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We encountered a 69-year-old man with lung adenocarcinoma and pulmonary sequestration. The cancer lesion was located in the left upper lobe, with sequestration of the left lower lobe. Left upper lobectomy was performed after induction chemoradiotherapy, but the sequestered lung lobe was preserved because the preoperative respiratory function was poor. Preservation of the sequestered lung during surgery for lung cancer should be considered in patients who have poor respiratory function and no signs of respiratory infection.

Increasing evidence suggests that an elevated peripheral monocyte count at presentation predicts a poor prognosis in various types of malignancy, including malignant lymphoma. In lung adenocarcinoma, tumor-associated macrophages (TAMs) were reported to be associated with a poor prognosis. However, it is unknown if an elevated peripheral monocyte count is associated with a poor prognosis in lung adenocarcinoma. This study assessed the prognostic impact of the preoperative peripheral monocyte count in lung adenocarcinoma.We retrospectively analyzed 302 consecutive patients with lung adenocarcinoma who received curative resection at Kitano Hospital. The receiver operating characteristic (ROC) curve for the peripheral monocyte count was used to determine the cut-off value. The relations between peripheral monocyte counts and clinicopathological factors were assessed. We also evaluated the impacts of possible prognostic factors including the preoperative peripheral monocyte count on survival, using the two-tailed log-rank test and Cox proportional hazards model. In addition, immunohistochemical staining for CD68 was performed to evaluate the monocytes in primary tumors.A peripheral monocyte count of 430mm(-3) was the optimal cut-off value for prognosis. An elevated peripheral monocyte count was significantly associated with sex, performance status, smoking history, chronic obstructive pulmonary disease and interstitial lung disease. The two-tailed log-rank test demonstrated that patients with an elevated peripheral monocyte count experienced a poorer recurrence-free survival (RFS) and overall survival (OS) (P=0.0063, P0.0001, respectively). In the multivariate analysis an elevated peripheral monocyte count was shown to be an independent prognostic factor for the RFS and OS (HR: 1.765; 95% CI: 1.071-2.910; P=0.0258, HR: 4.339; 95% CI: 2.032-9.263; P=0.0001, respectively). Furthermore, numbers of the monocytes in primary tumors significantly correlated with peripheral monocyte counts (r=0.627, P0.0001).The preoperative peripheral monocyte count is an important prognostic factor for patients with lung adenocarcinoma after curative resection.

Azygos vein aneurysm is very rare and most cases are detected incidentally. We report a safe resection of azygos vein aneurysm by video-assisted thoracoscopic surgery (VATS) under preoperative evaluation of thrombus by multidetector computed tomography (MDCT). A 60-year old woman presented to our department due to a mediastinal mass revealed by enhanced CT. A dynamic enhanced-CT scan showed a dilated azygos vein with great enhancement in the early phase. Under the diagnosis of azygos vein aneurysm, we analysed the aneurysm by MDCT and confirmed that there was no thrombus within the aneurysm. The resection of the aneurysm by VATS was performed safely. She was discharged 4 days after surgery.

Extrapleural pneumonectomy is an essential procedure in multimodality therapy of malignant pleural mesothelioma. However, radical resection may be difficult in a standard posterolateral thoracotomy because the edge of the diaphragm is located in the dead angle of the pleural cavity. We have tried a subcostal thoracotomy following a posterolateral thoracotomy (extended posterolateral-subcostal thoracotomy) for extrapleural pneumonectomy. With extended posterolateral-subcostal thoracotomy, ideal surgical resection, with en bloc removal of the lung, parietal pleura, pericardium and diaphragm, can be performed radically, but safely, without a second thoracotomy. We conclude that extended posterolateral-subcostal thoracotomy is an effective approach for extrapleural pneumonectomy.

