Influence of motor imagery of isometric flexor hallucis brevis activity on the excitability of spinal neural function.

PURPOSE: This study aimed to validate the preliminary steps of motor image voluntary training in patients who are prone to falling as toe flexion muscle strength decreases. MATERIALS AND METHODS: We recorded the F-wave in 30 healthy subjects (20 men, 10 women; mean age, 22.5 ± 2.1 years). First, in a resting condition, the muscle was relaxed during the F-wave recording. Subsequently, the motion of the left flexor hallucis brevis muscle is photographed. F-waves were recorded immediately and at 5, 10, and 15 min after motor imagery. The amplitude of the F/M ratio and persistence were measured. The intervention group watched the exercise task video used for F-wave measurement daily for 1 month, whereas the non-intervention group did not. The second measurement was performed 1 month later in each group. RESULTS: In the first measurement of the amplitude of the F/M ratio in both intervention and non-intervention groups, the image condition was significantly increased compared with the resting condition, but there was no significant difference in persistence. A significant decrease in the amplitude of the F/M ratio after image conditioning was observed in the second measurement of the intervention group. CONCLUSION: Although spinal nerve function excitement was enhanced during motor imagery, movement suppression was promoted, and spinal nerve excitability was suppressed when repeating the simple task. In the future, gradually upscaling the difficulty level of the toe flexion motor task used in the motor image may be necessary to prevent falls.

The landscape of somatic copy-number alteration across human cancers.

A powerful way to discover key genes with causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. Here we present high-resolution analyses of somatic copy-number alterations (SCNAs) from 3,131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across several cancer types, of which 122 cannot be explained by the presence of a known cancer target gene located within these regions. Several gene families are enriched among these regions of focal SCNA, including the BCL2 family of apoptosis regulators and the NF-kappaBeta pathway. We show that cancer cells containing amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend on the expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in several cancer types.

High-throughput oncogene mutation profiling in human cancer.

Systematic efforts are underway to decipher the genetic changes associated with tumor initiation and progression. However, widespread clinical application of this information is hampered by an inability to identify critical genetic events across the spectrum of human tumors with adequate sensitivity and scalability. Here, we have adapted high-throughput genotyping to query 238 known oncogene mutations across 1,000 human tumor samples. This approach established robust mutation distributions spanning 17 cancer types. Of 17 oncogenes analyzed, we found 14 to be mutated at least once, and 298 (30%) samples carried at least one mutation. Moreover, we identified previously unrecognized oncogene mutations in several tumor types and observed an unexpectedly high number of co-occurring mutations. These results offer a new dimension in tumor genetics, where mutations involving multiple cancer genes may be interrogated simultaneously and in 'real time' to guide cancer classification and rational therapeutic intervention.

A safe method for marking small pulmonary nodules with crystal violet.

INTRODUCTION: The number of cases of wedge resection of small-sized pulmonary nodules performed under video-assisted thoracoscopic surgery (VATS) is increasing. Computed tomography (CT)-guided marking with hook wires has been used to locate the nodules that are not identifiable under VATS. However, this method is invasive and is associated with a risk of complications. METHODS: We evaluated the usefulness of marking the pleural surface above the nodule using crystal violet for 22 small-sized pulmonary nodules. Following the collapse of the lung, a long stick with a cotton tip dipped in crystal violet was inserted from the thoracic port or a small thoracotomy, and was placed against the inside of the chest wall right above the nodule with reference to the preoperative CT image. The lung was then expanded, and the crystal violet-infiltrated tip stained the visceral pleura. Regardless of the marking point, wedge resection of the lung was performed. To evaluate the accuracy of the marking, we measured the distance from the center of the marking to the point on the visceral pleural nearest to the nodule (DMN) in the resected lung specimen. RESULTS: This marking method caused no morbidity during or after the operation. The DMN ranged between 0 and 50 mm (mean ± SD 18.2 ± 12.6 mm). In 18 of 22 cases (81.8%), the DMN was 20 mm or less. CONCLUSIONS: The intraoperative marking method using crystal violet was performed with reasonable accuracy. It also caused no morbidity. It was easy and non-invasive. This method can be used in the cases in which CT-guided percutaneous marking is not feasible due to the nodule's location.

