHODS: We retrospectively investigated 45 patients who underwent surgery for advanced lung cancer via the HCS procedure between 2000 and 2014, the indications for surgery being tumour invasion extending to the aorta arch in 5, descending aorta in 9, main pulmonary artery in 5, superior vena cava in 6, right or left atrium in 4, apical thoracic dome in 7 patients and mediastinal lymphadenopathy for left-sided lung cancer in 12. Preoperative chemo-radiation induction therapy was given to 33 of these patients. RESULTS: We performed 34 lobectomies, including 8 sleeve lobectomies, 10 pneumonectomies and 1 wedge resection of the lung. Cardiovascular reconstruction of the aortic arch was performed in 3, descending aorta in 4, subclavian arteries in 4, superior vena cava in 5, atrial wall in 4 and pulmonary artery in 12 patients with some overlap. En bloc chest wall resection was performed in 7 patients. Lymphadenectomy in the pre-tracheal and subcarinal areas was routinely performed. Forty-two operations (93%) were complete resections. No postoperative mortalities occurred and the 5-year survival rate for all patients was 53%. CONCLUSIONS: The HCS approach is suitable for advanced lung cancer, including invasion of mediastinal structures, the apical dome and mediastinal lymph nodes. It provides a wide view of the mediastinum and apex of the chest, and safe access to the thoracic great vessels, resulting in better long-term survival rates.

Total pleural covering technique for intractable pneumothorax in patient with Ehlers-Danlos syndrome.

We report a patient with vascular-type Ehlers-Danlos syndrome (vEDS) who developed pneumothorax and was treated with a total pleural covering technique (TPC). A 24-year-old man developed repeat pneumothorax with intermittent hemo-sputum. Based on unusual radiological manifestations of lung lesions and physical findings, EDS was suspected as an underlying cause of the pneumothorax. Surgical treatment was performed using a mediastinal fat pad and TPC, and no relapse was seen up to 2 years after surgery. TPC is a less invasive surgical approach for selected patients with vEDS. Accurate underlying diagnosis of vEDS and systemic evaluation of vascular complications are necessary before planning surgery.

Randomized Phase II Study of Adjuvant Chemotherapy with Long-term S-1 versus Cisplatin+S-1 in Completely Resected Stage II-IIIA Non-Small Cell Lung Cancer.

PURPOSE: The aims of this study were to evaluate the efficacy and safety of S-1 versus cisplatin (CDDP)+S-1 in patients with completely resected stage II and IIIA non-small cell lung cancer, and to identify predictive biomarkers whose expression in the tumors was significantly associated with patient outcome. EXPERIMENTAL DESIGN: A total of 200 patients were randomly assigned to receive either S-1 (40 mg/m(2) twice per day) for 2 consecutive weeks repeated every 3 weeks for 1 year (S group) or CDDP (60 mg/m(2)) on day 1 plus oral S-1 (40 mg/m(2) twice per day) for 2 consecutive weeks repeated every 3 weeks for four cycles (CS group) within 8 weeks after surgery. The primary endpoints were relapse-free survival (RFS) at 2 years and identification of predictive biomarkers whose expressions have been reported to be associated with CDDP or fluoropyrimidine sensitivity. RESULTS: The RFS rate at 2 years was 65.6% (95% confidence intervals; CI, 55.3-74.0%) in the S group and 58.1% (95% CI, 47.7-67.2%) in the CS group. The only gene with interaction of P < 0.05 was uridine monophosphate synthase (UMPS; P = 0.0348). The benefit that members of the S group had over members of the CS group was higher expression of UMPS. In vitro and in vivo experiments confirmed that overexpression of UMPS enhanced the antitumor effect of fluoropyrimidine. CONCLUSIONS: Adjuvant S-1 monotherapy might be preferable to CDDP+S-1 for patients with completely resected NSCLC. UMPS expression may define a patient subset that would benefit from long-term postoperative S-1 monotherapy.

Improved procedures and comparative results for video-assisted thoracoscopic extended thymectomy for myasthenia gravis.

