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Purpose: Targeting oncogenic driver mutations, such as sensitizing mutations in the epidermal growth factor receptor gene (EGFR), significantly improves the prognosis of patients with advanced non-squamous non-small-cell lung cancer (NS-NSCLC). As the number of genetic mutations that must be tested increases, the Oncomine Dx Target Test (ODxTT), which can simultaneously detect multiple cancer-related genes, is becoming the main test used, in preference to single-molecule testing. In this study, we evaluated the performance of ODxTT and cobas® EGFR Mutation Test v2 (cobas® EGFR), one of the single-molecule tests, in detecting EGFR mutations.Materials and methods: Samples from 211 patients who had been diagnosed with NS-NSCLC were tested simultaneously or sequentially with the cobas® EGFR Mutation Test and ODxTT. We compared the success rates and detection rates of both tests and evaluated their equivalence by determining the concordance rate and k-coefficient of the two tests.Results: The success rate in detecting EGFR mutations was 95.7% for ODxTT and 100% for cobas® EGFR. EGFR mutations were detected in 26.5% of samples with ODxTT and in 28.0% with cobas® EGFR. For the 200 samples successfully analyzed with both tests, the concordance rate and k-coefficient were 97.5% and 0.938, respectively. ODxTT failed to detect two exon 19 deletion mutations (p.E746_P753delinsVS and p.E746_P753delinsLS), and cobas® EGR failed to detect three instances of an exon 19 deletion (p.L747_P753delinsS), L861R, and an exon 20 insertion (p.P772_H733insV).Discussion: The success rate of ODxTT is slightly inferior to that of cobas® EGFR. ODxTT shared a high concordance rate and k-coefficient with cobas® EGFR in detecting EGFR mutations, but discordant results between the two tests were observed in a few cases, mainly due to the difference of detectable EGFR variants. Therefore, the advantages and limitations of each test must be clarified to ensure that genomic testing methods are used properly.

Increasing the T-cell immune response to Mycobacterium tuberculosis with an anti-programmed cell death 1 (anti-PD-1) antibody may ultimately have detrimental effects. We present the case of a patient with advanced non-small cell lung cancer who developed active tuberculosis (TB) after initial treatment with pembrolizumab, an anti-PD-1 antibody. Pembrolizumab was resumed after completing anti-TB treatment, and no relapse of TB was observed clinically or radiologically. Checkpoint inhibitor-related pneumonitis (CIP) is first suspected when a pulmonary shadow presents during treatment with an anti-PD-1 antibody. It is sometimes difficult to diagnose CIP using computed tomographic images alone. Careful testing, including bacterial examinations and bronchoscopic biopsy, should be performed.

Background Anti‐programmed death‐1 (PD‐1) immunotherapy can cause immune‐related pneumonitis, also known as checkpoint inhibitor pneumonitis (CIP). CIP that develops early after the initiation of anti‐PD‐1 immunotherapy is important because it is more severe than CIP that develops later. However, only a few studies have examined the risk factors for early‐onset CIP. Previous studies have reported several risk factors for CIP, including imaging findings of airway obstruction adjacent to lung tumors. However, the utility of this factor is debatable. Therefore, we investigated potential risk factors for early‐onset CIP, including tumor invasion in the central airway (TICA), in patients with non‐small cell lung cancer (NSCLC) receiving anti‐PD‐1 therapy. Methods We retrospectively analyzed the medical records and chest computed tomography scans of patients with NSCLC treated with anti‐PD‐1 antibodies at the Kanagawa Cancer Center in Japan between 1 January 2016, and 30 June 2018. The clinical characteristics and imaging findings, including TICA, were compared between patients with and without early‐onset CIP. Results Data from 181 eligible patients (114 receiving nivolumab and 67 receiving pembrolizumab) were analyzed. Early‐onset CIP occurred in 13 of 79 patients (16.5%) with TICA and 2 of 102 patients (2.0%) without TICA. In multivariate analysis, the odds ratio of early‐onset CIP for patients with TICA was 8.2 (95% confidence interval [CI]: 1.98–34.0, P = 0.0037). Conclusions TICA was strongly associated with early‐onset CIP in patients with NSCLC. Clinicians should carefully observe patients with TICA, especially within three months of anti‐PD‐1 antibody administration because of high CIP risk. Key points Significant study findings Tumor invasion in the central airway (TICA) was a predictor of early‐onset checkpoint inhibitor pneumonitis (CIP)TICA had good interobserver variability, indicating its utility in clinical practicePatients with TICA might have a higher immune status than patients without What this study adds This is the first study focusing on risk factors for CIP limited to early‐onset CIP., TICA was strongly associated with early‐onset CIP in patients with NSCLC. Clinicians should carefully observe patients with TICA, especially within three months of anti‐PD‐1 antibody administration because of high CIP risk.

Background Pleomorphic carcinoma (PC) of the lung is a rare type of lung cancer with aggressive characteristics and a poor prognosis. Because it is rare, the molecular characteristics of PC remain unclear. Methods A gene mutation analysis was performed using next-generation sequencing (NGS) in patients with PC of the lung who had undergone surgical resection. Results A total of nine patients were enrolled in the study. All the patients were male and eight had a history of smoking. Eight tumors contained spindle cells and three contained giant cells. Mutations considered significant were found in eight of the nine patients: in TP53 in five patients, in MET in two patients, and in ALK, ERBB2, PIK3CA, APC, NF1, and CDKN2A in one patient each. No EGFR mutation was detected in our analysis. Co-mutations were detected in three patients: TP53 with MET and NF1, TP53 with ERBB2, and PIK3CA with CDKN2A. Conclusions TP53 mutations were detected most frequently in PC of the lung with NGS analysis. Different co-mutations were seen in several specimens. Key points Significant findings of the study This study demonstrates that mutations in the TP53 gene are frequently found and co-mutations are sometimes found in pleomorphic carcinoma of the lung using genomic profiling analysis. What this study adds Our results will help to analogize the genetic characteristics and potential target of molecular-targeted agents of pleomorphic carcinoma of the lung.

Cisplatin-based chemotherapy is the standard adjuvant therapy for patients with completely resected stage II or III non-small cell lung cancer (NSCLC). However, the completion rate of four cycles of cisplatin-based chemotherapy is about 50%. This phase II study was conducted to evaluate the tolerability and efficacy of nedaplatin and irinotecan as adjuvant chemotherapy. Patients with pathological stage II or III NSCLC who underwent complete resection were enrolled. Treatment consisted of four cycles of nedaplatin (50 mg/m2) and irinotecan (50 mg/m2) on days 1 and 8 every 4 weeks. The primary end-point was the completion rate of four cycles of nedaplatin and irinotecan. Between January 2009 and March 2012, 39 patients (23 males and 16 females; median age 68 years) were registered. Overall, 36/39 (92.3%) patients completed four cycles. The median clinical follow-up time was 56 months (range 11–88 months). There were no differences in adverse events between patients with UGT1A1 polymorphisms and patients with wild-type UGT1A1. The median disease-free survival (DFS) was 49.4 months (95% confidence interval 14.2–84.5 months). Median overall survival (OS) was not reached. There were no treatment-related deaths, and adverse events were acceptable. The 5-year DFS and OS rates were 43.1 and 69.8%, respectively. Nedaplatin and irinotecan is a tolerable regimen for adjuvant chemotherapy, and was associated with adequate 5-year DFS and OS rates.