Background Malignant pleural mesotheliomas (MPMs) are aggressive tumors with a poor prognosis. We aimed to clarify the mechanisms of epithelial-to-mesenchymal transition (EMT) in MPMs by analyzing the expressions of EMT-associated transcription factors and E-cadherin in relation to tumor proliferation rates and patient survival. Methods One hundred nine patients with MPMs were investigated. Among these patients, there were 61 epithelioid tumors, 21 sarcomatoid tumors, 20 biphasic tumors, and 7 desmoplastic tumors. Immunohistochemical analyses were performed to evaluate the expressions of Snail, ZEB1, Twist, E-cadherin, and the Ki-67 proliferation index. Results The expressions of Snail and ZEB1 were significantly higher in the nonepithelioid tumors than in the epithelioid tumors ( p p = 0.0051, respectively). Furthermore, the E-cadherin expression was significantly lower in the Snail-high tumors than in the Snail-low tumors ( p = 0.0423). The E-cadherin expression was significantly lower in the nonepithelioid tumors than in the epithelioid tumors ( p = 0.0126). The Ki-67 proliferation index was significantly higher in the nonepithelioid tumors than in the epithelioid tumors ( p = 0.025). Patient survival was significantly lower in patients with Snail-high MPMs than in those with Snail-low MPMs ( p = 0.0016), especially in patients with nonepithelioid tumors ( p = 0.0089). The multivariate analysis also demonstrated that nuclear Snail expression was a significant predictor of poor prognosis in patients with MPMs ( p = 0.0142). Conclusions The Snail expression is associated with EMT and a poor prognosis in MPMs. Snail could be a potential molecular target for the treatment of patients with MPMs.

OBJECTIVES: Since few large-scale studies of patients with pleomorphic carcinoma have been documented, factors affecting survival after pulmonary resection for pleomorphic carcinoma, as well as its clinicopathological characteristics, are still unknown. For a better understanding of the patients undergoing resection of pulmonary pleomorphic carcinoma, we reviewed our experience with these patients. METHODS: Between 2002 and 2010, 26 patients with pulmonary pleomorphic carcinoma underwent macroscopically complete pulmonary resections. Various perioperative variables were investigated retrospectively to confirm a role for pulmonary resection and to analyse prognostic factors for overall survival and disease-free survival after lung resection. RESULTS: Twenty-four patients (92%) were male. Twenty-one patients (81%) were smokers and all of them smoked more than 30 packyears. In 25 patients (96%), the tumour was located peripherally. Twenty-three of these 25 patients revealed the tumour touching the visceral pleura widely in the preoperative chest computed tomography. In all 26 patients, the tumour was completely resected macroscopically; however, three patients (12%) had microscopically positive surgical margins. Among them, additional irradiation was conducted in two patients and additional surgical resection was performed in one patient. Combined resections were performed in 11 patients (42%), including chest wall resections in 7 patients. Overall survival rate after pulmonary resection was 48% at 5 years. Diseasefree survival rate after pulmonary resection was 33% at 5 years. Patients with tumours invading the visceral pleural surface and microscopically positive surgical margin had significantly worse overall survivals (P= 0.048 and 0.037, respectively). However, there were no significant prognostic factors for disease-free survival. CONCLUSIONS: Despite small number of cases, we found that pleural invasion suggested a worse prognosis for resection of pulmonary pleomorphic carcinoma. Surgical strategy might be constructed to achieve not only macroscopically, but also microscopically complete resection for such large tumours with aggressive nature and peripheral preference.

症例は胸部異常影を主訴に来院した81歳, 男性である.胸部X線と胸部CTでは左上葉に径1cmの末梢性の肺腫瘤陰影がみられた.気管支鏡下生検で扁平上皮癌を認め, cT1N0M0 stage Iと診断した.患者は高齢であり, 閉塞性換気障害と不整脈, 糖尿病も合併していることから, 手術侵襲の少ない胸腔鏡下肺部分切除術を施行した.術後創痛は少なく, 早期離床が可能であり, 術後合併症はなく, 術後肺機能の温存もみられた.高齢者や低肺機能などのハイリスク症例における末梢型早期肺癌 (特に扁平上皮癌) に対して, 胸腔鏡下縮小手術は侵襲の少ない外科的治療である.