Clinicopathological analysis of small-sized anterior mediastinal tumors.

PURPOSE: The purpose of this study was to determine the clinicopathological findings and prognosis of small-sized anterior mediastinal tumors (SSAMTs). METHODS: A retrospective study was conducted on 43 patients who underwent surgery between January 1989 and December 2011 for SSAMTs. RESULTS: From the preoperative radiological findings, the tumors were classified into solid (n = 28) and cystic lesions (n = 15). The pathological diagnoses of the solid lesions included thymoma (n = 24), thymic carcinoma (n = 1), mucosa-associated lymphoid tissue lymphoma (n = 1), teratoma (n = 1) and neurofibroma (n = 1), and those of the cystic lesions included thymic cysts (n = 8), thymoma (n = 3), bronchogenic cysts (n = 2), teratoma, (n = 1) and a pericardial cyst (n = 1). The 27 thymomas were composed of stages I (n = 22), II (n = 3), III (n = 1) and IVb (n = 1). The overall survival in the 43 patients was 97.1 % at 5 years. In the 28 patients with solid lesions, the overall survival was 95.8 % at 5 years. All patients with cystic lesions were still alive at the last follow-up. CONCLUSION: Cystic lesions of SSAMTs were benign lesions or stage I thymoma, and most of the solid lesions of SSAMTs were stage I or II thymomas. SSAMTs are good candidates for video-assisted thoracic surgery procedures, as conversion to sternotomy can be selected based on the intraoperative findings of pericardial invasion and a rapid pathological diagnosis of thymic carcinoma.

Sensitive mutation detection in heterogeneous cancer specimens by massively parallel picoliter reactor sequencing.

The sensitivity of conventional DNA sequencing in tumor biopsies is limited by stromal contamination and by genetic heterogeneity within the cancer. Here, we show that microreactor-based pyrosequencing can detect rare cancer-associated sequence variations by independent and parallel sampling of multiple representatives of a given DNA fragment. This technology can thereby facilitate accurate molecular diagnosis of heterogeneous cancer specimens and enable patient selection for targeted cancer therapies.

Characterizing the cancer genome in lung adenocarcinoma.

Somatic alterations in cellular DNA underlie almost all human cancers. The prospect of targeted therapies and the development of high-resolution, genome-wide approaches are now spurring systematic efforts to characterize cancer genomes. Here we report a large-scale project to characterize copy-number alterations in primary lung adenocarcinomas. By analysis of a large collection of tumours (n = 371) using dense single nucleotide polymorphism arrays, we identify a total of 57 significantly recurrent events. We find that 26 of 39 autosomal chromosome arms show consistent large-scale copy-number gain or loss, of which only a handful have been linked to a specific gene. We also identify 31 recurrent focal events, including 24 amplifications and 7 homozygous deletions. Only six of these focal events are currently associated with known mutations in lung carcinomas. The most common event, amplification of chromosome 14q13.3, is found in approximately 12% of samples. On the basis of genomic and functional analyses, we identify NKX2-1 (NK2 homeobox 1, also called TITF1), which lies in the minimal 14q13.3 amplification interval and encodes a lineage-specific transcription factor, as a novel candidate proto-oncogene involved in a significant fraction of lung adenocarcinomas. More generally, our results indicate that many of the genes that are involved in lung adenocarcinoma remain to be discovered.

Middle lobe preservation and fixation: right upper and lower sleeve bilobectomy. How to do it.

We herein report the case of a 65-year-old female with primary lung cancer who underwent a right upper and lower sleeve bilobectomy. The radiological findings revealed that the tumor was located in the superior segment of the right lower lobe and had invaded the posterior segment of the upper lobe and the truncus intermedius. We performed a right upper and lower sleeve bilobectomy. A latissimus dorsi flap was utilized to separate the thoracic cavity into upper and lower portions, and the preserved middle lobe was fixed in the upper portion to prevent torsion. Postoperative radiography showed good expansion of the middle lobe.

Pedunculated solitary fibrous tumor of the pleura manifesting as a migrating chest mass: report of a case.