INTRODUCTION: We previously introduced video-assisted thoracoscopic ET (VATS-ET) as a therapeutic option for MG with acceptable results. We have conducted further investigations to improve the procedure without deterioration of operative results, including myasthenia gravis (MG) remission rate and palliation rate. Here, we report the details of our current procedure, as well as surgical results and patient outcomes as compared with the original VATS-ET procedure. MATERIAL AND METHODS: From January 2002 to September 2013, we performed a VATS-ET procedure with an anterior chest wall lifting method for 77 patients who had MG with or without a thymoma. During that period, we investigated the appropriate indications and improved the procedure. RESULTS: Our current indication for this procedure is MG with the anti-acetylcholine receptor antibody or sero-negative type, or MG with a thymoma <5 cm in diameter without invasion to adjacent organs. With our procedure, the thymus and surrounding tissue are sufficiently resected using a bilateral thoracoscopic surgical method without neck incision. Remission and palliation rates were found to be equivalent to those obtained with the original VATS-ET procedure. CONCLUSION: VATS-ET is suitable for select patients with MG with or without a thymoma. In addition, our current method has shown to be effective while also offering cosmetic advantages as compared with the original, neck incision needed, VATS-ET method.

Simple technique for reconstruction of superior vena cava and brachiocephalic vein after removal for thoracic malignancies.

A ringed polytetrafluoroethylene graft was applied to reduce clamping time for a patent major vein. In case 1, after suturing the ringed graft to the right appendage, the other end was inserted in the distal direction of the left brachiocephalic vein and secured by ligation. In case 2, to repair an extensive superior vena cava defect, the graft was wrapped with the remnant venous wall and fixed with a continuous suture. Only 5 minutes were required to reconstruct the left brachiocephalic vein and 20 minutes for the superior vena cava. Long-term graft patency was obtained without thrombosis.

Pulmonary pleomorphic carcinoma with rapid progression.

We describe a case of pleomorphic carcinoma showing a recurrent tumor with massive hemorrhage and myxoid change in the chest wall 2 months after complete resection. Whereas specimens from the initial surgery revealed both adenosquamous carcinoma and sarcomatous elements, the recurrent tumor predominantly consisted of a sarcomatous element. The recurrent tumor had stronger immunoreactivity for mesenchymal markers than the primary tumor, indicating that the sarcomatous element had more malignant potential than the epithelial element.

Pathological status of mediastinal lymph nodes after preoperative concurrent chemoradiotherapy determines prognosis in patients with non-small cell lung cancer.

OBJECTIVES: The benefits of preoperative chemoradiotherapy for advanced nonsmall cell lung cancer (NSCLC) remain controversial. To evaluate prognostic indicators of clinical N2 NSCLC patients treated with concurrent chemotherapy followed by pulmonary resection, we performed a retrospective study. METHODS: We retrospectively investigated 52 patients with pathologically proven N2 NSCLC who underwent concurrent chemoradiotherapy before pulmonary resection. Each received 2 cycles of cisplatin-vinca alkaloid-based chemotherapy every 4 weeks. Radiotherapy, directed at the tumor and mediastinal nodes, was started on day 2 at a median dose of 44 Gy. A thoracotomy was performed 6 to 8 weeks after completion of chemoradiotherapy. RESULTS: The overall 5-year survival rate for the 52 patients was 38%. Complete pathological response by the tumor was found in 11 (21%). Down-staging of nodal stage occurred in 29 patients, (56%) and overall survival was better in those with lower pathological N status. The 5-year survival rate was 58% for pathological N0-N1 disease and 0% for N2 disease. While the response to induction therapy by the primary tumor was correlated with postoperative nodal stage, multivariate analysis revealed postoperative nodal stage as an independent prognostic factor. CONCLUSION: Pathological status of mediastinal lymph nodes in response to preoperative concurrent chemoradiotherapy determined prognosis in our patients.

Pulmonary carcinosarcoma with an osteosarcomatous component.

Pulmonary carcinosarcoma is a rare disease entity defined as a neoplasm, which has biphasic features consisting of both epithelial and sarcomatous components. It has been reported that the most frequent epithelial component is squamous cell carcinoma, while the most frequent sarcomatous component is rhabdomyosarcoma. Pulmonary carcinosarcomas with osteosarcoma components are even rarer. We report a case of a potentially curative resection for carcinosarcoma with an osteosarcoma component. Thoracic surgeons should be aware of this rare tumor when lung tumors with ossification are encountered.

Thymic carcinoma with adenoid cystic carcinomalike features with distant metastases.

Adenoid cystic carcinoma (ACC), which is a subtype of the nonpapillary adenocarcinoma of the thymus, is extremely rare. We report a patient with thymic carcinoma with ACC-like features presented with multiple bone and pulmonary metastases that underwent surgery. The present case firstly demonstrated that thymic carcinoma with ACC-like features could have metastatic potential.

Nutritional status of patients undergoing chemoradiotherapy for lung cancer.