V-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations are attractive molecular targets for cancer treatment. Detection of BRAF gene mutation and analyses in non-small cell lung cancer (NSCLC) are of great scientific interest.The study included 581 NSCLC patients (377 males, 204 female) undergoing pulmonary resection. BRAF gene mutations were screened using the PCR-SSCP method and were confirmed by direct DNA sequencing. Mutations of epidermal growth factor receptor (EGFR), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2), and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) gene were also analyzed.Five patients (0.8%) had BRAF mutations within exon 15. In 581 NSCLC patients, EGFR gene mutations within exons 18 to 21 were detected in 191 (32.8%) patients, KRAS codon 12 mutations in 56 (9.6%) patients, and ERBB2 codon 20 mutations in 11 (1.8%) patients. All mutations were mutually exclusive. The NSCLC patients with BRAF mutations were proved to be men who were heavy smokers.PCR-SSCP analysis of BRAF exon 15 in NSCLC patients without other gene mutations may be sufficient to identify candidates for treatment.

Large cell neuroendocrine carcinoma (LCNEC) is a relatively rare tumor in malignant lung neoplasms. The prognosis of LCNEC is poor and there is no consensus on the treatment for LCNEC. We report our retrospective assessment of 11 patients of LCNEC from 1999 to 2008. Three of 11 patients had malignant exudate at thoracotomy. Seven patients received limited resection. There was a recurrence even after complete surgical resection in its early stage. Four patients received platinum-based chemotherapy for adjuvant therapy or recurrence. The response to platinum-based chemotherapy was relatively good and may be comparable to that of small cell lung cancer. The overall 5-year survival rate was 30.3%. Pulmonary LCNEC represents an aggressive tumor and multimodal treatment is required.

The Wnt family encodes multi-functional signalling glycoproteins regulating various normal and pathological processes including tumourigenesis. Wnt2B overexpression is thought to affect tumour progression through the activation of the canonical Wnt pathway.Experimental studies were conducted using a Wnt2B-inhibiting vector to establish gene therapy against Wnt2B2-overexpressing tumours. A replication-deficient recombinant adenoviral vector expressing short hairpin RNA targeting Wnt2B (Ad-shWnt2B) was constructed. Three Wnt2B2-overexpressing human tumour cells, including A549 cells, Hela cells and PANC1 cells, were used. Thereafter, cell viability was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Next, a human tumour xenograft model in nude mice was prepared by subcutaneously implanting tumours derived from A549 cells. Ad-shWnt2B was administered via intratumoural injection every 4days.First, immunohistochemical studies revealed that high levels of Wnt2B expression appeared in proliferative normal tissues and many human tumour tissues. Furthermore, the Wnt2B2 gene expression was associated with c-Myc and survivin expressions in human lung cancer. Transduction with Ad-shWnt2B effectively downregulated the Wnt2B2 expression in all the three Wnt2B2-overexpressing tumour cells (p0.0001). The transduction with Ad-shWnt2B significantly reduced the percentage of viable cells in all the Wnt2B2-overexpressing tumour cells (p0.005). In addition, transduction with Ad-shWnt2B significantly downregulated c-Myc and survivin in A549 cells (p0.005). Furthermore, the treatment with Ad-shWnt2B exerted a significant antitumour effect against the Wnt2B2-overexpressing A549 xenografts by inducing apoptosis (p0.01).Cancer gene therapy using an adenoviral vector expressing short hairpin RNA (shRNA) against Wnt2B was, therefore, found to have a strong antitumour effect against Wnt2B2-overexpressing tumours.

