Efficacy and tolerability of nanoparticle albumin-bound paclitaxel in combination with carboplatin as a late-phase chemotherapy for recurrent and advanced non-small-cell lung cancer: A multi-center study of the Fukushima lung cancer association group of surgeons.

The present retrospective multi-center study aimed to evaluate the efficacy and feasibility of nanoparticle albumin-bound (nab)-paclitaxel plus carboplatin as a second or late-phase chemotherapy in patients with non-small cell lung cancer (NSCLC). A total of 25 patients with recurrent or advanced NSCLC who had received previous chemotherapy were treated with nab-paclitaxel (70-100 mg/m2, intravenously) on days 1, 8 and 15 every 28 days with a carboplatin area under the concentration-time curve of 4-6 on day 1. The overall response rate, disease control rate, progression-free survival (PFS), overall survival (OS) and toxicities were statistically evaluated. Of the 25 patients, there were 9 cases of recurrent disease following surgery, 16 cases of advanced disease, 13 cases of adenocarcinoma, 11 cases of squamous cell carcinoma and 1 case of large cell carcinoma. A total of 13 patients received second-line chemotherapy and 12 received fourth-line or later chemotherapy. One patient exhibited a complete response, 7 had a partial response, 10 exhibited stable disease and 7 had progressive disease. The overall response rate was 32.0% and the disease control rate was 72.0%. The median PFS and median OS following nab-paclitaxel treatment were 4.0 and 14.0 months, respectively. Frequent treatment-associated adverse events were myelosuppression, peripheral neuropathy, gastrointestinal symptoms and baldness, the majority of which were grade 1-2. Grade 3-4 neutropenia, thrombocytopenia and anemia occurred in 7 (28.0%), 3 (12.0%) and 2 (8.0%) patients, respectively. No patients experienced grade 3-4 sensory neuropathy and no grade 5 adverse effects were observed. Nab-paclitaxel plus carboplatin as second-phase or later chemotherapy provided a small but significant survival benefit for patients with recurrent or advanced NSCLC, with tolerable adverse effects. To the best of our knowledge, the results of the present study demonstrated for the first time that nab-paclitaxel plus carboplatin is a promising and feasible late-phase chemotherapeutic agent for NSCLC.

Recurrent Intrapulmonary Solitary Fibrous Tumor With Malignant Transformation.

Intrapulmonary solitary fibrous tumor (SFT) of the pleura; the so-called inverted pattern, which appears to grow into the lung parenchyma, is extremely rare. We experienced a 66-year-old woman with an intrapulmonary SFT that recurred locally with malignant transformation 2 years after wedge resection of the left upper lobe for the primary tumor. Subsequently, she underwent a lobectomy of the residual left upper lobe. Six years after the second operation she was well, without rerecurrence. Complete excision and long-term follow-up of intrapulmonary SFTs of the pleura are important, even when the primary tumor displays benign histopathologic features.

Ground-glass nodule in a patient with echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK)-positive lung cancer: a case report.

BACKGROUND: Grand-glass nodule for CT image has thought to be less aggressive tumor in lung cancer. Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK)-positive lung cancer presenting with Ground-glass nodules (GGNs) is relatively rare, and few such cases have been reported. CASE PRESENTATION: An asymptomatic 56-year-old woman exhibited a 1.1-cm GGN in the lower lobe of the left lung on computed tomography during a medical checkup. Positron emission tomography showed no difference in uptake by the nodule compared with other organs. We elected to perform surgery because the nodule included a solid component and had grown only slightly during the last 2 years according to thin-section computed tomography. Partial resection of the lower left lung was performed by video-assisted thoracic surgery. Pathological examination revealed mucus-producing high columnar epithelium forming an irregular tubular-acinar-like structure partly replacing the alveolar epithelium on hematoxylin and eosin staining. More than 50 % of the tumor demonstrated a lepidic growth pattern. The tumor was negative for epidermal growth factor receptor mutation but positive for the EML4-ALK fusion oncogene according to fluorescence in situ hybridization. CONCLUSIONS: We herein report a case of EML4-ALK-positive lung cancer presenting with a GGN along with a review of the relevant literature, including histopathological findings and imaging features. We consider that EML4-ALK-positive lung cancer is often highly progressive and that careful follow-up is therefore essential in these patients.

Concomitant metastatic lung tumor and hamartoma.

A 65-year-old woman who had undergone surgery for rectal cancer was referred to our hospital with an abnormal shadow on chest X-ray. Chest computed tomography (CT) revealed a 3-cm-diameter mass with ill-defined margins in the left lower lobe and a well-defined, 1-cm-diameter, round nodule in the right upper lobe. Transbronchial lung biopsy (TBLB) of the left lung tumor revealed metastatic adenocarcinoma originating from the rectal cancer. The patient underwent synchronous partial resection of the right upper lobe and left lower lobectomy under video-assisted thoracoscopic surgery (VATS). The pathological diagnosis of the right lung tumor was chondromatous hamartoma, and the left lung tumor was metastasis originating from the rectal cancer. The patient's postoperative course was uneventful, and she was well and free of disease 4 years after pulmonary metastasectomy.