We report the case of solitary fibrous tumor of the pleura, which appeared to change its location. A computed tomography (CT) scan done at a previous hospital showed a tumor in the posterior mediastinum, suggesting that it was neurogenic. However, on the initial preoperative CT scan, the tumor seemed to have moved anteriorly, but when contrast material was injected; the tumor appeared in its original position. Video-assisted thoracoscopic surgery (VATS) revealed a pedunculated and free-moving tumor, originating from the visceral pleura. We diagnosed this unusual migrating tumor as a pedunculated solitary fibrous tumor of the pleura.

Excision repair cross complementation group 1 polymorphisms predict overall survival after platinum-based chemotherapy for completely resected non-small-cell lung cancer.

BACKGROUND: It has been reported that the expression of excision repair cross-complementation group 1 (ERCC1) protein predicts the effect of platinum-based chemotherapy and overall survival in the several cancers. And there are some reports suggesting that the polymorphism of the ERCC1 may predict the effect of platinum-based chemotherapy and survival of the patients. We have already reported that the expression of ERCC1 protein predicts survival after platinum-based chemotherapy for 90 completely resected non-small-cell lung cancers (NSCLC). MATERIALS AND METHODS: We investigated the ERCC1 polymorphisms (C8092A and C118T) whether these factors influence for the prognosis of these 90 NSCLC patients treated with platinum-based chemotherapy. RESULTS: Two of the ERCC1 polymorphisms, C8092A and C118T, affected the prognosis of the NSCLC patients who received adjuvant and/or neoadjuvant platinum-based chemotherapy. The wild type, C/C of the codon 8092, was associated with better prognosis than C/A or A/A types (P=0.0154) and the wild type C/C of the codon 118 was associated with better prognosis than C/T or T/T types (P=0.0307). This effect was not seen in an independent group of 55 completely resected NSCLC patients who were treated with surgery alone. The combination of low expression of ERCC1 protein together with the C/C type codon 8092 and C/C type codon 118 polymorphism of the ERCC1 gene was associated with the best prognosis. CONCLUSIONS: Our data seem to suggest that the ERCC1 protein expression and polymorphism of ERCC1 may predict the survival of patients who are treated with platinum-based chemotherapy.

LKB1 gene alterations in surgically resectable adenocarcinoma of the lung.

PURPOSE: Germline mutations of LKB1 (also known as SKT11; locus 19p13.3) cause the occurrence of autosomal dominant Peutz-Jeghers syndrome (PJS). Nearly half of the non-small cell lung cancer (NSCLC) cell lines and one-third of lung adenocarcinoma in Caucasian patients have an LKB1 mutation. METHODS: This study examined the mutational hot spots of the LKB1 gene in surgical resectable lung adenocarcinoma. Exons 1, 6, and 7 of the LKB1 gene were sequenced in 174 Japanese patients with lung adenocarcinoma (including 157 men and 17 women). RESULTS: Only five patients had LKB1 gene alterations (2.9%). All of them were male smokers, and no LKB1 mutation was observed in any of the females. The details of LKB1 alterations were: one 5 bp deletion in intron 5, one Gly to Phe substitution at codon 279 of exon 6, and three Pro to Leu substitutions at codon 281 of exon 6. The P281L alteration and 5 bp deletion in the intron 5 were found to be germline polymorphisms. The G279F was confirmed to be a novel somatic mutation. None of the five patients with an LKB1 alteration showed either an EGFR or K-ras mutation. CONCLUSION: The LKB1 gene alteration is rare in Japanese patients with lung adenocarcinoma, and is generally limited to male smokers.

CHRNA5 gene D398N polymorphism in Japanese lung adenocarcinoma.