High levels of intratumoral thymidylate synthase (TS) expression are associated with resistance to 5-fluorourcil (5-FU). In order to establish a new treatment method for 5-FU-resistant tumors, the efficacy of gene therapy was investigated using an adenoviral vector expressing short hairpin RNA (shRNA) targeting TS. A replication-deficient recombinant adenoviral vector expressing shRNA targeting TS was constructed under the control of the human U6 promoter (Ad-shTS). Three 5-FU-resistant cancer cell lines, DLD-1/5FU, KM12C/5FU and NUGC-3/5FU, were used. Transduction with Ad-shTS effectively downregulated TS expression in all three 5-FU-resistant tumor cells. MTT assays demonstrated that treatment with Ad-shTS significantly inhibited the growth of all three 5-FU-resistant tumor cells. Furthermore, combined treatment with Ad-shTS and 5-FU demonstrated significantly greater inhibition of tumor cell growth in comparison to 5-FU treatment alone and Ad-shTS treatment alone. S-1, a combination of tegafur, gimeracil and oteracil potassium, was used for the 5-FU treatment by in vivo experiments. The combined treatment of Ad-shTS and S-1 was found to have the strongest antitumor effect against 5-FU-resistant DLD-1/5FU xenografts in nude mice in comparison to S-1 treatment alone and Ad-shTS treatment alone. Furthermore, the apoptotic index in tumors treated with combined Ad-shTS and S-1 was significantly higher in comparison to that in tumors treated with S-1 alone and that in tumors treated with Ad-shTS alone. Consequently, the combined treatment of the TS-inhibiting adenoviral vector and S-1 has effective antitumor activity against 5-FU-resistant tumors.

従来より肺摘除術後特有の合併症として, 術後胸腔内出血及び縦隔変位が問題とされてきた.我々はこれら合併症を防止するために, 胸腔バルーンの留置を臨床的に試みた.症例は11例であり, 基礎疾患は肺癌8例と膿胸3例である.術式は肺摘除術9例, 胸膜肺摘除術1例で, 他の1例は部分膿胸での大網被覆術に使用した.術中に胸腔バルーンを留置し, 空気を450～600ml注入した.9例では胸腔ドレーンを別に留置し (1型), 2例では胸腔ドレーンと一体化した改良型 (II型) を使用した.更に8例で胸腔バルーン抜去後にSF6胸腔内注入も併用した.その結果, 術後2日間における排液量に減少がみられた.術後2日目の測定では胸腔バルーン留置による呼吸循環動態への悪影響はなく, 胸腔バルーン留置による合併症もなかった.胸腔バルーンの留置は肺摘除術の術後において安全かつ簡便な方法であり, 遷延する術後胸腔内出血と縦隔変位を同時に防止できる有用な方法と思う.

The insulin-like growth factor 1 receptor (IGF1R) is widely expressed in normal tissues and many malignancies in humans. We investigated the clinical significance of the expression of the IGF1R gene in human lung adenocarcinoma.A total of 238 patients with lung adenocarcinoma were investigated. Quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) assays were performed to evaluate the gene expression of IGF1R, and immunohistochemical staining was done to evaluate the protein expression of IGF1R.Among the 238 patients with lung adenocarcinoma, 107 tumors (45.0%) were IGF1R-low and 131 tumors (55.0%) were IGF1R-high. The IGF1R gene expression ratio was significantly lower in moderately to poorly differentiated adenocarcinomas than in well-differentiated adenocarcinomas (P = 0.0388). Gene expression of IGF1R was significantly correlated with protein expression of IGF1R (r = 0.7163, P0.0001). Regarding patient survival, overall survival was significantly lower in patients with IGF1R-low tumors than in those with IGF1R-high tumors (63.2% versus 76.1% 5-year survival, P = 0.0188). Multivariate analysis using a Cox proportional-hazards model demonstrated that IGF1R gene status was a significant prognostic factor predicting overall survival of patients with lung adenocarcinoma (hazard ratio 1.800; P = 0.0321). Moreover, the disease-free survival rate was significantly lower in patients with IGF1R-low tumors than in those with IGF1R-high tumors (49.2% versus 64.6% 5-year survival, P = 0.0084).The present study suggests the level of IGF1R expression to be a useful prognostic marker for patients with dedifferentiated lung adenocarcinoma.