Introduction The purpose of this study was to evaluate the natural course of the progression of pulmonary subsolid nodules (SSNs). Materials and Methods Eight facilities participated in this study. A total of 795 patients with 1229 SSNs were assessed for the frequency of invasive adenocarcinomas. SSNs were classified into three categories: pure ground-glass nodules (PGGNs), heterogeneous GGNs (HGGNs) (solid component detected only in lung windows), and part-solid nodules. Results The mean prospective follow-up period was 4.3 ± 2.5 years. SSNs were classified at baseline as follows: 1046 PGGNs, 81 HGGNs, and 102 part-solid nodules. Among the 1046 PGGNs, 13 (1.2%) developed into HGGNs and 56 (5.4%) developed into part-solid nodules. Among the 81 HGGNs, 16 (19.8%) developed into part-solid nodules. Thus, the SSNs at the final follow-up were classified as follows: 977 PGGNs, 78 HGGNs, and 174 part-solid nodules. Of the 977 PGGNs, 35 were resected (nine minimally invasive adenocarcinomas [MIAs], 21 adenocarcinomas in situ [AIS], and five atypical adenomatous hyperplasias). Of the 78 HGGNs, seven were resected (five MIAs and two AIS). Of the 174 part-solid nodules, 49 were resected (12 invasive adenocarcinomas, 26 MIAs, 10 AIS, and one adenomatous hyperplasia). For the PGGNs, the mean period until their development into part-solid nodules was 3.8 ± 2.0 years, whereas the mean period for the HGGNs was 2.1 ± 2.3 years ( p = 0.0004). Conclusion This study revealed the frequencies and periods of development from PGGNs and HGGNs into part-solid nodules. Invasive adenocarcinomas were diagnosed only among the part-solid nodules, corresponding to 1% of all 1229 SSNs.

Continuation maintenance therapy with pemetrexed (PEM) and bevacizumab (BEV) following induction therapy with cisplatin (CDDP), PEM, and BEV is beneficial in advanced non-squamous non-small-cell lung cancer (NS-NSCLC), but the survival benefit of addition of BEV to CDDP/PEM as induction therapy is still unclear. The aim of this phase II study was to evaluate the feasibility and safety of a CDDP/PEM/BEV regimen in Japanese patients with EGFR wild-type NS-NSCLC.This study included 25 patients who receive intravenous CDDP, PEM, and BEV (15 mg/kg) from August 2010 to February 2013. The primary endpoint of this study was the response rate (RR) and the secondary endpoint was progression free survival (PFS), overall survival (OS), and safety.The median cycles of induction chemotherapy were four (range 1-6). RR was 64%. Most patients (64%) transitioned to maintenance therapy. The median PFS was 9.7 months. Median OS was 21.6 months. Haematological adverse events reaching grade 3 to 4 were neutropenia (8%) without febrile neutropenia, thrombocytopenia (4%), and anemia (4%). BEV-related non-haematological toxicities of grade 3/4 were hypertension (16%), thrombosis (4%), and gastrointestinal perforation (4%). Each adverse events was controllable, and there were no treatment-related deaths.CDDP/PEM/BEV regimen is effective and tolerable in patients with EGFR wild-type advanced NS-NSCLC, but should be paid attention to some BEV-related toxicities.

Although programmed death (PD)-1 immune checkpoint therapies target the immune system, the relationship between inflammatory factors and the clinical outcome of anti-PD-1 therapy for nonsmall cell lung cancer (NSCLC) is not fully understood. Here we examined the association between soluble immune mediators and the outcome of treatment with PD-1 inhibitors in patients with advanced/recurrent NSCLC. In two independent cohorts, we assessed the levels of 88 different soluble immune mediators in peripheral blood before and after anti-PD-1 treatment, and evaluated their associations with clinical outcomes. In the training cohort, the plasma levels of chitinase 3-like-1 and GM-CSF before treatment (p = 0.006 and p = 0.005, respectively) and changes in the plasma levels of CXCL2, VEGF, IFNα2, and MMP2 after treatment (p0.001, p = 0.019, p = 0.019, and p = 0.012, respectively) were significantly correlated with PFS. The change in the plasma CXCL2 level was also significantly associated with treatment-related AEs (p = 0.017). In the validation cohort, however, only the changes in the plasma levels of CXCL2 and MMP2 after treatment were associated with PFS (p = 0.003 and p = 0.006, respectively), and these changes were maintained during the course of anti-PD-1 therapy in patients who showed better clinical outcomes, even in those with tumor pseudoprogression. Since CXCL2 and MMP2 can be easily measured by minimally invasive blood sampling, they could be useful for monitoring of clinical outcomes in NSCLC patients receiving PD-1 inhibitor therapy.

Background Preclinical studies have demonstrated that docetaxel and bevacizumab may act synergistically by decreasing endothelial cell proliferation and preventing circulating endothelial progenitor mobilization. The objective of this study was to assess the efficacy and safety of a combination therapy of bevacizumab, cisplatin, and docetaxel in chemotherapy-naive Japanese patients with advanced non-squamous non-small-cell lung cancer (NSCLC). Methods Eligible patients were chemotherapy-naive and had advanced/recurrent non-squamous NSCLC. The patients received 4 cycles of docetaxel (60 mg/m2), cisplatin (80 mg/m2), and bevacizumab (15 mg/kg) once every 3 weeks, followed by bevacizumab as maintenance therapy, every 3 weeks until disease progression or attainment of unacceptable toxicity level. The primary endpoint was objective response rate (ORR). The numbers of circulating endothelial cells (CEC) were also estimated on days 1 and 8 of the first cycle for the exploratory analysis of efficacy prediction. Results A total of 47 patients were enrolled from October 2010 to April 2012. Bevacizumab as maintenance therapy was administered to 41 patients (87.2%), and the median number of total treatment cycles was 9 (range: 1–36). ORR, median progression-free survival (PFS), and median overall survival of the patients were 74.5%, 9.0 months, and 27.5 months, respectively. The most common grade 3/4 adverse event was neutropenia (95.7%), followed by leukopenia (59.6%) and hypertension (46.8%). PFS was longer in patients with ≥10 count increase in CECs than that in patients with

Background Palpation is the most important means of locating lung tumors and resecting them with sufficient margins. This study aimed to predict the palpability of pulmonary lesions using high-resolution computed tomography. Methods Eighty-six pulmonary lesions were palpated in fresh resected lung specimens from July 2013 to March 2014. The following parameters were compared between 10 impalpable and 76 palpable lesions: maximum tumor size in pulmonary and bone window level settings, consolidation tumor size in pulmonary window level setting, and pleural-tumor distance. In 54 adenocarcinomas, the lepidic component and fibrosis foci rates were compared between the two groups. Results Tumor size in bone window level setting and the consolidation tumor size were significantly smaller in the impalpable group (both p Conclusions Tumor size in bone window level setting or a consolidation tumor size ≤5 mm and pleural-tumor distance ≥ 5 mm are simple criteria that are potentially useful indicators for preoperative marking to locate small-sized lepidic-predominant adenocarcinomas with few fibrotic foci.