BACKGROUND: Recently, to identify genetic factors that modify lung cancer risk, CHRNA5 non-synonymous variant amino acid position 398 (D398N) was identified. The site was a highly conserved in the second cellular loop of the nicotinic acetylcholine receptor subunit protein. MATERIALS AND METHODS: We have investigated CHRNA5 gene polymorphism status in 302 surgically treated lung adenocarcinoma cases from Nagoya City University Hospital. The presence or absence of CHRNA5 polymorphism was analyzed by direct sequences. EGFR mutations status was already investigated and reported. RESULTS: We detected nine cases (2.98%) of CHRNA5 polymorphism (D398N) in our cohort. Total EGFR mutations were present in 129 patients (42.7%). The polymorphism statuses were not correlated with gender (women; 2.1% versus men; 3.7%, P = 0.5119), smoking status (never smoker; 2.0% versus smoker; 4.0%, P = 0.3339), pathological stages (stage I; 2.6% versus stage II-IV; 3.8%, P = 0.7246), and EGFR mutation status of the lung adenocarcinomas (mutation; 2.3% versus wild type; 3.7%, P = 0.7373). In this analysis, CHRNA5 polymorphism (D398N) patients had significantly worse prognosis (5/9 were dead; mean survival = 27.1 mo) than the patients with CHRNA5 wild type (74/293 were dead; mean survival = 113.9 mo) (log-rank test; P = 0.0146). CONCLUSION: Although CHRNA5 polymorphism is rare from Japanese lung cancer, polymorphism status might be correlated with shorter survival.

Thymoma with dissemination: efficacy of macroscopic total resection of disseminated nodules.

BACKGROUND: Advanced thymomas with disseminated nodules are difficult to manage, and the treatment strategy remains undefined. METHODS: A total of 28 thymoma patients with pleural and/or pericardial disseminated nodules were treated at Nagoya City University Hospital. Among them, 21 patients underwent resection of thymoma and pleural disseminated nodules. These patients were reviewed in the present study. RESULTS: Preoperative steroid pulse therapy was performed in 14 patients. Macroscopic total resection of all tumors was achieved in 15 patients. Postoperative adjuvant radiotherapy was performed for the mediastinum in 20 patients and hemithoracic irradiation (HTR) in 11 patients. The overall survival rate of operated 21 patients was 73.1% at 5 years. The patients who underwent resection showed a better prognosis than the patients without resection (p = 0.0006). Relapse was diagnosed in 14 of 21 patients who underwent resection. Disease-free survival was 67.5% at 1 year, 39.8% at 3 years, and 13.3% at 5 years. HTR alone did not improve the disease-free survival. Among the patients who underwent total resection, relapse-free survival was better than in the patients with subtotal resection (p = 0.009). Achievement of a trimodality therapy with preoperative steroid pulse, total resection, and postoperative HTR was associated with prolonged relapse-free survival in the operated patients (p = 0.027, hazard ratio 6.452). CONCLUSIONS: Pursuing total resection for thymoma and disseminated nodules may be beneficial for stage IV thymoma. The combination of preoperative steroid pulse therapy, macroscopic total resection, and postoperative HTR may prolong the interval to relapse, but it did not lead to cure.

[A case of non-small cell lung cancer with EGFR mutation responding to S-1 after a therapy with gefitinib].

A 78-year-old man had underwent right upper lobectomy for lung adenocarcinoma in July 1998(pT1N0M0, pStage Ia). In January2003, computed tomography showed a tumor in right lower lobe of lung, which grew slowly. He was treated with UFT. In April 2004, computed tomographyshowed multiple nodules in both lung, which was considered of metastasis of lung cancer. The increase of the nodules were observed, and treatment with gefitinib was started. Insertion mutation at EGFR in exon 20 was seen from the primarylung cancer. Since tumor growth occurred despite gefitinib administration, we converted gefitinib into S-1 using 80 mg/day for 28 days, followed by 14 days rest. Chest computed tomographyshowed a partial response. No side effect was observed, and continued internal use of S-1 until January 2007 when it was impossible to continue, and meanwhile, the increase of the tumor was not seen.

Met gene copy number predicts the prognosis for completely resected non-small cell lung cancer.