Survivin, a member of the inhibitor of apoptosis protein family, affects tumorigenesis. Recently, survivin is reported to be a target of the canonical Wnt pathway, which activates the transcription of various tumor-associated target genes. One hundred and twenty-two non-small cell lung cancers (NSCLCs) were investigated to evaluate survivin gene expression in relation to the expression of Wnt1 (a novel member of the canonical Wnt pathway) and Wnt5a (a novel member of the non-canonical Wnt pathway). The survivin gene expression was evaluated by semi-quantitative RT-PCR. The protein expression of pan-survivin, Wnt1, and Wn5a were investigated by immunohistochemistry. The apoptotic index and the Ki-67 proliferation index were also evaluated. Sixty-four tumors (52.5%) were survivin-high tumors, 65 tumors were Wnt1-high tumors, and 67 tumors (54.9%) were Wnt5a-high tumors. The standardized survivin gene expression significantly correlated with the apoptotic index (P

We previously reported that the blood-brain barrier (BBB) function was deteriorated in vessels located in the hippocampus in stroke-prone spontaneously hypertensive rats (SHRSP). In order to assess whether substances with oxidative stress such as amyloid-beta (Abeta) can be scavenged in the BBB-damaged vessels, we examined the gene expression of representative efflux and influx transporters of Abeta, such as low-density lipoprotein receptor (LDLR), LDL-related protein 1 (LRP1), and the receptor for advanced glycation end product (RAGE) in the hippocampus of SHRSP with the BBB impairment and Wistar Kyoto rats (WKY) without the impairment. Real-time quantitative reverse transcriptase-polymerase chain reaction analysis revealed that LDLR gene expression was increased in the samples of SHRSP compared with those of WKY, while there was no significant difference in LRP1 or RAGE gene expression between SHRSP and WKY. Western blot analysis revealed that the protein expression of LDLR was increased in the samples of SHRSP compared with those of WKY. Immunoelectron microscopic examination revealed that the LDLR expression was seen in the luminal and abluminal cytoplasmic membranes and vesicular structures of the endothelial cells and the cytoplasm of perivascular cells, especially in vessels with immunoreactivity of albumin showing increased vascular permeability. These findings suggest that the expression of LDLR was increased in the hippocampus of SHRSP compared with that of WKY and was seen in the luminal and abluminal cytoplasmic membranes and vesicular structures of endothelial cells, suggesting a role of LDLR in the vessels with BBB impairment.

SUMMARY Design and implementation of a system for assembly code generation (from a feature-based geometric model) is discussed. Assembly code is further used in design for assembly evaluation procedures for produce assembly analysis. Assembly features are classified into three groups: geometric assembly features, non-geometric assembly features and operational assembly features. The first two groups of features have existed in computer-aided design databases, while the last one has existed in an assembly sequence. Algorithms for identifying the first two groups of features are presented. A tree processor to convert assembly features into assembly code is also developed. Finally, examples are presented.

An 80-year-old male was admitted because of a giant mass in the left lower lobe of the lung on a routine chest X-ray. Chest computed tomography verified this to be a well-defined heterogeneous mass as described with no associated lymphadenopathy. FDG-PET depicted moderately marginal FDG uptake. The patient underwent a left lower lobectomy and lymphadenectomy. Grossly, the tumor measured 60 × 50 mm and was uniformly filled with a pure white, pudding-like friable substance. No lymph node metastasis was observed microscopically. Histologically, the tumor showed a dense proliferation of rounded or spindled malignant cells with a frequent mitotic activity and an increased nuclear-to-cytoplasmic ratio. The immunohistochemical staining was positive for vimentin, negative for cytokeratin, keratin-wide, EMA, CD34. A SYT-SSX2 fusion gene transcript was detected as a result of RT-PCR analysis. Because of these results, the tumor was diagnosed as a monophasic synovial sarcoma.

Reported herein is a case of medulloblastoma with myogenic differentiation in a 3-year-old girl who died 1 year after appearance of clinical signs. Magnetic resonance imaging indicated a mass lesion in the cerebellar vermis. She underwent total resection of the tumor, followed by chemotherapy and radiotherapy in the brain and spinal cord. The resected specimen mainly consisted of densely packed cells with round-to-oval highly chromatic nuclei surrounded by scanty cytoplasm and focally of long spindle-shaped cells with elongated nuclei and eosinophilic cytoplasm showing discernible cross-striations. Immunohistochemistry indicated partial expression of synaptophysin in the former area and focal expression of desmin in the latter area. The diagnosis was medulloblastoma with myogenic differentiation, also known as medullomyoblastoma. Autopsy indicated disseminated proliferation of immature neuroglial cells with highly chromatic nuclei and scanty cytoplasm showing partial expression of synaptophysin, neurofilaments, and GFAP, and focal proliferation of round-to-oval immature cells showing immunoreactivity of myoglobin. The tumor cells had large nuclei, frequent mitoses, apoptoses, nuclear molding, and cell wrapping, indicating moderate anaplasia. Their Ki-67 labeling index was 54%. In addition, some tumor cells had double immunopositivity for synaptophysin or neurofilament and myoglobin, suggesting that the neuroectodermal cells may undergo differentiation into rhabdomyoblasts.