Prediction of recurrence for non-small cell lung cancer by combined analysis of molecular markers and 18F 2-fluoro-2-deoxy-D-glucose positron emission tomography.

PURPOSE: Numerous biomarkers have been reported to reflect prognosis in patients with non-small cell lung cancer, but most of them remain controversial in terms of the clinical benefits. The aim of this study is to establish a novel procedure in combined analyses of molecular markers and biomedical image for precise prediction for patient prognosis of non-small cell lung cancer. EXPERIMENTAL DESIGN: Molecular markers related to cell cycle and proliferation and (18)F 2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) were retrospectively analyzed for their utility as prognostic parameters in 54 patients with non-small cell lung cancer. Expression of ten representative molecular markers (Glut-1, proliferating cell nuclear antigen, Ki-67, cyclin B1, cyclin D1, cyclin E, E2F-1, p21, p27, and p53) were immunohistochemically analyzed using tissue microarray. The maximum standardized uptake value (SUVmax) on FDG-PET was analyzed as a semiquantitative value of FDG uptake of the primary tumor. RESULTS: Several molecular markers were significantly correlated with some of clinicopathological parameters, whereas none of each marker were correlated with recurrence or survival. Hierarchical clustering analysis in combination of immunohistochemical analysis of molecular expressions and SUVmax divided them into three subgroups significantly different in two-year recurrent-free survival (Cluster A, 56.3%; B, 100%; C 93.8%). These clustering subgroups were also significantly correlated with disease recurrence (p=0.0282). CONCLUSIONS: Hierarchical clustering analysis, based on molecular markers and FDG accumulation, could be an efficient tool for prediction of recurrence and survival in patients with non-small cell lung cancer.

Long-term outcomes after video-assisted thoracic surgery (VATS) lobectomy versus lobectomy via open thoracotomy for clinical stage IA non-small cell lung cancer.

BACKGROUND: Video-assisted thoracic surgery (VATS) lobectomy is a standard treatment for lung cancer. This study retrospectively compared long-term outcomes after VATS lobectomy versus lobectomy via open thoracotomy for clinical stage IA non-small cell lung cancer (NSCLC). METHODS: From July 2002 to June 2012, 160 patients were diagnosed with clinical stage IA NSCLC and underwent lobectomy. Of these, 114 underwent VATS lobectomy and 46 underwent lobectomy via open thoracotomy. RESULTS: The 5-year disease-free survival (DFS) rate was 88.0% in the VATS group and 77.1% in the thoracotomy group for clinical stage IA NSCLC (p = 0.1504), and 91.5% in the VATS group and 93.8% in the thoracotomy group for pathological stage IA NSCLC (p = 0.2662). The 5-year overall survival (OS) rate was 94.1% in the VATS group and 81.8% in the thoracotomy group for clinical stage IA NSCLC (p = 0.0268), and 94.8% in the VATS group and 96.2% in the thoracotomy group for pathological stage IA NSCLC (p = 0.5545). The rate of accurate preoperative staging was 71.9% in the VATS group and 56.5% in the thoracotomy group (p = 0.2611). Inconsistencies between the clinical and pathological stages were mainly related to tumor size, nodal status, and pleural invasion. Local recurrence occurred for one lesion in the VATS group and six lesions (five patients) in the thoracotomy group (p = 0.0495). CONCLUSIONS: The DFS and OS were not inferior after VATS compared with thoracotomy. Local control was significantly better after VATS than after thoracotomy. Preoperative staging lacked sufficient accuracy.

Recent advances in immunotherapy for non-small-cell lung cancer.

Despite of recent development in the field of molecular targeted therapies, lung cancer is a leading cause of cancer death in the world. Remarkable progress has been made recently in immunotherapy for patients with non-small-cell lung cancer (NSCLC), with several modalities, concepts, and treatment settings being investigated. In vaccine development, large-scale clinical trials such as those with L-BLP25, belagenpumatucel-L, TG4010, and talactoferrin are already ongoing and some results have been reported. A trial of a vaccine as adjuvant therapy for patients with completely resected NSCLC is also ongoing with one of the major cancer-testis antigens, melanoma-associated antigen (MAGE)-A3. More recently, the effectiveness of multiple peptide vaccines has also been shown. Recently developed unique treatment modalities are the immune checkpoint inhibitors, such as antibodies against PD-1 and PD-L1, which also show promise. However, although therapeutic cancer vaccines are generally thought to be safe, severe adverse events should be monitored carefully when using immune checkpoint inhibitors. Here, we discuss recent advances and future perspectives of immunotherapy for patients with NSCLC.

