Mitsuhiro Isaka

Assessment of mutational profile of Japanese lung adenocarcinoma patients by multitarget assays: A prospective, single‐institute study

Integration of mutational profiling to identify driver genetic alterations in a clinical setting is necessary to facilitate personalized lung cancer medicine. A tumor genotyping panel was developed and the Shizuoka Lung Cancer Mutation Study was initiated as a prospective tumor genotyping study. This study reports the frequency of driver genetic alterations in Japanese lung adenocarcinoma patients, and clinicopathologic correlations with each genotype.

Recurrence of mediastinal node cancer after lobe-specific systematic nodal dissection for non-small-cell lung cancer.

OBJECTIVES The standard surgical treatment for patients with non-small-cell lung cancer (NSCLC) is lobectomy with systematic nodal dissection (SND). Lobe-specific patterns of nodal metastases have been recognized, and lobe-specific SND (L-SND) has been reported. We performed L-SND depending on patient-related factors, such as age or the presence of diabetes or respiratory dysfunction, or in the context of specific tumour-related factors, such as the presence of a tumour with a wide area of ground-glass opacity. METHODS Between September 2002 and December 2008, 335 consecutive patients with clinical and intraoperative N0 NSCLC underwent curative lobectomies at Shizuoka Cancer Center Hospital. Among these 335 patients, 206 underwent SND (Group A) and 129 underwent L-SND. Of the 129 patients undergoing L-SND, 98 underwent L-SND due to patient-related factors (Group B) and 31 underwent L-SND due to tumour-related factors (Group C). RESULTS There were no significant differences in morbidity or blood loss between patients undergoing SND or L-SND, but there was a significant difference in the mean operative times. The 5-year disease-free survival (5-DFS) and 5-year overall survival (5-OS) of patients in Group C were 100%. Although the patients in Group B showed no significant difference in 5-DFS and 5-OS compared with Group A, patients in Group B had significantly more initial recurrence of mediastinal node cancer than did the Group A patients (P = 0.0050). CONCLUSIONS The recurrence of mediastinal node cancer in patients undergoing L-SND was significantly greater than that in those undergoing SND.

Epithelioid inflammatory myofibroblastic sarcoma arising in the pleural cavity

A 57-year-old Japanese man presented with massive right pleural effusion, and a huge tumor arising in the pleural cavity was detected by chest computed tomography. A thoracoscopic tumor biopsy revealed that the tumor protruded extensively into the pleural cavity, and its gross appearance was cystic and glossy. Microscopically, the tumor cells were rounded and epithelioid in shape. Prominent and abundant myxoid stroma was also present together with an inflammatory infiltrate, and the tumor was anaplastic lymphoma kinase (ALK)-immunopositive. Fluorescence in situ hybridization revealed that the Ran-binding protein 2-ALK fusion gene was present. Taken together, these findings supported the diagnosis of epithelioid inflammatory myofibroblastic sarcoma (EIMS), which is a variant of an inflammatory myofibrobrastic tumor. This is the first reported case of an EIMS arising in the pleural cavity.

Surgery for secondary spontaneous pneumothorax: risk factors for recurrence and morbidity

OBJECTIVES Secondary spontaneous pneumothorax (SSP) is more common in elderly patients; it has high rates of recurrence and mortality, even if surgery is performed. There has been little study on the surgical treatment of SSP. Therefore, we analysed the outcomes of surgical treatment of SSP patients, and investigated the risk factors of recurrence and morbidity. METHODS We studied 97 consecutive surgical treatments on 94 patients with SSP who had emphysematous changes of lung retrospectively. Emphysematous changes on preoperative computed tomography image were evaluated by the Goddard score, which is a visual scoring system. First, video-assisted thoracoscopic surgery was performed, followed by bullectomy for the responsible lesions. RESULTS The rate of morbidity was 20.6% and that of mortality was 4.1%. Recurrence rate was 9.3%. By multivariate analysis, a Goddard score≥7 (odds ratio: 8.93, P=0.033) and treatment of bulla without the use of staplers (odds ratio: 11.57, P=0.019) were significant risk factors for morbidity, while pulmonary fibrosis tended to increase the risk of recurrence (hazard ratio: 4.21, P=0.051), and a Goddard score≥7 (hazard ratio: 7.79, P=0.023) was a significant risk factor for recurrence. CONCLUSIONS Surgical treatment in patients with SSP had favourable results. Treatment in which the base of the bulla cannot be definitely shut off with staplers is associated with increased morbidity. Significant emphysematous change on preoperative computed tomography image and pulmonary fibrosis are predictors of recurrence. Patients with these findings should be investigated in terms of the indications of surgery and additional treatment, not only bullectomy.