The Met oncogene encodes the tyrosine kinase receptor for hepatocyte growth factor (HGF). Uncontrolled activation of Met is oncogenic and has been implicated in the growth, invasion and metastasis in a variety of tumors. Several distinct mechanisms including amplification, translocation or mutation of Met may underlie uncontrolled Met activation. In several solid tumors, amplification and mutation of Met were reported to be associated with tumorigenesis, invasion and metastasis. The present study evaluated the amplification and mutation of Met in a large number of non-small cell lung cancer (NSCLC). Among 213 NSCLC patients, increased Met copy number was identified in 12 patients (5.6%) and associated with a worse prognosis (P = 0.0414). The mutation of Met in 534 NSCLC patients was also evaluated. In these patients there were no previously reported mutations within the juxtamembrane (JM) domain (R988C, T1010I, S1058P and G1085X). However, a somatic exon 14 deleting splice variant in 3 (1.7%) of 178 NSCLC samples was identified for which sequencing was performed. Met amplification and mutation were rare in Japanese NSCLC. However, the results support a critical role of Met gene dose in NSCLC, suggesting that Met may be a specific molecular therapeutic target in selected NSCLC patients with increased Met copy number.

Expression of excision repair cross-complementation group 1 and class III beta-tubulin predict survival after chemotherapy for completely resected non-small cell lung cancer.

In this study, we examined the expression of excision repair cross-complementation group 1 (ERCC1) protein in 90 completely resected lung cancer samples from patients who received adjuvant or neo-adjuvant platinum-based chemotherapy. Epidermal growth factor receptor (EGFR) was also studied in these samples. We also examined class III beta-tubulin protein expression in 50 patients treated with a platinum-based drug plus paclitaxel. Among 90 patients treated with platinum-based chemotherapy, the loss of ERCC1 protein expression was associated with a better prognosis (p=0.0068). The effect of ERCC1 expression on survival was not seen in a separate set of 59 patients who underwent curative resection but did not receive adjuvant chemotherapy. Among 50 patients treated with a platinum-based drug plus paclitaxel, loss of class III beta-tubulin protein expression was also associated with a better prognosis (p=0.0303). When combined, patients with a tumor that was negative for both ERCC1 and class III beta-tubulin had a significantly longer overall survival than those with a tumor that expressed either ERCC1 or class III beta-tubulin (p=0.0230). There was no relationship between the presence of an EGFR mutation and the patients' survival after the platinum-based chemotherapy. In conclusion, we found that the loss of ERCC1 and class III beta-tubulin protein expression were predictors of better survival in patients who received a platinum-based plus taxane chemotherapy.

Epidermal growth factor receptor gene amplification and gefitinib sensitivity in patients with recurrent lung cancer.

To evaluate the epidermal growth factor receptor (EGFR) protein expression, gene mutations and amplification as predictors of clinical outcome in patients with non-small-cell lung cancer (NSCLC) receiving gefitinib, we have performed fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). We investigated the EGFR amplification and EGFR protein expression statuses in 27 surgically treated non-small-cell lung cancer (NSCLC) cases. These patients experienced relapse after surgery and received gefitinib 250 mg/day. The presence or absence of EGFR mutations of kinase domains was analyzed by genotyping analysis and sequences, and already reported. EGFR mutations were found from 15/27 lung cancer patients. EGFR mutation status was significantly correlated with better prognosis (log-rank test P=0.0023). Smoking status (never smoker vs. smoker, P=0.0032), and pathological subtypes (adenocarcinoma vs. non-adenocarcinoma, P=0.0011), but not EGFR amplification (P=0.1278), were correlated with survival of lung cancers. EGFR IHC results were correlated with FISH results (P=0.0125), but not correlated with prognosis (P=0.7921). Thus, the EGFR gene amplification or protein expression is not a predictor of gefitinib efficacy in Japanese patients with NSCLC. We have also evaluated the EGFR mutation status and clinico-pathological features for 27 NSCLC patients who had undergone surgery followed by treatment with gefitinib at the National Hospital Organization, Kinki-chuo Chest Medical Center. The EGFR mutation status, especially exon19 mutation was correlated with good response to gefitinib than exon 21 point mutation.

Frequently increased epidermal growth factor receptor (EGFR) copy numbers and decreased BRCA1 mRNA expression in Japanese triple-negative breast cancers.

