[Show abstract][Hide abstract] ABSTRACT: Despite considerable recent progress in the treatment of lung adenocarcinoma, there has been little progress in the development of efficacious molecular targeted therapies for squamous cell lung cancer. In addition to the recent comprehensive genome-wide characterization of squamous cell lung cancer, it is also important to genotype this form of cancer. We therefore conducted the Shizuoka Lung Cancer Mutation Study to analyze driver mutations in patients with thoracic malignancies. Here we report the results of genotyping in patients with squamous cell lung cancer.
BMC Cancer 10/2014; 14(1):786. · 3.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It is unclear whether there is a difference in the effect of gefitinib treatment between patients with postoperative recurrent non-small cell lung cancer (NSCLC) and those with stage IV NSCLC harboring mutations in the epidermal growth factor receptor (EGFR).
International Journal of Clinical Oncology 10/2014; · 2.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Genetic alterations in malignant pleural mesothelioma (MPM) patients are not well-understood.
Patients and methods
Surgical specimens and tumor biopsies from 42 patients with MPM were collected from 2003 to 2012. The samples were analyzed for mutations in EGFR, KRAS, BRAF, PIK3CA, NRAS, MEK1, AKT1, PTEN, and HER2 and amplifications in EGFR, MET, PIK3CA, FGFR1, and FGFR2. In addition, 21 patients’ samples were analyzed using amplicon-based massively parallel sequencing for actionable mutations in 48 cancer-related genes.
Genetic alterations were detected in 4 patients (one KRAS mutation and 3 PIK3CA amplifications). Patients harboring genetic alterations showed significantly poorer survival than patients with no genetic alterations. Moreover, significance was maintained if the patients only harbored PIK3CA amplification. A total 16 genetic mutations were identified in the 9 patients’ samples (4 TP53 mutations, 3 APC mutations, 3 PIK3CA mutations, and 2 VHL mutations, etc.) by deep sequencing. Conclusions: Genetic alterations that are potential targets for molecular targeted therapy were detected in MPM. Amplicon-based massively parallel sequencing was shown to have the advantage of more comprehensive genetic analysis. Further investigation in a larger cohort is necessary to uncover more targetable genetic alterations in MPM and to validate their clinical significance.
[Show abstract][Hide abstract] ABSTRACT: Background
The chest wall is the most common neighboring structure involved by locally advanced lung cancers. However, the optimal treatment strategy for such tumors has not been established. This phase II trial was therefore conducted with the aim of evaluating whether induction chemoradiotherapy followed by surgery improves the survival of patients with T3N0 or T3N1 lung cancer involving the chest wall.
Patients with resectable T3N0 or T3N1 non-small cell lung cancer involving the chest wall were candidates for this study. Induction therapy consisted of two cycles of cisplatin and vinorelbine chemotherapy concurrent with 40 Gy of radiation. Surgical resection was performed 3 to 6 weeks after the last day of chemotherapy.
From January 2009 to November 2012, 51 eligible patients (40 stage IIB and 11 stage IIIA tumors) were entered in this study. Induction therapy was completed as planned in 49 (96%) patients, and 25 (51%) had a partial response revealed on computed tomography. Forty-eight patients underwent pulmonary resection combined with chest wall resection, and 44 (92%) underwent a complete resection. Pathologic examinations of the resected specimens revealed no viable tumor cells in 12 (25%) cases and minimal residual disease in 31 (65%) cases. Five patients experienced major postoperative complications, and 1 patient died of postoperative exacerbation of interstitial pneumonia.
The initial results of this study showed the treatment regimen to be safe and feasible with a high rate of a pathologic response for patients with lung cancer involving the chest wall in a multiinstitutional setting.
The Annals of Thoracic Surgery 10/2014; · 3.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Inherited factor VII (FVII) deficiency is a rare recessive inherited coagulation disorder with limited available information, especially in patients undergoing major thoracic surgery. In addition, an optimal management strategy for the disease has not been defined. We herein report a case involving a 61-year-old man with asymptomatic FVII deficiency who underwent a right middle and lower lobectomy to treat lung cancer. To the best of our knowledge, the present report is the first to describe the use of recombinant activated FVII continuous infusion for bleeding control after a major thoracic surgery in a patient with inherited FVII deficiency.