Risk factors for both recurrence and survival in patients with pathological stage I non-small-cell lung cancer

OBJECTIVES Even after curative resection, a significant fraction of patients with stage I non-small-cell lung cancer (NSCLC) die primarily because of systemic relapse. The purpose of the present study was to investigate the risk factors for both recurrence and poor survival in patients with pathological (p-) stage I NSCLC. METHODS We retrospectively reviewed 467 consecutive patients from a single institution with completely resected p-stage I NSCLC. Patients with multiple lung tumours or malignancies from other organs and those who had undergone preoperative therapies were excluded. The correlation between clinicopathological factors and surgical outcomes, including disease-free survival (DFS) and overall survival (OS), was analysed. The clinicopathological factors examined were age, gender, smoking history, serum carcinoembryonic antigen (CEA) levels, serum cytokeratin 19 fragment levels, surgical procedure, tumour histology, p-stage, angiolymphatic invasion and differentiation grade. RESULTS The 5-year DFS and OS rates of the total study population were 91.4 and 92.8%, respectively. Multivariate analysis results indicated that high serum CEA levels (>5.0 ng/ml) and p-stage IB were independent factors for recurrence, whereas older age (>70 years), high serum CEA levels and p-stage IB were independent factors for poor survival. The risks of recurrence and death in patients with both high serum CEA levels and p-stage IB was 10.3 and 5.2 times higher than those observed in patients with both normal serum CEA levels and p-stage IA, respectively. CONCLUSIONS High serum CEA levels and p-stage IB were independent factors for both recurrence and poor survival in p-stage I NSCLC patients.

Molecular profiling of small cell lung cancer in a Japanese cohort

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. RESULTS 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, E542K, E545K, E545Q), an AKT1 mutation (n=1, E17K), 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). CONCLUSION 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.

High-resolution computed tomography findings of early mucinous adenocarcinomas and their pathologic characteristics in 22 surgically resected cases.

BACKGROUND The pathological criteria of early-stage mucinous adenocarcinoma of the lung have recently been defined; however, its characteristic radiologic imaging findings are still poorly understood. Thus, this study aimed to clarify the radiologic and pathological findings of early-stage mucinous adenocarcinoma. MATERIALS AND METHODS In this study, we clinicopathologically reviewed 22 cases of surgically resected mucinous adenocarcinoma in situ (AIS) and minimal invasive adenocarcinoma (MIA), and attempted to elucidate the characteristic radiologic features of early mucinous adenocarcinomas using high-resolution computed tomography (HRCT). RESULTS Radiologically, the mean value of the maximum diameter of 22 tumours was 2.1 cm (range, 1.0-2.9 cm). Based on the HRCT findings, the tumours were divided into part-solid ground glass nodules (n=11) and solid nodules (n=11). The mean CT attenuation value was 25.7 HU (range, 17-35 HU). All tumours, except 3 tumours pathologically diagnosed as AIS, showed air-containing features. According to the preoperative CT findings, 7 (35%) cases were diagnosed as inflammatory nodules. Of these, 4 cases had lobular-bounded margins, and 3 showed vaguely outlined ground glass shadows. CONCLUSION The characteristic HRCT findings of mucinous AIS and MIA were solid or part-solid nodules with air-containing spaces. However, some AIS and MIA nodules showed lobular-bounded margins or marginally vaguely outlined ground glass shadows, and were difficult to differentiate from inflammatory nodules.