Both amrubicin (Am) and S-1 are effective against non-small-cell lung cancer (NSCLC), and preclinical studies have demonstrated that the effect of tegafur/uracil, the original compound of S-1, in combination with Am significantly inhibits tumor growth.We conducted a phase I/II study of Am and S-1 against pretreated NSCLC without EGFR mutation. We fixed the dose of S-1 at 40 mg/m(2) on days 1-14 and escalated the Am dose in increments of 5 mg/m(2) from a starting dose of 30 mg/m(2)/day on days 1-3 and repeated the cycle every 4 weeks.Twenty-six patients were registered. In phase I, at an Am dose of 35 mg/m(2)/day, three patients experienced grade 2 leukopenia during S-1 administration, and S-1 was withdrawn. Another patient developed grade 2 serum bilirubin in the first cycle. DLTs were observed in four of six patients at this dose level, and therefore, 30 mg/m(2)/day was set as the recommended dose for Am. Twenty patients received this recommended Am dose. Febrile neutropenia was observed in two patients, and one patient developed a grade 4 increase in serum creatinine. Grade 3 vomiting, infection, hypotension, and urinary retention were observed in one patient each, respectively. Other toxicities were mild, and there were no treatment-related deaths. Two patients showed a CR, three showed a PR, and the overall response rate was 25.0%. The median progression-free and the median survival times were 3.8 and 15.6 months, respectively, and the 1-year survival rate was 60%.Am and S-1 every 4 weeks is an effective combination for pretreated NSCLC without EGFR mutation.

We conducted a phase II study of nedaplatin (NP) and irinotecan (CPT) with concurrent thoracic radiotherapy (TRT) followed by docetaxel for locally advanced non-small cell lung cancer (NSCLC) to determine the safety and efficacy of the treatment. Patients with stage IIIA or IIIB NSCLC were treated with 3 cycles of chemotherapy comprising NP at 50 mg/mFifteen patients were registered, and 8 were able to receive the entire treatment regimen. Grade 4 neutropenia and thrombocytopenia occurred in 6 and 1 patient, respectively, receiving NP and CPT with concurrent TRT. Major non-hematological toxicities were nausea, vomiting and fatigue. Grade 3 pneumonitis and esophagitis occurred in one patient each, and 4 patients developed febrile neutropenia. Docetaxel consolidation was associated with mild toxicities. Two patients died of late pulmonary failure 3 to 4 months after treatment completion, and the study was terminated. Twelve patients responded, and the median survival time, and the 1-year and 3-year survival rates were 39.3 months, 86.7% and 60.0%, respectively. In conclusion, NP and CPT with concurrent TRT is effective for patients with locally advanced NSCLC, but frequently induces pulmonary damage.

There have been reports on the use of erlotinib in non-small cell lung cancer (NSCLC) patients after gefitinib resistance occurs, and it has been stated that erlotinib may be beneficial in patients with long stable disease (SD) previously treated with gefitinib.We retrospectively studied gefitinib-resistant NSCLC patients with favorable clinical features, who received erlotinib following disease progression after gefitinib treatment of more than 6 months.A total of 21 patients with NSCLC were included. Partial response was seen in 2 cases (9%), SD in 6 cases (19%), and progressive disease (PD) in 13 cases (62%). Disease control (DC) was achieved with erlotinib in 8 cases (36%). The median survival time (MST) was 369 days in DC cases and 133 days in PD cases. There were no statistical differences between DC cases and PD cases in terms of MST relative to sex, smoking and skin rash.Subsequent erlotinib therapy is one of the therapeutic options in the treatment of gefitinib-resistant NSCLC in which prior gefitinib has shown long-term SD of more than 6 months.

We divided pulmonary adenocarcinoma of ≤ 20 mm into air-containing and solid-density types based on a percentage reduction of the maximum tumor diameter in the mediastinal window image compared to the area in the lung window image on thin-section (TS) CT of ≥ 50% (air-containing type) and50% (solid-density type). No relapse occurred in patients with air-containing type. The prognosis of solid-density type may be poor even when the tumor size is 20mm or smaller. We investigated whether CT findings for these tumors could serve as prognostic factors.The subjects were 105 patients with solid-density type pulmonary adenocarcinoma that was identified on TSCT and found to have a diameter of 20mm or smaller after surgical resection during the period from April 1997 to November 2004. Notches, air bronchogram, pleural retraction, spiculation, venous involvement, and ground glass opacity were examined on TSCT, and their associations with pathological findings (i.e., pleural invasion, lymphatic permeation, vascular invasion, lymph node metastasis, and Noguchi's classification) and relapse were investigated using chi-square test and Cox proportional hazards model.The incidence of relapse was significantly higher in cases with notches. The incidence of notches increased with tumor growth and notches were frequent in Noguchi type D tumors, reflecting poorly differentiated adenocarcinoma. Lymphatic permeation and type D cases were independent factors associated with a poor prognosis using Cox proportional hazards model.TSCT findings may be useful for prediction of the prognosis of solid-density type pulmonary adenocarcinoma.

Study objectives Previously, we reported that small pulmonary adenocarcinomas (tumor diameter 20 mm or less) could be classified according to attenuation on thin-section CT (TS-CT) images as either ‘air-containing type’ or ‘solid-density type’ (Lung Cancer 2002;36:49–57). Air-containing type was defined as having areas where TOM (tumor opacity on mediastinal window images) was half or less than half the size of those noted on lung window images. Solid-density type was defined as having areas where TOM was greater than half the size of those noted on lung window images. Our findings indicated that there was no microscopic evidence of metastasis with air-type nor any relapses nor deaths, after resection. By contrast, patients with solid-density types demonstrated a poor prognosis. At this time, the histopathological characteristics of areas of TOM have not been fully investigated. The purpose of this study is to define the correlations between TOM and histopathological findings of small lung adenocarcinomas. Method We retrospectively reviewed the records and CT scans of 134 patients, who had undergone surgical resection of peripheral adenocarcninomas. All tumor diameters were 20 mm or less in size. All 134 patients had undergone TS-CT prior to surgery. TS-CT Images were acquired by a model X-Vigor/Real or an Aquillion CT scanner (Toshiba Medical Systems). Thin-section images of tumors were obtained at 135 kVp at 250 mAs with 1–2 mm section thicknesses. All images were photographed using mediastinal (level, 40 HU; width, 400 HU) and lung (level, −600 HU; width, 1600 HU) window settings. We researched the histopathological components corresponding to the areas of TOM. Results Areas of TOM demonstrated five possible histopathological findings; (1) collapse (C), (2) collapse with bronchioloalveolarcell carcinoma (CwB), (3) adenocarcinoma cells (Cells), (4) fibroblasts (F), and (5) mucus (M). Areas of TOM in air-containing type adenocarcinomas (52 cases) demonstrated predominantly C and/or CwB (C/CwB type, 44 cases). Areas of TOM in solid-density type adenocarcinomas (82 cases), in comparison, demonstrated predominantly Cells and/or Cells/F (Cell/F type, 67 cases). We noted a statistically significant difference between the histopathological findings of the areas of TOM of air-containing type and solid-density type tumors. The 39 cases of Cell/F type adenocarcinomas revealed microscopic evidence of metastasis (pleural involvement, vascular invasion, lymphatic permeation, or lymphnode metastasis). Whereas, no C/CwB type adenocarcinomas cases revealed any microscopic metastasis. The prognosis of C/CwB type after resection is better than for Cell/F type. Conclusion We found that air-containing type adenocarcinomas demonstrated C/CwB type, and that solid-density type adenocarcinomas demonstrated Cell/F type. The histopathological findings of small pulmonary adenocarcinomas could be classified into three groups: C/CwB type, Cell/F type and M type. The prognosis of C/CwB type is better than for Cell/F type. Our results indicate that there are clear correlations between the areas of TOM and the histopathological components of small pulmonary adenocarcinomas. Therefore TS-CT findings are a useful aid in determining the best surgical methods.