General Thoracic and Cardiovascular Surgery 07/2014;
[Show abstract][Hide abstract] ABSTRACT: Pleural effusion is frequently observed in patients with advanced lung cancer. Although effusion can be obtained less invasively and repeatedly, its use in multiplexed molecular profiling has not been fully investigated.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 07/2014; 9(7):1048-52. · 4.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives
Advances in the molecular profiling of lung adenocarcinoma over the past decade have led to a paradigm shift in its diagnosis and treatment. However, there are very few reports on the molecular profiles of small cell lung cancers (SCLCs). We therefore conducted the present Shizuoka Lung Cancer Mutation Study to analyze genomic aberrations in patients with thoracic malignancies.
Materials and Methods
We collected samples of SCLC from a biobank system and analyzed their molecular profiles. We assessed 23 mutations in nine genes (EGFR, KRAS, BRAF, PIK3CA, NRAS, MEK1, AKT1, PTEN, and HER2) using pyrosequencing plus capillary electrophoresis. We also amplified EGFR, MET, PIK3CA, FGFR1, and FGFR2 using quantitative real-time polymerase chain reaction (PCR) and the fusion genes ALK, ROS1, and RET using reverse transcription PCR.
Between July 2011 and January 2013, 60 SCLC patients were enrolled in the study. Samples included eight surgically resected snap-frozen samples, 50 formalin-fixed paraffin-embedded samples, and seven pleural effusion samples. We detected 13 genomic aberrations in nine cases (15%), including an EGFR mutation (n = 1, G719A), a KRAS mutation (n = 1, G12D), PIK3CA mutations (n = 3, E542 K, E545 K, E545Q), an AKT1 mutation (n = 1, E17 K), a MET amplification (n = 1), and PIK3CA amplifications (n = 6). EGFR and KRAS mutations were found in patients with combined SCLC and adenocarcinoma. No significant differences were detected in the characteristics of patients with and without genomic aberrations. However, serum neuron-specific enolase and progastrin-releasing peptide levels were significantly higher in patients without genomic aberrations than in those with aberrations (p = 0.01 and 0.04, respectively).
Genomic aberrations were found in 15% SCLC patients, with PIK3CA amplifications most frequently observed. To further our understanding of the molecular profiles of SCLC, comprehensive mutational analyses should be conducted using massive parallel sequencing.
Lung cancer (Amsterdam, Netherlands) 05/2014; · 3.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Our previous study found unique adenosquamous carcinomas (ADSQs) containing a mucoepidermoid carcinoma (MEC)-like component and a characteristic p63 staining pattern. This study focused on these unique ADSQs.
Thirty ADSQ cases were studied histologically and by immunohistochemistry for TTF-1 and p63. Of these 30 ADSQs, eight were selected as unique ADSQs. The clinicopathological characteristics of these ADSQs were further studied, and the gene rearrangement of mammalian mastermind-like 2 (MAML2) was investigated by fluorescence in situ hybridization (FISH) for differentiation from pulmonary MEC.
The clinicopathological characteristics between the eight ADSQs and the other ADSQ cases showed no statistically significant differences, except for serum CEA level. Histologically, the eight ADSQs contained varying degrees of the MEC-like component, which consisted of solid nests with mucin-filled cysts or a cribriform-like structure. Immunohistochemically, p63-positive nuclei characteristically encircled the tumor nests, although TTF-1 was completely negative. All unique ADSQs not only had a variable degree of squamous cell carcinoma component in addition to the MEC-like component, but also contained a small tubular adenocarcinoma component in three tumors. FISH analysis revealed no MAML2 gene rearrangement in the eight ADSQs.
Of the 30 ADSQs investigated in this study, eight contained a MEC-like component with a characteristic p63 basilar staining pattern similar to that of bronchial basal cells. These unique ADSQs shared clinical characteristics with ordinary ADSQs, but clinicopathologically differed from pulmonary ordinary MEC. Therefore, these unique ADSQs may be either a novel ADSQ subtype originating from bronchial epithelium or variant-type MEC.
Lung cancer (Amsterdam, Netherlands) 04/2014; · 3.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Little is known about the prognostic value of positive sputum cytology in patients with non-small cell lung cancer (NSCLC). Patients and Methods We retrospectively examined the clinicopathological data of 30 patients who had undergone complete resection for NSCLC with positive sputum cytology between September 2002 and June 2011. Results Distant recurrence occurred significantly more frequently in the patients with adenocarcinoma (Ad) than in those with squamous cell carcinoma (p = 0.01). The most frequent metastatic site after surgery was the brain, occurring in five patients with Ad. The 5-year disease-free survival (DFS) and overall survival (OS) rates of the 30 patients were 53 and 49%, respectively. In multivariate analyses, radiographic feature of pneumonic-type shadow and pathological N (pN) 1-2 status were the independent factors significantly correlated with poor DFS (p = 0.009, 0.001, respectively), whereas pN 1-2 status was the only independent factor significantly correlated with poor OS (p = 0.009). Conclusion Surgical outcome for NSCLC with positive sputum cytology was unfavorable at our institution. Close surveillance after a curative resection is mandatory for those patients presenting with radiographic feature of pneumonic-type shadow as those with lymph node metastases because they are at high risk for recurrence.