Impaired nutrition is an important predictor of perioperative complications in lung cancer patients, and preoperative chemoradiotherapy increases the risk of such complications. The goal of this study was to assess the effect of an immune-enhancing diet on nutritional status in patients undergoing lung resection after chemoradiotherapy. We compared the preoperative nutritional status in 15 patients with lung cancer undergoing lung resection without chemoradiotherapy and 15 who had chemoradiotherapy. Body mass index and lymphocyte counts were lower in patients who had chemoradiotherapy. Although there was no difference in the rate of postoperative morbidity between groups, the chemoradiotherapy patients were more likely to have severe complications postoperatively. After chemoradiotherapy in 12 patients, 6 received oral Impact for 5 days, and 6 had a conventional diet before surgery. Oral intake of Impact for 5 days before surgery modified the decrease in transferrin and lymphocytes after the operation. Preoperative immunonutrition may improve the perioperative nutritional status after induction chemoradiotherapy in patients undergoing lung cancer surgery, and reduce the severity of postoperative complications. These potential benefits need to be confirmed in a randomized controlled trial.

Surgical results and staging of non-small cell lung cancer with interlobar pleural invasion.

The aim of this study was to compare the survival rates of non-small cell lung cancer (NSCLC) with interlobar pleural invasion (IPI) with that of patients with other T2 and T3 diseases according to the seventh TNM staging system. One thousand and one patients with pathologic T2 and T3 NSCLC (according to the seventh staging criteria) treated between 1980 and 2004 were retrospectively evaluated. Among these, 682 patients were pathologically staged as T2 without IPI (T2 group), 25 as T2 with IPI (IPI group) and 294 as T3 (T3 group). The 5-year survival rate for the T2, IPI and T3 groups were 52.0, 31.1 and 36.3%, respectively. In patients without nodal involvement, the 5-year survival rates of the T2N0, IPIN0 and T3N0 groups were 60.9, 40.0 and 45.9%, respectively. The survival rate was significantly different between the T3N0 and T2N0 groups (P < 0.001) and between the IPIN0 and T2N0 (P = 0.020) groups. There was no significant difference in the survival rate between the IPIN0 and T3N0 groups (P = 0.644). In patients without nodal involvement, the survival of NSCLC with IPI is similar to that of the T3 disease.

Intrapulmonary neurofibroma independent of neurofibromatosis type 1.

Intrapulmonary neurofibromas without neurofibromatosis type 1 are rare-so rare that only 11 cases have been reported previously. This case report describes a 37-year-old woman who was otherwise healthy. Chest radiography and computed tomography showed a solitary nodule, 20 mm diameter, in the left lung. The tumor was removed and examined. It was not encapsulated but was covered with an intact bronchial mucosa and lacked a clear partition into two areas of Antoni A (a palisading cellular component) and Antoni B (a loose myxoid component). Tumor cells were strongly positive for neuron-specific enolase and S-100 protein. These data characterized the tumor as a rare benign neurofibroma. The patient shows no sign of recurrence after 12 months of follow-up. We reviewed and characterized surgically resected cases of intrapulmonary neurofibroma without neurofibromatosis type 1 especially in comparison with cases of endotracheobronchial neurofibroma.

Clinical implications of the margin cytology findings and margin/tumor size ratio in patients who underwent pulmonary excision for peripheral non-small cell lung cancer.

PURPOSE: A pulmonary wedge resection is useful for the treatment of peripheral non-small cell lung cancer (NSCLC). The margin/tumor size ratio (M/T) is a predictor of positive margin cytology findings in these procedures, although the long-term clinical implications remain unclear. This relationship was investigated in this study. METHODS: Thirty-seven cases with a high surgical risk without additional pulmonary resection were selected from those accrued in a multicenter prospective study of optimal margin distance for pulmonary excision of peripheral NSCLC and followed for more than 5 years (range 5.3-14 years). RESULTS: Both the M/T and margin cytology findings were indicators of cancer recurrence and survival. All seven cases of surgical margin recurrence had a cytology-positive surgical margin. The 5-year survival rate was 54.2% (n = 24) for M/T < 1 and 84.6% for M/T ≥ 1 (n = 13, P = 0.05), while it was 38.5% for positive margin (n = 13) and 79.2% for negative margin (n = 24) cases (P = 0.001). In addition, the margin cytology findings were an independent prognostic factor. CONCLUSION: A pulmonary wedge resection for peripheral NSCLC should result in a negative malignant margin, which might be obtained from a sufficient tumor margin ratio of M/T ≥ 1.