Background: Non-small cell lung cancer has several types of pathology and is moderately responsive to anticancer drugs, but specific chemotherapy regimens for each have not been established. Methods: We compared the outcomes of patients with squamous and nonsquamous cell carcinoma of the lung, which were compiled from four of our own studies of nedaplatin (NP) with irinotecan (CPT). Results: One hundred twenty-one patients with stage IIIB/IV non-small cell lung cancer received 50 to 100 mg/m 2 NP and 50 to 60 mg/m 2 CPT per cycle. Eighty-six patients were men and 35 were women, with a median age of 70 years (range, 29-84 years). Seventeen, 88, 8, and 8 patients had a performance status of 0, 1, 2, and 3, respectively. Twenty seven of the 121 patients had squamous cell carcinoma. Responses to the NP and CPT regimen were complete in two cases and partial in 45. The response rate was 51.9 and 35.1% in patients with squamous and nonsquamous cell carcinoma, respectively. Comparisons of survival revealed that the median survival time, 1-year survival rate, and 2-year survival rate were 14.5 and 9.1 months, 63.0 and 39.4%, and 29.6 and 19.1% for patients with squamous and nonsquamous cell carcinoma, respectively. Conclusions: The NP and CPT regimen is suggested to be more active against squamous cell carcinoma of the lung, and a comparative study to confirm this is recommended.

The fusion gene EML4-ALK (echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene) was recently identified as a novel genetic alteration in non-small-cell lung cancer. The clinicopathological features of EML4-ALK-positive adenocarcinoma are reported to include its high incidence in young, non-smoking patients, tumors that show distinct solid or acinar growth patterns with or without signet-ring cell histology, and its mutually exclusive occurrence with mutations in EGFR and KRAS. However, the clinical findings have not been well described. Here, we report a case of EML4-ALK-positive lung adenocarcinoma that showed multiple metachronous lesions on the pleura and pulmonary field, suspected to be a recurrence of lung adenocarcinoma after a 20-year disease-free interval. The slow clinical course may be characteristic of EML4-ALK-positive lung adenocarcinoma. Therefore, long-term observation of patients with EML4-ALK-positive lung adenocarcinomas is required after surgery.

Orphan No More The glutamate receptor δ2 (GluD2), another member of the ionotropic glutamate receptor family, has long been considered to be an orphan receptor because there are no known endogenous ligands. Nevertheless, GluD2 is essential for the normal development of cerebellar circuits. Using immunocytochemistry, binding assays, electrophysiology, and freeze-fracture electron microscopy, Matsuda et al. (p. 363 ) found that Cbln1, a soluble protein secreted from cerebellar granule cells, binds to the extracellular N terminus of GluD2 on Purkinje cells. Binding has two independent consequences: First, it leads to presynaptic differentiation and second, it causes postsynaptic clustering of several important synapse-specific molecules. Both events are needed for synapse formation between granule cells and Purkinje cells.

Cbln1, which belongs to the C1q/tumor necrosis factor superfamily, is a unique molecule that is not only required for maintaining normal parallel fiber (PF)-Purkinje cell synapses, but is also capable of inducing new PF synapses in adult cerebellum. Although Cbln1 is reportedly released from granule cells, where and how Cbln1 binds in the cerebellum has remained largely unclear, partly because Cbln1 undergoes proteolysis to yield various fragments that are differentially detected by different antibodies. To circumvent this problem, we characterized the Cbln1-binding site using recombinant Cbln1. An immunohistochemical analysis revealed that recombinant Cbln1 preferentially bound to PF-Purkinje cell synapses in primary cultures and acute slice preparations in a saturable and replaceable manner. Specific binding was observed for intact Cbln1 that had formed a hexamer, but not for the N-terminal or C-terminal fragments of Cbln1 fused to other proteins. Similarly, mutant Cbln1 that had formed a trimer did not bind to the Purkinje cells. Immunoreactivity for the recombinant Cbln1 was observed in weaver cerebellum (which lacks granule cells) but was absent in pcd cerebellum (which lacks Purkinje cells), suggesting that the binding site was located on the postsynaptic sites of PF-Purkinje cell synapses. Finally, a subcellular fractionation analysis revealed that recombinant Cbln1 bound to the synaptosomal and postsynaptic density fractions. These results indicate that Cbln1, released from granule cells as hexamers, specifically binds to a putative receptor located at the postsynaptic sites of PF-Purkinje cell synapses, where it induces synaptogenesis.

Background and Objectives: Advanced invasive thymomas are not usually manageable by surgical resection and radiotherapy. We reviewed our experience with a multidisciplinary approach and evaluated chemotherapy in the treatment of invasive thymoma. Patients and Methods: Seventeen consecutive patients with invasive thymoma were treated with multimodality therapy consisting of chemotherapy, surgery, and/or radiotherapy. Four patients had stage III disease with superior vena cava invasion, nine had stage IVa disease, and four had stage IVb disease. The chemotherapy regimen consisted of cisplatin, doxorubicin, and methylprednisolone (CAMP). Chemotherapy was administered in a neoadjuvant setting to the 14 patients and in an adjuvant setting to the remaining three patients. Surgical resection was intended in all patients. After those treatments, chemotherapy and/or radiation therapy were performed. Results: All but one of the 14 patients with induction chemotherapy responded to the CAMP therapy, and the response rate was 92.9%. Seven of these patients underwent complete remission after surgical resection and chemoradiotherapy, and the others underwent partial remission. All three patients treated with surgical resection and then chemotherapy with or without radiotherapy also achieved complete remission. Tumor progression after multimodality therapy occurred in 10 patients. After retreatment, eight of these patients were alive at the time of analysis, with a median survival time after recurrence of 30 months. The 5- and 10-year overall survival rates for all patients were both 80.7%. The major side effect of CAMP therapy was acceptable neutropenia. Conclusions: CAMP therapy was highly effective for invasive thymomas, and the multimodality therapy containing this chemotherapy brought about good disease control in the majority of patients. We believe that this multidisciplinary treatment with CAMP therapy, surgery, and radiotherapy is a justifiable initial treatment for patients with advanced invasive thymoma. Furthermore, appropriate treatments are essential for the long-term survival of patients with recurrences after multimodality therapy.

Squamous cell carcinoma (SCC) of the lung is moderately responsive to anticancer drugs, but no specific chemotherapy regimens have yet been established. We conducted a multicenter phase II study of nedaplatin (NP) and irinotecan (CPT) for SCC of the lung. Fifty patients underwent 4 to 6 cycles of chemotherapy comprising of NP at 100 mg/m(2) on day 1 and CPT at 60 mg/m(2) on days 1 and 8 every 4 weeks. Twenty-seven patients received 4 to 6 cycles of chemotherapy (median=4 cycles). Major toxicities included neutropenia (46.0%), grade 3 or 4 anorexia (22.0%), febrile neutropenia (16.0%), diarrhea (12.0%), hyponatremia (12.0%), grade 4 anemia (10.0%), thrombocytopenia (10.0%) and infection (10.0%). There were no treatment-related deaths. One patient achieved a complete response and 16 a partial response, with an overall response rate of 34.0%. The median survival time was 11.8 months (95% CI=8.3-15.8 months) and the 2-year survival rate was 22.0%. In conclusion, the NP and CPT regimen is not recommend for further evaluation for patients with advanced SCC of the lung.