The Thoracic and Cardiovascular Surgeon 03/2014; · 0.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study is to investigate the underlying biologic mechanisms of 2-[(18)F]-fluoro-2-deoxy-d-glucose ((18)F-FDG) uptake on positron emission tomography (PET) in non-small cell lung cancer (NSCLC).
One-hundred forty patients with NSCLC who underwent (18)F-FDG PET were included in the study. Tumor sections were stained by immunohistochemistry for glucose transporter 1 (GLUT1), GLUT3, hypoxia-inducible factor-1 alpha (HIF-1α), hexokinase I, vascular endothelial growth factor (VEGF), microvessels (CD34), epidermal growth factor receptor (EGFR), and molecules relevant to PI3K/Akt/mTOR signaling pathway (PTEN, p-Akt, p-mTOR and p-S6). We also conducted in vitro studies of (18)F-FDG uptake and mTOR inhibition in NSCLC cells.
High (18)F-FDG uptake was significantly associated with poor prognosis in NSCLC patients. (18)F-FDG uptake was significantly correlated with GLUT1, hexokinase I, HIF-1α, VEGF, CD34, p-Akt, p-mTOR and EGFR. PTEN expression showed inverse correlation with (18)F-FDG uptake. In in vitro study, (18)F-FDG uptake was markedly decreased by the inhibition of GLUT1 and GLUT1 upregulation by the induction of HIF-1α increased the (18)F-FDG uptake. Inhibition of both mTOR complex1 (mTORC1) and mTORC2 suppressed cell growth, but activity of mTORC1 regulated the (18)F-FDG uptake. NCI-H1650 cells with PTEN loss showed the highest (18)F-FDG uptake and the least sensitivity to mTOR inhibitors.
The amount of (18)F-FDG accumulation is associated with molecules relevant to glucose metabolism, hypoxia, angiogenesis and mTOR signaling pathway. Especially, PTEN status may affect not only (18)F-FDG uptake but also effect of mTOR inhibitors on the growth of NSCLC.
Lung cancer (Amsterdam, Netherlands) 12/2013; · 3.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We herein present a case of synchronous multiple thymoma that was suspected based on the findings of positron emission tomography with fluorine-18-labeled-fluorodeoxyglucose ((18)F-FDG PET). The patient was a 70-year-old male with two similarly sized and heterogeneously enhanced masses on the right side of the anterior mediastinum on chest computed tomography. (18)F-FDG PET revealed variation in FDG accumulation between the masses, in which the maximum standardized uptake value was 4.4 in Tumor 1 and 8.7 in Tumor 2. Based on these imaging findings, the masses were suspected to be independent, likely synchronous double primary thymoma. Total thymectomy with removal of the two tumors was performed via median sternotomy. A pathological examination identified Tumor 1 as type AB thymoma and Tumor 2 as type A thymoma. This is the first reported case of synchronous multiple thymoma which was suspected based on a variation in the (18)F-FDG PET findings between the tumors.
General Thoracic and Cardiovascular Surgery 12/2013;
[Show abstract][Hide abstract] ABSTRACT: Pleural dissemination detected by computed tomography (CT) is considered to be unfavorable for patients with non-small-cell lung cancer (NSCLC). However, the prognosis of NSCLC patients who are diagnosed with pleural dissemination at the time of surgery has yet to be adequately elucidated. To assess the outcomes of platinum-based chemotherapy in NSCLC patients in whom pleural dissemination was detected during exploratory thoracotomy with or without a videoscope, the clinical records of NSCLC patients who were admitted to Shizuoka Cancer Center between September, 2002 and April, 2009 were reviewed. A total of 19 patients were included in this study, 12 males and 7 females, with a median age of 65 years. All patients were diagnosed with adenocarcinoma and 6 were epidermal growth factor receptor (EGFR) gene mutation-positive. The median number of treatment cycles of first-line platinum-based chemotherapy was 4 (range, 1-6 cycles) and the objective response rate was 21% [95% confidence interval (CI): 8.5-43]. The median progression-free and overall survival were 10.4 (95% CI: 6.3-18.4) and 50.5 months (95% CI: 32.5-98.0), respectively. Of the 18 patients with reported disease progression, 9 (50%) developed locoregional tumor progression. In conclusion, NSCLC patients in whom pleural dissemination is detected during surgery tend to have a favorable prognosis for survival. Systemic chemotherapy and additional local treatment may improve their clinical outcomes.