Low dihydropyrimidine dehydrogenase correlates with prolonged survival in patients with lung adenocarcinoma treated with 5-fluorouracil.

BACKGROUND: The enzyme dihydropyrimidine dehydrogenase (DPD) is involved in the metabolism of 5-fluorouracil (5-FU). The aim of this study was to clarify the correlation between the expression of DPD and the efficacy of 5-FU therapy in patients with lung adenocarcinoma (AD). PATIENTS AND METHODS: We examined surgically resected specimens from 90 stage I to IIIA patients with lung ADs to determine the level of intra-tumoral DPD mRNA. RESULTS: Administration of 5-FU improved the prognosis of patients with low DPD-expressing tumors, whereas it did not do so for patients with high DPD expressing tumors. Patients with low DPD-expressing tumors administered with 5-FU had a significantly better prognosis than those who underwent surgery alone. A Cox proportional hazards regression model revealed that administration of 5-FU was an independent variable to predict prognosis in patients with low DPD-expressing tumors. CONCLUSION: Quantification of DPD mRNA levels is useful for determining the subgroup of lung AD patients who would benefit most from 5-FU after surgery.

Epithelial to mesenchymal transition is a determinant of sensitivity to chemoradiotherapy in non-small cell lung cancer.

BACKGROUND: The epithelial to mesenchymal transition (EMT) is a fundamental biological process during which epithelial cells change to a mesenchymal phenotype; it has a profound impact on cancer progression. The purpose of this study was to clarify the role of EMT in the sensitivity of non-small cell lung cancer (NSCLC) to chemoradiotherapy (CRT). METHODS: We evaluated the correlation between EMT and sensitivity to chemotherapy or radiotherapy using NSCLC cells induced to undergo EMT with epidermal growth factor or transforming growth factor-ß1. Immunohistochemistry was used to examine the expression of EMT markers, E-cadherin, cytokeratin, N-cadherin, and vimentin in 50 tumor specimens obtained from patients with NSCLC both before and after CRT. RESULTS: The EMT resulted in increased malignant potential and reduced sensitivity to cisplatin and paclitaxel in NSCLC cells. Furthermore, chronic exposure to cisplatin, paclitaxel, or radiation altered the cells into therapy-resistant sub-lines that showed phenotypic changes such as a spindle-cell shape and increased EMT marker expression. Also, decreased expression of epithelial markers and upregulation of mesenchymal markers were detected in surgically resected specimens after CRT compared with biopsy specimens obtained before treatment. The disease-free survival rate of patients with EMT marker-positive tumors was significantly lower than that of those with EMT marker-negative tumors. CONCLUSIONS: The EMT marker expression was detected in NSCLC tumors after CRT, indicating that EMT changes are associated with insensitivity to CRT. New therapeutic combinations using EMT-signaling inhibitors may be needed to circumvent the resistance of some types of cancer to CRT.

The transmembrane adaptor Cbp/PAG1 controls the malignant potential of human non-small cell lung cancers that have c-src upregulation.

The tyrosine kinase c-Src is upregulated in various human cancers, although the precise regulatory mechanism underlying this upregulation is unclear. We previously reported that a transmembrane adaptor Csk-binding protein (Cbp; PAG1) plays an important role in controlling the cell transformation that is induced by the activation of c-Src. To elucidate the in vivo role of Cbp, we examined the function of Cbp in lung cancer cell lines and tissues. In this study, we found that Cbp was markedly downregulated in human non-small cell lung cancer (NSCLC) cells. The ectopic expression of Cbp suppressed the anchorage-independent growth of the NSCLC cell lines (A549 and Lu99) that had upregulated c-Src, whereas the Cbp expression had little effect on other NSCLC cell lines (PC9 and Lu65) that express normal levels of c-Src. The expression of Cbp suppressed the kinase activity of c-Src in A549 cells by recruiting c-Src and its negative regulator, C-terminal Src kinase (Csk), to lipid rafts. The treatment with Src inhibitors, such as PP2, dasatinib, and saracatinib, also suppressed the growth of A549 cells. Furthermore, Cbp expression attenuated the ability of A549 cells to form tumors in nude mice, invade in vitro, and metastasize in vivo. In addition, we found a significant inverse correlation between the level of Cbp expression and the extent of lymph node metastasis in human lung cancers. These results indicate that Cbp is required for the Csk-mediated inactivation of c-Src and may control the promotion of malignancy in NSCLC tumors that are characterized by c-Src upregulation.