With the advent of the molecular-targeted therapy, rapid progress has been made in the treatment of advanced or recurrent non-small-cell lung cancer (NSCLC). Although surgical complete resection remains the standard and most promising treatment, the clinical significance of epidermal growth factor receptor (EGFR) gene mutations in early-stage NSCLC remains uncertain.We investigated the prognostic value of EGFR mutations in surgically resected pathological stage I NSCLC. A total of 388 consecutive patients with NSCLC who underwent complete tumor resection in our hospital from 2006 through 2008 were studied retrospectively. Formalin-fixed, paraffin-embedded tissue sections were used to isolate DNA from carcinoma lesions. Mutational analyses of EGFR gene were performed by loop-hybrid mobility shift assay, a highly sensitive polymerase chain reaction-based method.Mutations of EGFR were detected in 185 of the 388 patients (47.7%). EGFR mutations were more frequently found in women (110 of 185, 59.5%), adenocarcinoma (183 of 185, 98.9%), patients with no vascular invasion (139 of 185, 75.1%) and nonsmokers (106 of 185, 57.3%). In patients with pathological stage I adenocarcinoma, both overall survival (OS) and disease-free survival (DFS) were significantly higher in patients with EGFR mutation than in those with wild-type EGFR. Furthermore, patients with exon 21 mutation have better DFS than those with exon 19 mutation in stage IB adenocarcinoma. Cox's proportional hazard model indicated that EGFR status was an independent variable for predicting the OS and DFS in patients with pathological stage IB adenocarcinoma.Our results suggest that EGFR mutations might be a prognostic factor in patients with pathological stage I lung adenocarcinoma.

We evaluated the tolerability and activity of the combination of weekly paclitaxel (PTX) and gemcitabine (GEM) in second-line treatment of advanced non-small cell lung cancer (NSCLC) after treatment with platinum-based chemotherapy.PTX (100 mg/m(2)) and GEM (1,000 mg/m(2)) were administered to patients with previous treated NSCLC on days 1 and 8 every 3 weeks.A total of 40 patients (performance status 0/1/2, 7/27/6 pts) were enrolled. The response rate was 32.5% (95% confidence interval: 18.0-47.0%). The median survival time was 41.7 weeks (95% confidence interval: 28.5-54.7 weeks). The median time to disease progression was 19 weeks. Hematological toxicities (grade 3 or 4) observed included neutropenia in 60%, anemia in 15%, and thrombocytopenia in 12.5% of patients. Non-hematological toxicities were mild, with the exception of grade 3 diarrhea, pneumonitis, and rash in one patient each. There were no deaths due to toxicity.The combination of weekly PTX and GEM is a feasible, well-tolerated, and active means of second-line treatment of advanced NSCLC.

Purpose: The safety and efficacy of weekly chemotherapy with paclitaxel and carboplatin for the treatment of patients with refractory or relapsed small-cell lung cancer (SCLC) were evaluated. Patients and methods: Paclitaxel (100 mg/m2) and carboplatin (with a target area under the concentration versus time curve of 2 mg min/ml using the Calvert formula) were administered to patients with previously- treated SCLC on days 1 and 8 at every 3–4 weeks. Results: A total of 29 patients (pts) [male/female, 26/3 pts; median age 62.7 years (43–74); performance status 0/1/2, 9/10/10 pts] were enrolled between March 2000 and June 2002. The mean number of cycles administered per pt was 3 (1–7). The overall response rate was 69% (95% confidence interval 52–86%), and 83% (15/18) in sensitive pts and 45% (5/11) in refractory pts (P

Drug-induced vessel vasculitis is a rare complication of chemotherapy. In particular, few reports have investigated drug-induced large vessel vasculitis. We herein report the case of a 57-year-old woman with advanced lung adenocarcinoma who developed perinuclear anti-neutrophil cytoplastic antibodies (p-ANCA)-positive periaortitis induced by bevacizumab combination chemotherapy. With the increasing use of combination therapy with bevacizumab, the incidence of vascular complications will potentially increase. A noninfectious fever occurring during chemotherapy might be a sign of vasculitis; therefore, we must ensure that possible periaortitis is not overlooked.

Objective: In patients with clinical T1 N0 M0 lung adenocarcinoma, we investigated whether the proportion of ground-glass opacity area measured on high-resolution computed tomography was valuable for predicting the existence of lymph node metastasis, lymphatic invasion, or vascular invasion. Methods: Between 1994 and 1999, 111 patients with clinical stage IA adenocarcinoma underwent surgical resection of the lung at our hospital. Of these, 96 patients received high-resolution computed tomography of the chest, and they constituted the study population. The tumors were semiquantitatively classified into 5 groups on the basis of the proportion of ground-glass opacity area to whole tumor shadow on high-resolution computed tomography: group I, 0%; group II, 1% to 25%; group III, 26% to 50%; group IV, 51% to 75%; and group V, 76% to 100%. Correlations of computed tomographic findings, pathologic results of lymph node metastasis and lymphatic and vascular invasion, and the histologic subtype according to the new World Health Organization classification were examined. We also investigated the characteristics of the patients with ground-glass opacity areas on high-resolution computed tomography and their value for predicting lymph node metastasis. Results: Among the 96 patients, 15 (15.6%) had mediastinal lymph node metastases, and 3 (3.1%) had hilar node metastases. Regarding the proportion of the ground-glass opacity area of the tumors, 15 (15.6%) tumors were classified as group V, 11 (11.5%) as group IV, 9 (9.3%) as group III, 22 (22.9%) as group II, and 39 (40.6%) as group I, respectively. Of the 18 patients with lymph node metastases, no patients were found in groups IV and V, 2 (22.2%) were found in group III, 4 (18.2%) were found in group II, and 12 (30.8%) were found in group I (trend P =. 003), respectively. Twenty-six patients classified into groups IV and V also showed neither lymphatic invasion nor recurrence. All the smaller tumors (≤2.0 cm) in group IV or V were histologically proved to be bronchioloalveolar carcinoma. Adjusted for smoking status and other characteristics, patients without ground-glass opacity on high-resolution computed tomography had a significantly increased risk of concurrent lymph node metastasis compared with those with ground-glass opacity. Conclusion: In patients with clinical T1 N0 M0 adenocarcinoma, the proportion of ground-glass opacity area on thin-section computed tomography scans was a strong predictor for tumor aggressiveness and thus could be a useful index for planning limited surgical resection for these patients. J Thorac Cardiovasc Surg 2002;124:278-84

Detailed reports on mucinous adenocarcinoma (formerly "mucinous bronchioloalveolar carcinoma") have not been published. We evaluated the correlation between thin-section computed tomography findings and the clinicopathologic characteristics and prognosis of mucinous adenocarcinoma.From April 1997 to March 2008, 45 resected lung carcinomas were diagnosed as mucinous adenocarcinoma. Five cases of multiple lung cancers or ambiguous mucinous adenocarcinoma were excluded. Tumors were classified as "solitary-type" or "pneumonic-type" tumors according to the thin-section computed tomography findings. We evaluated the clinicopathologic characteristics and the epidermal growth factor receptor and KRAS gene mutation statuses and correlated the thin-section computed tomography findings with patient prognoses.Thirty patients had solitary-type and 10 had pneumonic-type tumors. The lesions in 23, 14, and 3 patients were classified as pathologic stage I, stage II, and stage III, respectively. Five patients had adenocarcinoma in situ, 9 had minimally invasive adenocarcinoma, and 26 had invasive mucinous adenocarcinoma. Thirteen patients showed recurrences, which were classified as intrapulmonary metastases in all patients. The 5-year overall and relapse-free survival rates were 83.3% and 88.8%, respectively, in patients with solitary-type tumors and 20.0% and 0%, respectively, in patients with pneumonic-type tumors (p0.001). The median follow-up time for surviving patients was 81 months. KRAS mutations were detected in 30 patients, but epidermal growth factor receptor mutations were absent in all patients.Our results indicated that thin-section computed tomography findings for mucinous adenocarcinoma were useful in predicting prognosis before surgical resection. Further studies are required to improve the treatment strategy for mucinous adenocarcinoma.