Molecular and Clinical Oncology 11/2013; 1(6):949-952.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to investigate the relationship between the expression levels of thymidylate synthase (TS) and 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG) uptake on positron emission tomography (PET) in various thoracic neoplasms. In total, 392 patients [non-small cell lung cancer (NSCLC) (n=140), malignant pleural mesothelioma (MPM) (n=21), pulmonary metastatic tumors (PMT) (n=148), thymic epithelial tumors (n=49) and pulmonary neuroendocrine (NE) tumor (n=34)] who underwent 18F-FDG PET before treatment were included in this study. Tumor sections were stained using immunohistochemistry for determination of TS, orotate phosphoribosyltransferase (OPRT), dihydropyrimidine dehydrogenase (DPD), vascular endothelial growth factor (VEGF), microvessel density (MVD), CD34 and p53. The expression of TS in thoracic neoplasms had a positivity of 58% (230/392), and the positive rates of TS expression in NSCLC, PMT, thymic epithelial tumor, NE tumor and MPM samples were 56, 57, 57, 85 and 47%, respectively. The positivity of TS expression was significantly higher in NE tumors compared to that in other thoracic tumors. A statistically significant correlation between TS expression and 18F-FDG uptake was observed in thoracic neoplasms, in particular primary lung adenocarcinomas, high-grade NE tumors, thymomas and MPMs. Moreover, TS expression was closely associated with angiogenesis, DPD, OPRT and p53. Our results indicated that SUVmax by 18F-FDG uptake may be an alternative biomarker for predicting TS expression in patients with primary lung adenocarcinoma, high-grade NE tumor, thymoma and MPM.
[Show abstract][Hide abstract] ABSTRACT: The use of staplers for thoracic surgery has been widely accepted and regarded as a safe procedure. However, complications of stapling are occasionally experienced. The aim of this retrospective study was to analyze complications of bronchial stapling.
A retrospective multi-institutional review was conducted by the Central Japan Lung Cancer Surgery Study Group, comprising 29 institutions. All instances of bronchial stapling in thoracic surgery were reviewed during the research period.
Bronchial stapling was performed 2,030 times, using 36 kinds of staplers. The total number of complications related to stapling was 36 (1.8 %); 31 events occurred intraoperatively and five events occurred postoperatively. The intraoperative complications were air leakage (N = 20) and stapling failure (N = 11), which were caused by stapler-tissue thickness mismatch (N = 17), stapler defect (N = 3), tissue fragility (N = 2), and unknown reasons (N = 9). In all 31 cases, intraoperative complications were recovered intraoperatively with additional suturing, and no further complications were observed postoperatively. The postoperative complications were bronchopleural fistula (BPF) (N = 4) and bleeding from the chest wall (intercostal artery) (N = 1). The rate of BPF was 0.2 % (4 of 2,030). Two of four BPFs induced critical conditions. Postoperative bleeding was caused by the use of Duet TRS(TM). Both total complications and BPF occurred more frequently in the main bronchus than in the lobar or segmental bronchus. No relationship was seen between the incidence of complications and cartridge colors in lobar bronchial stapling. The compression types of staplers were associated with the incidence of complication.
Intraoperative and postoperative complications of bronchial stapling were studied. Generally, bronchial stapling in recent thoracic surgery was safe, but rare postoperative complications may induce critical conditions. Knowledge of potential complications and causes of bronchial stapling may decrease the incidence of stapling complications.
World Journal of Surgery 10/2013; · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It is widely recognized that pulmonary neuroendocrine tumors (PNET) include a spectrum that ranges from low-grade typical carcinoid (TC) and atypical carcinoid (AC) to high-grade large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC). However, little is known about the usefulness of 2-[(18)F]-fluoro-2-deoxy-D-glucose ((18)F-FDG) positron-emission tomography (PET) in such tumors. We therefore, conducted a study including the analysis of the underlying biology of (18)F-FDG uptake.
Thirty-four patients with early-stage PNETs who underwent (18)F-FDG PET before treatment were included in this study. Tumor sections were stained by immunohistochemistry for glucose transporter-1 (Glut1 and Glut3), hypoxia-inducible factor-1 alpha (HIF-1α), hexokinase-I, vascular endothelial growth factor (VEGF), microvessel density (MVD) determined by CD34 and (Akt)/mammalian target of rapamycin (mTOR) signaling pathway.