BACKGROUND: Triple-negative breast cancer (estrogen receptor-, progesterone receptor-, and HER2-negative) (TNBC) is a high risk breast cancer that lacks specific therapy targeting these proteins. METHODS: We studied 969 consecutive Japanese patients diagnosed with invasive breast cancer from January 1981 to December 2003, and selected TNBCs based on the immunohistochemical data. Analyses of epidermal growth factor receptor (EGFR) gene mutations and amplification, and BRCA1 mRNA expression were performed on these samples using TaqMan PCR assays. The prognostic significance of TNBCs was also explored. Median follow-up was 8.3 years. RESULTS: A total of 110 (11.3%) patients had TNBCs in our series. Genotyping of the EGFR gene was performed to detect 14 known EGFR mutations, but none was identified. However, EGFR gene copy number was increased in 21% of TNBCs, while only 2% of ER- and PgR-positive, HER2-negative tumors showed slightly increased EGFR gene copy numbers. Thirty-one percent of TNBCs stained positive for EGFR protein by immunohistochemistry. BRCA1 mRNA expression was also decreased in TNBCs compared with controls. Triple negativity was significantly associated with grade 3 tumors, TP53 protein accumulation, and high Ki67 expression. TNBC patients had shorter disease-free survival than non-TNBC in node-negative breast cancers. CONCLUSION: TNBCs have an aggressive clinical course, and EGFR and BRCA1 might be candidate therapeutic targets in this disease.

EGFR polymorphism of the kinase domain in Japanese lung cancer.

BACKGROUND: Mutations of the epidermal growth factor receptor (EGFR) gene at kinase domain have been reported in non-small-cell lung cancer (NSCLC), and some common somatic mutations in EGFR have been examined for their ability to predict sensitivity to gefitinib or erlotinib. However, EGFR mutations at exon 20 have been reported to predict resistance to gefitinib therapy. MATERIALS AND METHODS: We investigated the EGFR mutations and/or polymorphism statuses at kinase domain in 303 surgically treated non-small cell lung cancer (NSCLC) cases. One hundred ninety-four adenocarcinoma cases were included. The presence or absence of EGFR polymorphism of kinase domains was analyzed by direct sequences. We have also investigated EGFR polymorphism status at exon 20 for 23 NSCLC patients who had undergone surgery followed by treatment with gefitinib at the National Hospital Organization, Kinki-chuo Chest Medical Center. RESULTS: EGFR mutations at kinase domain were found in 75 of 303 lung cancer patients. During sequencing of EGFR tyrosine kinase domain in tumors, 86 EGFR polymorphism (G2607A) cases were identified at exon 20. G2067A polymorphism was significantly higher in nonadenocarcinomas (37.4%) than in adenocarcinoma (25.3%, P = 0.0415). The polymorphism status did not correlate with gender, smoking (never smoker versus smoker), and EGFR mutations. In 46 total gefitinib treated NSCLC patients, there was a tendency toward better prognosis in EGFR wild type (GG) patients than AG + AA patients. EGFR polymorphism in Japanese lung cancers seemed to be less frequent than Caucasian lung cancers. CONCLUSIONS: EGFR-tyrosine kinase polymorphism might be associated with clinicopathological background of lung cancers.

Fibroblast growth factor receptor 4 mutation and polymorphism in Japanese lung cancer.

We investigated the FGFR4 mutation status at the kinase domain and FGFR4 single nucleotide polymorphism (SNP) at codon 388 in surgically treated non-small cell lung cancer (NSCLC) cases. The presence or absence of FGFR4 mutations of kinase domains was analyzed by direct sequences (n=147), and the presence of FGFR4 Arg388 allele was analyzed by genotyping assay using LightCycler hybridization probes (n=387). FGFR4 mutations were not present in our lung cancer patients. In 61.8% of patients, homo- or heterozygous Arg388 allele was present. No correlation existed between the FGFR4 genotype and clinicopathological features such as gender, smoking status and pathological subtypes. EGFR mutation status was not correlated with the FGFR4 genotype of lung cancers. In node-negative patients, the FGFR4 genotype was not correlated with disease outcome, while in the node-positive patients FGFR4 Arg388 was significantly associated with worse survival. This association was not attributed to patient response to adjuvant chemotherapy. Therefore, the role of FGFR4 polymorphism is a prognostic marker for advanced NSCLC in Japanese patients.