We conducted a phase II study of combination chemotherapy with paclitaxel (Pac) and irinotecan (CPT) to determine the effects and toxicities in patients 70 years or older with unresectable non-small cell lung cancer (NSCLC). Eligible patients were entered to receive three courses of Pac at 160 mg/m2 and CPT at 60 mg/m2 every 2-3 weeks. Twenty-one patients were registered. Thirteen patients were male and 8 were female, with a median age of 72 years (range: 70-82 years). Eight patients had a performance status (PS) of 0 and the other 13 patients had a PS of 1. Six and 15 patients were stage IIIB and stage IV, respectively. Ten patients received 3 to 6 cycles of the chemotherapy. Of the hematological toxicities, grade 4 neutropenia was observed in 23.8% of the patients. Of the non-hematological toxicities, grade 3 or 4 fatigue, anorexia and nausea were observed in 5, 3 and 4 patients, respectively. Three of 6 patients with infection developed grade 3 pneumonia. Grade 3 allergy with rash occurred in a patient. Cerebral infarction occurred in two patients and grade 3 peripheral neuropathy in one. The outcome of the Pac and CPT regimen in 21 patients was 8 PR, 10 SD and three PD, and the response rate was 38.1% The median survival time was 9.1 months. The one- and 2-year survival rates were 38.1% and 19.0%, respectively. The Pac plus CPT regimen is feasible and active with moderate toxicity for elderly patients with NSCLC.

The prognostic value of maximum standardized uptake value (maxSUV) on (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) is known for localized pulmonary adenocarcinoma, which is most commonly non-mucinous adenocarcinoma. We examined the validity of thin-section computed tomography (TS-CT) and FDG-PET findings in mucinous adenocarcinoma.TS-CT and FDG-PET were performed on 25 patients with mucinous lung adenocarcinoma that was subsequently resected between January 2009 and March 2013. Based on the percentage reduction of maximum tumor diameter on the mediastinal window image compared with the diameter on the lung window image on TS-CT, tumors were classified as air-type (≥50%) or solid-type (50%). All resected specimens were pathologically diagnosed according to the International Association for the Study of Lung Cancer (IASLC) classification, and the diameter of the pathological invasive area was assessed.Most mucinous adenocarcinomas were located in the lower lobe. All except two were classified as solid-type tumor on TS-CT. Multiple regression analysis revealed the correlation of maxSUV with pathological tumor size and diameter of pathological invasive area; these two parameters showed no significant correlation with each other (r=0.354, p=0.083). maxSUV was significantly lower for tumors with invasive area ≤5 mm than for tumors with invasive area5mm (1.62 vs. 3.77, p=0.01), but no statistically significant difference was found in terms of other pathological invasive findings such as the presence of lymphatic or vascular invasion, pleural involvement, or predominant histological subtype.Most mucinous adenocarcinomas had appearances of solid-type tumor on TS-CT. maxSUV on FDG-PET indicates the pathological invasive area in mucinous adenocarcinoma as well as non-mucinous adenocarcinoma.

No standard second-line combination chemotherapy has yet been established for patients with recurrent small cell lung cancer (RSCLC).Patients with RSCLC were treated with nedaplatin (NP) at 50 mg/m2 and irinotecan (CPT) at 50 mg/m2 on days 1 and 8 every 4 weeks for four cycles.The clinical outcomes of 12 patients (9 male and 3 female; age range 48-76 years, median 62 years) were retrospectively analyzed. Seven of the patients showed sensitive relapse. Two patients had a performance status of 2. Nine of the patients were able to receive 4 to 6 courses of NP and CPT chemotherapy. Grade 3 or 4 anemia, neutropenia and thrombocytopenia occurred in 25.0%, 50.0% and 41.7% of patients, respectively. There were no grade 3 or 4 non-hematologic toxicities except for febrile neutropenia in 1 patient. There was no treatment-related death. Nine patients achieved PR, and the objective response rate was 75.0%. The median survival time was 11.1 months (range 4.8 to 31.3+ months) and the 1-year survival rate was 50.0%.NP and CPT in combination are effective and safe for patients with RSCLC.

The standard chemotherapy for Japanese patients with extensive disease of small-cell lung cancer (ED-SCLC) is cisplatin and irinotecan.Patients with untreated ED-SCLC were treated with nedaplatin (NP) at 50 mg/m(2) and irinotecan (CPT) at 50 mg/m(2) on days 1 and 8 every 4 weeks for four cycles.Twenty-five patients were registered. Nineteen patients were male and six female, with a median age of 64 years (50-79 years). Two patients had a performance status of 2. Nineteen of them were able to receive 4 courses of NP and CPT chemotherapy. Grade 3 or 4 anemia, neutropenia, and thrombocytopenia occurred in 8.0, 68.0, and 36.0 % of patients, respectively. Other grade 3 toxicities were SGOT, hyponatremia, fatigue, vomiting, diarrhea, hypotension, febrile neutropenia, oral hemorrhage, and pneumonia. Grade 4 fatigue occurred in one patient. There was no treatment-related death. The overall response rate was 100 %. The median progression-free and overall survivals were 6.6 and 16.0 months, respectively, and the 2-year survival rate was 28 %.NP with CPT is effective and safe for patients with ED-SCLC.

No standard chemotherapy has been established for patients with large-cell neuroendocrine carcinoma (LCNEC).Patients with LCNEC of the lung were treated with nedaplatin (NP) at 50 mg/m(2) and irinotecan at 50 mg/m(2) on days 1 and 8 every four weeks for four cycles.Data for 18 of the LCNEC patients were retrospectively analyzed. All patients were male, with a performance status 0 or 1, and the median age was 68 (range 58-80) years. Nine patients received adjuvant chemotherapy after undergoing complete surgical resection. Fourteen patients were able to receive four cycles of nedaplatin and irinotecan. Grade 4 leukopenia and neutropenia occurred in 5.6% and 16.7%, respectively. Four patients experienced grade 3 non-hematologic toxicities, such as diarrhea, enterocolitis, duodenal perforation and myocardial infarction. There were no treatment-related deaths. Two patients achieved complete response and four achieved partial response, and the median survival time was 12.3 months for the nine patients with advanced disease.Nedaplatin plus irinotecan is effective and safe for patients with LCNEC of the lung.