Multiple therapeutic peptide vaccines consisting of combined novel cancer testis antigens and anti-angiogenic peptides for patients with non-small cell lung cancer.

BACKGROUND: Vaccine treatment using multiple peptides derived from multiple proteins is considered to be a promising option for cancer immune therapy, but scientific evidence supporting the therapeutic efficacy of multiple peptides is limited. METHODS: We conducted phase I trials using a mixture of multiple therapeutic peptide vaccines to evaluate their safety, immunogenicity and clinical response in patients with advanced/recurrent NSCLC. We administered two different combinations of four HLA-A24-restricted peptides. Two were peptides derived from vascular endothelial growth factor receptor 1 (VEGFR1) and 2 (VEGFR2), and the third was a peptide derived from up-regulated lung cancer 10 (URLC10, which is also called lymphocyte antigen 6 complex locus K [LY6K]). The fourth peptide used was derived from TTK protein kinase (TTK) or cell division associated 1 (CDCA1). Vaccines were administered weekly by subcutaneous injection into the axillary region of patients with montanide ISA-51 incomplete Freund's adjuvant, until the disease was judged to have progressed or patients requested to be withdrawn from the trial. Immunological responses were primarily evaluated using an IFN-gamma ELiSPOT assay. RESULTS: Vaccinations were well tolerated with no severe treatment-associated adverse events except for the reactions that occurred at the injection sites. Peptide-specific T cell responses against at least one peptide were observed in 13 of the 15 patients enrolled. Although no patient exhibited complete or partial responses, seven patients (47%) had stable disease for at least 2 months. The median overall survival time was 398 days, and the 1- and 2-year survival rates were 58.3% and 32.8%, respectively. CONCLUSION: Peptide vaccine therapy using a mixture of four novel peptides was found to be safe, and is expected to induce strong specific T cell responses. TRIAL REGISTRATION: These studies were registered with ClinicalTrials.gov NCT00633724 and NCT00874588.

Prognostic impact of p53 protein overexpression in patients with node-negative lung adenocarcinoma.

Prognostic value of p53 protein expression in node-negative lung adenocarcinoma is still controversy. The expression of p53 protein was examined immunohistochemically in lung adenocarcinoma using monoclonal antibody BP53-12. A total 131 cases of primary lung adenocarcinoma were examined. Relationship between expression of p53 protein and clinicopathologic factors were studied. Overexpression of p53 protein was found in 19 patients (14.5%). Univariate and multivariate analysis showed that overexpression of p53 protein was an independent prognostic factor in node-negative lung adenocarcinoma. p53 alteration could be a valuable predictor for prognosis in node-negative lung adenocarcinoma.

[Tissue array analysis of the aberrant expression of HLA class I molecules in human non small cell lung cancer].

A clinical significance of the aberrant expression of HLA class I molecules including HLA class I and HLA-G was analyzed using tissue array analysis. Our institute has established a two millimeter spot sized tissue array set of 105 clinical cases of resected human non small cell lung cancer tissues. A loss of HLA class I was observed in the 58.3% of cancer tissues. The aberrant expression of HLA G was also observed in the 55.2% of cancer tissues. Statistically significant correlations were observed among HLA class I expression and tumor size, nodal involvement and pathological stage. Survival analyses were shown that the HLA class I loss was correlated to a recurrence free survival time. The HLA-G expression did not correlate with any clinico-pathological parameters. A loss of HLA class I was probably involved due to a cancer progression in human non-small cell lung cancer through the mechanism of immune escape from the host immune system.

Extent of mediastinal lymph node dissection for clinical T1 non-small cell lung cancer.

The present study was designed to determine the extent of lymph node dissection for clinical T1 non-small cell lung cancer without negatively influencing curability. The study included 192 cases with clinical T1 non-small cell lung cancers who underwent lobectomy with mediastinal lymphadenectomy. Among 69 cases with right upper lobe tumors, metastasis was found in subcarinal lymph node in one case only. No metastasis was found in subcarinal node in cases free of metastasis in hilar and/or superior mediastinal nodes. Among 33 cases with right lower lobe tumors, metastasis was detected in the superior mediastinal node only in cases with metastasis in hilar and/or subcarinal nodes. Among 51 cases with left upper lobe tumors, no metastasis was found in the subcarinal node. Among 22 cases with left lower lobe tumors, metastasis was found in the superior mediastinal nodes only in cases with metastasis in hilar and/or subcarinal nodes. We propose the following scheme for the extent of mediastinal node dissection. Dissection of mediastinal node for clinical T1 non-small cell lung cancer cannot be omitted. But, 1) for upper lobe tumors, subcarinal lymphadenectomy could be omitted if no metastasis is found in hilar and superior mediastinal nodes based on gross and microscopic examination of frozen sections. 2) Similarly, for lower lobe tumors, superior mediastinal lymphadenectomy could be omitted if no metastasis is detected in the hilar and subcarinal nodes.