(18)F-FDG uptake correlated significantly with Glut1, HIF-1α, VEGF and CD34 expression. Uptake of (18)F-FDG tended to increase from low-grade to high-grade PNETs. Tumor metabolic activity was a useful marker for predicting postoperative prognosis in patients with early-stage PNETs.
The amount of (18)F-FDG uptake is determined by the presence of glucose metabolism, hypoxia and angiogenesis.
Anticancer research 10/2013; 33(10):4219-4228. · 1.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Interstitial lung disease (ILD) has been associated with primary lung cancer and an increased risk of postoperative acute exacerbation (AE). The effectiveness of 2--fluoro-2-deoxy-D-glucose ((18)F-FDG) positron emission tomography (PET) for staging lung cancer is well established. This study investigates the association of FDG uptake on PET in patients with AE of ILD.
The subjects of this retrospective study were 1309 patients with lung cancer, who underwent pulmonary resection at Shizuoka Cancer Center between September, 2002 and January, 2011. ILD was diagnosed with chest computed tomography in 95 patients, 81 of whom underwent (18)F-FDG PET before surgery. Six patients suffered from AE after surgery (AE group), while the remaining 75 (non-AE group) did not. We investigated the clinico-pathological findings and the results of FDG uptake on PET using the value of the I/M ratio, which is the ratio of the peak of standardized uptake value (SUV) of the ILD area to the mean SUV of the mediastinum.
There was no significant difference in clinico-pathological findings, but a significance difference in the I/M ratio (P = 0.0102).
The FDG uptake in PET may be a predictive factor for AE of ILD in patients who have undergone lung cancer surgery.
[Show abstract][Hide abstract] ABSTRACT: Mixed squamous cell and glandular papilloma (mixed papilloma) of the lung is exceedingly rare, with only 18 cases reported in the literature. Herein, we report a case of mixed papilloma and its associated immunohistochemical and positron emission tomographic (PET) findings. A 60-year-old Japanese male with a smoking history of 40 pack-years presented with a smooth-edged pulmonary lesion in the right S5 segment on computed tomography (CT). F18-fluorodeoxyglucose (FDG) PET revealed abnormally increased FDG uptake in the mass (maximum standardized uptake value, 3.4). We performed right middle lobectomy and combined partial resection of the S8 segment. The 1.8-cm tumor that filled the enlarged lumen of the B5b was histologically diagnosed as mixed papilloma. Immunohistochemically, the pseudostratified columnar epithelium was positive for cytokeratin (CK) 5/6 and CK7. p40 positivity was predominant in the basal and squamous cells. Thyroid transcription factor-1 and carcinoembryonic antigen were negative on immunostaining. Malignant features were absent. The postoperative course has been uneventful for 3 months after the surgery. No recurrences were reported after the surgical resection of the mixed papilloma. Therefore, surgical resection may be considered the mainstay of curative treatment.
Annals of thoracic and cardiovascular surgery : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia. 08/2013;
[Show abstract][Hide abstract] ABSTRACT: Postoperative infection is one of the most frequently observed complications after lung resection and should be addressed in perioperative management. This study evaluated the clinical significance of chest tube tip culture relevant to postoperative infection.
From September 2002 to December 2011, 1,438 patients who underwent lung cancer operations in Shizuoka Cancer Center Hospital were evaluated. Postoperative infections, including surgical site infection, postoperative pneumonia, and postoperative empyema without fistula, were defined as those occurring within 30 days of thoracotomy.
Postoperative infections developed in 84 of the 1,438 patients (5.8%), including 42 (2.9%) with surgical site infection, 36 (2.5%) with pneumonia, and 13 (0.9%) with empyema. The sensitivity, specificity, and positive predictive value of chest tube tip culture were 23%, 98%, and 41.3%, respectively. Multivariate analysis demonstrated that the independent risk factors associated with the development of postoperative infections were coexisting diabetes mellitus and positive chest tube tip culture. Positive chest tube tip culture was the only independent risk factor associated with surgical site infection. The independent risk factors associated with postoperative pneumonia were age 70 years or older, coexisting diabetes mellitus, and positive chest tube tip culture. Finally, positive chest tube tip culture was the only independent risk factor associated with postoperative empyema.
Positive chest tube tip culture strongly predicts postoperative infections in lung cancer surgery and necessitates careful observation in the perioperative period.
The Annals of thoracic surgery 08/2013; · 3.45 Impact Factor