To study the characteristics of lung cancer, appearing as small solid nodules on initial computed tomography (CT) findings, and to determine an appropriate follow-up duration so as to differentiate between malignancy and benign tumor.We analyzed the records of 34 patients who had undergone surgical resection of lung cancer, which appeared as small solid nodules on initial CT findings. We studied the CT findings, volume doubling times (VDT), follow-up durations, pathological and clinical findings.VDT is classified as follows: (1) slow growth group (SGG), with a VDT of more than 700 days and (2) rapid growth group (RGG), with a VDT of less than 700 days. The median VDT of the SGG was 1083 days, and the RGG was 256 days (p0.01). The median duration for follow-up of the SGG was 1218 days, and 179 days for the RGG. A statistical difference was noted in the follow-up durations (p0.01). There were no statistical differences in the preoperative thin-section CT (TSCT) findings, or in the pathological findings. The RGG included more patients with smoking histories. The CT findings of RGG tended to reveal changed in base lung field such as emphysema, and lung fibrosis.Generally, lung cancer appearing as small solid nodules on initial CT findings grew rapidly, but there were some cases which displayed slow growth patterns. These cases required follow up for over two years, before diagnosis was possible. We concluded the appropriate maximum followup duration is three years.

Background Maximum standardized uptake value (SUVmax) of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) has been found to have prognostic value. We previously reported the correlation between SUVmax and pathological invasive area, and determined an SUVmax cut-off value of 2.15 for predicting the recurrence potential of an invasive area of diameter 5 mm. Here, we evaluate the validity of FDG-PET for prediction of recurrence in pathological stage IA lung adenocarcinoma. Methods From February 2006 to May 2008, 100 patients with pathological stage IA lung adenocarcinoma underwent complete resection at our hospital. Tumors were classified as air-type or solid-type based on thin-section computed tomography (TS-CT) findings and the influence of TS-CT classification, SUVmax, and clinicopathologic features were evaluated in terms of the incidence of recurrence. Results Unlike air-type adenocarcinomas, recurrent disease was detected in 8 of 62 solid-type adenocarcinomas. SUVmax and diameter of invasive area were significantly correlated with recurrence and a shorter time to recurrence. All 8 recurrent cases had pathological invasive area >5 mm. All except one case of recurrence were solid-type adenocarcinomas with SUVmax ≥ 2.15. Three-year disease-free survival rates were 100% in air-type adenocarcinomas, 97.1% in solid-type adenocarcinomas with SUVmax Conclusion Combined evaluation of TS-CT classification and SUVmax had significant value in predicting recurrence in stage IA lung adenocarcinoma, reflecting the aggressiveness of primary lung adenocarcinoma. Prediction of tumor aggressiveness could contribute to decision-making regarding the choice of surgical procedure and treatment after surgery.

We prospectively investigated the outcome of personalized second-line treatment based on epidermal growth factor receptor (EGFR) gene status in previously treated patients with advanced non-small cell lung cancer (NSCLC). EGFR gene status was evaluable by LH-mobility shift assay in registered patients. Gefitinib (Gef) treatment was recommended if the patients had EGFR mutation (mEGFR). EGFR gene status was evaluable in 146 patients. Seventy-four of the patients were female, 82 were smokers, and 122 had adenocarcinoma. Overall, 67 patients had mEGFR and received Gef. Forty-nine of 79 patients with wild-type EGFR (wEGFR) received other chemotherapies or radiation but 30 selected best supportive care only as a second-line treatment. Patients with mEGFR survived significantly longer than patients with wEGFR (p0.0001). However, the survival of patients who received other forms of chemotherapy was not different from that of patients who received best supportive care only as a second-line treatment in patients with wEGFR. Examination of the association between overall survival after first-line chemotherapy and prognostic factors using multivariate regression analysis showed that mEGFR and response to first-line chemotherapy were independent factors (p = 0.003 and p = 0.003, respectively). Selection of second-line treatment according to EGFR gene status may be useful for patients with NSCLC.

In 1997, Lo et al. (1) first described the presence of fetal DNA in maternal plasma and serum. Cell-free DNA offered a new source of fetal genetic material for noninvasive prenatal diagnosis. They developed a real-time, quantitative PCR assay to measure the concentration of fetal DNA and analyzed SRY, a single-copy Y-chromosome-specific sequence, to quantify the number of genome-equivalents per milliliter of blood when a woman carries a male fetus (2). The results revealed that the concentrations of fetal DNA in maternal plasma DNA during the first and third trimesters were 3.4% and 6.2%, respectively. They estimated a mean of 25.4 copies of fetal DNA circulates per milliliter of maternal plasma samples during early pregnancy. They also demonstrated that after delivery, cell-free fetal DNA is cleared very rapidly from the maternal circulation, with a half-life in the order of minutes (3). Thus, the relatively high concentration of fetal cell-free DNA suggests that extensive and time-consuming fetal DNA enrichment procedures would not be necessary when using fetal DNA from maternal plasma for diagnostic purposes. Although the potential of fetal cell-free DNA analysis for the prenatal diagnosis of fetal gender (2) and rhesus D status (4)(5) has been presented, the accuracy of prenatal diagnosis has not been described. If fetal gender could be determined, the number of invasive procedures required to determine X-linked genetic disorders would be reduced. The present study evaluated the diagnostic accuracy of fetal gender determination using cell-free DNA from maternal plasma obtained at early gestation. Pregnant women (n = 302), carrying a single fetus between 7 and 16 weeks of gestation, …

OBJECTIVE We reported that adenocarcinomas with a bubblelike appearance (BLA) appear similar to old inflammation (J Comput Assist Tomogr 2009;33:42-48). The histopathological, clinical, and biological characteristics of adenocarcinomas with BLA need more investigation. METHODS We retrospectively reviewed the records of 26 patients who had undergone surgical resection between 1993 and 2008. We analyzed correlations between thin-section computed tomographic (TS-CT), histopathological, and clinical findings. We analyzed epidermal growth factor receptor and K-ras gene mutations. RESULTS The TS-CT findings are unique with one pattern that was the same in all the 26 cases: (1) polygonal with straight and concave margins, (2) slight peripheral ground-glass opacity areas, (3) 3 or more dilated air bronchograms, and (4) clear pleural indentations. The histopathological findings were identical with our TS-CT findings. The mean tumor doubling time was 1165 days. Epidermal growth factor receptor mutations were observed in 17 cases. There were no K-ras mutations. After resection, the 5-year survival rate is 100%. CONCLUSION The adenocarcinomas with BLA have unique TS-CT, histopathological, and clinical findings.

Objectives: We conducted a phase II study of combination chemotherapy with paclitaxel (Pac) and irinotecan (CPT) alternating with gefitinib (Gef) to determine the qualitative and quantitative toxicities and efficacy of this combination against advanced non-small-cell lung cancer (NSCLC). Patients and Methods: Patients with stage IIIB or IV NSCLC were treated with CPT at 60 mg/m 2 and Pac at 160 mg/m 2 on day 1 followed by Gef at 250 mg per day on days 8 to 14 every 3 weeks. Results: Between April 2005 and March 2006, 16 patients received the chemotherapy with Pac and CPT alternating with Gef. Eleven patients received 4 to 6 cycles, except for 5 patients who discontinued treatment in the second or third cycles because of disease progression in 2, grade 3 pneumonitis with pulmonary infiltration in 2, and decreased performance status in 1. Grade 3 toxicities were neutropenia, an increased glutamic pyruvic transaminase level, allergy, pneumonitis, anorexia, and fatigue. Elevation of the serum glutamic oxaloacetic transaminase level after 1 cycle was the only grade 4 toxicity. Seven of 16 patients achieved a partial response and the overall response rate in the prospective study was 43.8%. The median survival time was 18.1 months. The 1- and 2-year survival rates were 56.3% and 43.8%, respectively. Conclusion: Pac and CPT combined with Gef was not effective enough for NSCLC.