Disseminated calcifying tumor of the pleura: review of the literature and a case report with immunohistochemical study of its histogenesis.

Calcifying tumor of the pleura is a rare benign tumor, similar to the calcifying fibrous pseudotumor originally described in the subcutaneous and deep soft tissues of the extremities, trunk, and neck. Calcifying tumors of the pleura have also been reported infrequently as disseminated lesions. Here we report a case of disseminated calcifying tumor of the pleura, with some new findings obtained in this study, and review the literature of disseminated calcifying tumor of the pleura.

Low-Dose Edaravone Injection into the Clamped Aorta Prevents Ischemic Spinal Cord Injury

Previous studies have indicated that high-dose intravenous edaravone (3-10mg/kg) protects against ischemic spinal cord injury. This study examined whether direct injection of low-dose edaravone into the clamped segment of the aorta prevents ischemic spinal cord injury. Spinal cord ischemia was induced in rabbits by aortic clamping below the renal artery and above the aortic bifurcation for 15min at normothermia. In groups A and B, 3 and 1mg/kg of edaravone, respectively, was injected into the clamped segment of the aorta immediately following aortic clamping. In group C, saline was injected. Neurological function was assessed at 8, 24, and 48hr and 7 days after reperfusion with Tarlov criteria. The spinal cord was histologically examined at 7 days with hematoxylin-eosin staining and in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. The Tarlov score remained grade 4 throughout the period in groups A and B, whereas it dropped to grade 0 or 1 at 7 days in group C, significantly higher in the former two groups. The number of intact motor neurons was significantly greater in groups A and B with less necrotic motor neurons than in group C. There was no significant difference in terms of spinal cord protection between groups A and B. There was no TUNEL-positive neuron in any group, indicating the absence of apoptosis. Low-dose intra-aortic edaravone injection prevents immediate neuronal injury by reducing neuronal cell damage in the early stage as well as delayed neuronal injury at 7 days.

A clinicopathological study of peripheral, small-sized high-grade neuroendocrine tumours of the lung: differences between small-cell lung carcinoma and large-cell neuroendocrine carcinoma.

OBJECTIVES Small-cell lung carcinoma (SCLC) and large-cell neuroendocrine carcinoma (LCNEC) are categorized as high-grade neuroendocrine tumours because of their poor prognosis compared with those of other neuroendocrine tumours of the lung. There have been no clinicopathological studies focusing on small-sized high-grade neuroendocrine tumours. We analysed clinicopathological features of peripheral, small-sized high-grade neuroendocrine tumours of the lung retrospectively. METHODS A total of 28 patients with peripheral, small-sized tumours (maximum diameter of 3.0 cm) of SCLC and LCNEC underwent surgical resection in our hospital and were enrolled in this study. RESULTS Of 28 tumours, 18 were SCLC and 10 were LCNEC. In terms of serum tumour marker levels, carcinoembryonic antigen was elevated in 50% of both types of tumour, and progastrin-releasing peptide was elevated in 28% of SCLC and 10% of LCNEC. With regard to preoperative diagnosis, only seven SCLC cases were correctly diagnosed as SCLC, but no LCNEC case was correctly diagnosed before surgery. Lymphatic involvement was significantly more frequent in SCLC than in LCNEC (P = 0.013). Although adjuvant chemotherapy was carried out more frequently in the patients with SCLC than LCNEC, the recurrence rate after the standard surgery was significantly higher in the patients with SCLC than LCNEC (P = 0.0037). There was a significant difference between SCLC and LCNEC in terms of overall survival in clinical-stage IA small-sized tumours (P = 0.029). CONCLUSIONS In peripheral, small-sized high-grade neuroendocrine tumours, there are several clinicopathological differences between SCLC and LCNEC. This study suggested that the prognosis of patients with LCNEC tended to be better than for those with SCLC in small-sized tumours.