Background The optimal treatment method for thymoma with pleural dissemination remains controversial. We analyzed our experience with a multimodality approach and evaluated the role of extrapleural pneumonectomy (EPP) in the treatment of disseminated thymoma. Methods Multimodality therapy was used to treat 11 consecutive patients with invasive thymoma disseminated into the pleural cavity. Disease was stage IVa in 9 and stage IVb disease with lymph node metastasis in 2. Our treatment strategy for those patients was induction chemotherapy with cisplatin, doxorubicin, and methylprednisolone (CAMP therapy), followed by thymectomy combined with resection of the visible disseminated nodules and postoperative radiotherapy. EPP was applied for 4 patients who had chemoresistant tumors or pleural refractory recurrence. Results Eight patients underwent induction chemotherapy. The response rate to CAMP was 85%. Thymectomy with or without the resection of disseminated pleural tumors was performed in 7 patients and EPP in 3. Postoperative radiotherapy was administered in 6. All patients except 1 with EPP had recurrence: pleural recurrence in 7, lung in 1, and multiple organs in 2. Nine patients were retreated with chemotherapy, radiotherapy, pulmonary metastasectomy, or pleurectomy. One underwent EPP for pleural recurrence. Consequently, among the 7 patients without EPP, only 1 was alive without disease and 4 were alive with pleural recurrence. In contrast, 3 of the 4 patients with EPP had no local failure and were alive without recurrence. Conclusions In multimodality therapy for thymoma with pleural dissemination, EPP offers good local control and may lead to cure.

Concerning the complications resulting from percutaneous needle biopsy (PNB), although cases of tumor seeding into the needle track have occasionally been reported, there were only two cases of pleural recurrences to date. The aim of this study was to elucidate the real risk of pleural recurrence after needle biopsy in patients with resected early stage lung cancer.Between 1986 and 2000, 335 patients with stage I nonsmall cell lung cancer underwent complete resection of the lung tumor. We retrospectively reviewed their medical records and investigated the relationship between the diagnostic methods used and the cancer recurrence patterns.Preoperative diagnoses were obtained for 290 patients; 220 were diagnosed by bronchoscopy and 66 by PNB. Among the patients without a preoperative diagnosis, 27 were diagnosed by intraoperative needle biopsy and 14 by wedge resection of the lung. Tumors diagnosed by needle biopsy including PNB and intraoperative needle biopsy were smaller and showed less vessel invasion than those diagnosed by other methods (p0.01). After surgical resection, 9 patients had pleural recurrence and 1 patient, needle track implantation. Seven of these 10 patients were diagnosed by needle biopsy using 18G cutting type needle. Pleural recurrence or needle track implantation was observed for 8.6% of the patients who underwent a needle biopsy, whereas it was 0.9% for patients who were examined using other diagnostic modalities (p = 0.0009).Needle biopsy especially using a cutting-type biopsy needle can cause a pleural recurrence in addition to needle track implantation.

Background: To evaluate the efficacy and safety of combination chemotherapy of cisplatin (5-day continuous infusion) and docetaxel for the treatment of previously untreated patients with advanced non-small-cell lung cancer (NSCLC). Materials and Methods: Eligible patients had an ECOG performance status of 0–2 with measurable NSCLC. Patients received continuous infusion cisplatin 20 mg/m2/day on 5 days and bolus docetaxel 60 mg/m2/day (day 1; PiD therapy) at a 4-week interval. Results: Forty-three patients were enrolled. The mean number of cycles administered per patient was 2, and ranged from 1 to 4. The response rate was 49% (95% confidence interval, 33.9–63.8%). The median survival time was 47 weeks and the 1-year survival rate was 47%. The major toxic effects were grade 3 or 4, neutropenia (88%), leukopenia (81%), thrombocytopenia (14%) and anemia (42%). There were no treatment-related deaths. Conclusion: PiD therapy was a well-tolerated and active regimen for patients with advanced NSCLC. The major toxicity was neutropenia.

To evaluate the efficacy and safety of combination chemotherapy with cisplatin and vinorelbine for the treatment of previously untreated patients with advanced non-small-cell lung cancer (NSCLC).Eligible patients were those with measurable NSCLC. They were treated with two or more cycles of a regimen consisting of vinorelbine 25 mg/m(2) on days 1 and 8 and cisplatin 80 mg/m(2) on day 1 every 3 weeks.A total of 45 patients were enrolled. The response rate was 51.1% (23/45; 95% CI 35.8% to 66.3%). The median survival was 286 days with a 1-year survival rate of 40%. The median number of treatment cycles was 2. The major toxic effect was neutropenia of grade 3 or higher (84%). Nonhematological toxicities, including vomiting (62%), were mild (grade 2 or less). There were no treatment-related deaths.The high response rate and good tolerability proved this combination therapy to be a safe and effective treatment for advanced NSCLC.

The majority of thymomas are found in the anterior mediastinum. Occasionally, some have been found in the neck, pulmonary hilus, or posterior mediastinum.1 We present here a case of thymoma that developed entirely in the middle mediastinum, and the origin of this tumor is discussed. To our knowledge, a case of middle mediastinal thymoma including image findings has never been reported in the literature.

Background The rapid aging of the population in Japan has been accompanied by an increased rate of surgery for lung cancer among elderly patients. It is thus an urgent priority to map out a treatment strategy for elderly patients with primary lung cancer. Although surgical resection remains standard treatment for early stage non–small-cell lung cancer (NSCLC), it is now essential to confirm the status of epidermal growth factor receptor (EGFR) gene mutations when planning treatment strategies. Furthermore, several studies have reported that EGFR mutations are an independent prognostic marker in NSCLC. However, the relations between age group and the molecular and pathological characteristics of NSCLC remain unclear. We studied the status of EGFR mutations in elderly patients with NSCLC and examined the relations of EGFR mutations to clinicopathological factors and outcomes according to age group. Methods A total of 388 consecutive patients with NSCLC who underwent complete tumor resection in our hospital from 2006 through 2008 were studied retrospectively. Formalin-fixed, paraffin-embedded tissue sections were used to isolate DNA from carcinoma lesions. Mutational analyses of EGFR gene exons 19, 20, and 21 and KRAS gene exons 12 and 13 were performed by loop-hybrid mobility shift assay, a highly sensitive polymerase chain reaction-based method. Results EGFR mutations were detected in 185 (47.7%) and KRAS mutations were detected in 33 (8.5%) of the 388 patients. EGFR mutations were found in a significantly higher proportion of patients younger than 80 years (younger group; 178/359, 49.6%) than in patients 80 years or older (older group; 7/29, 24.1%) (P = 0.008). In contrast, KRAS mutations were more common in the older group (6/29, 20.7%) than in the younger group (27/359, 7.5%) (P = 0.014). The older group showed a trend toward a higher rate of 5-year overall survival among elderly patients with EGFR mutations (100%) than among those with wild-type EGFR (66.2%), but the difference was not significant. Conclusions Our results suggest that the EGFR status of patients with NSCLC differs between patients 80 years or older and those younger than 80 years. EGFR mutation status might be a prognostic marker in elderly patients with completely resected NSCLC. Electronic supplementary material The online version of this article (doi:10.1186/1471-2407-14-610) contains supplementary material, which is available to authorized users.