SAMP8, senescence-accelerated mice with age-related deficits in memory and learning, are known to show age-related increases of amyloid precursor protein (APP) expression and to be under elevated oxidative stress. The receptor for advanced glycation end product (RAGE) is a representative influx transporter of APP or amyloid-beta (A beta) protein in cerebral vessels, while low-density lipoprotein receptor (LDLR) and LDL-related protein 1 (LRP1) are efflux transporters. These receptors play roles not only in clearance of A beta protein but also in control of oxidative stress. In this study, we examined the gene and protein expressions of these receptors, by real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting, and immunohistochemical techniques. SAMR1 mice with lower expression of APP were as controls. The gene and protein expressions of RAGE were lower in SAMP8 brains than in SAMR1. Those of LDLR were higher in SAMP8 brains than those of SAMR1. There were no differences in the expressions of LRP1 between SAMP8 and SAMR1. Immunosignals of RAGE and LDLR were seen in the cytoplasm of CD34-positive endothelial cells and also in astrocytes, in both strains of mice. These findings suggest that the lower expression of RAGE and the higher expression of LDLR may contribute to clearance of toxic substances and, in addition, be related to elevated oxidative stress in SAMP8 brains.

Aims: We previously reported that the blood-brain barrier (BBB) function was impaired in vessels in the hippocampus in 3-month-old stroke-prone spontaneously hypertensive rats (SHRSP). In this study, we examined gene and protein expressions of P-glycoprotein, a representative efflux transporter of cerebral vessels, in the BBB-damaged hippocampal vessels of SHRSP and in the vessels of Wistar Kyoto (WKY) rats as controls, to clarify roles of the efflux transporter in the BBB-damaged vessels. Methods: The expression of P-glycoprotein in hippocampal and cortical samples was examined by real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting and immunoelectron microscopic techniques. Results: Real-time RT-PCR and Western blotting analyses revealed that the gene and protein expressions of P-glycoprotein were increased in the hippocampal samples of 3-month-old SHRSP compared with hippocampal samples of 3-month-old WKY rats or with cortical samples of SHRSP. The gene expression of P-glycoprotein was also increased in the hippocampal samples of 4-week-old SHRSP. Immunoelectron microscopic examination revealed that immunosignals of P-glycoprotein were seen in the luminal and ab-luminal cytoplasmic membranes of endothelial cells and the basal lamina, that the labelling density of P-glycoprotein in the vessel wall was higher in the hippocampus of 3-month-old SHRSP than in other groups and that the immunosignals of P-glycoprotein were occasionally co-located with those of albumin. Conclusions: These findings indicate that the expression of P-glycoprotein is increased in BBB-damaged hippocampal vessels in hypertensive SHRSP compared with those in WKY rats.

受傷後3ヵ月の外傷性中間気管支幹断裂症例に気道再建術を施行したので報告した.症例は17歳・男性で, 交通事故のため近医にて入院した.この時, 両側気胸の診断下に両側胸腔ドレナージ術を受け, 保存的治療のみで退院となった.その後, 胸部X線上右中下葉の無気肺が疑われたため, 当院に入院した.気管支鏡検査で肉芽形成による中間気管支幹の完全閉塞を認めた.肺血流シソチでは右中下葉への血流低下を認めたが, 肺換気シンチでは右中下葉へのXeの拡散とwash outの遅延がみられた.開胸時所見では右中下葉の含気性は保たれており, 中間幹気管支形成術 (iiSR) を施行した.術後経過は順調であった.外傷性気管支断裂症例では術前術中における末梢肺の評価は大切であり, 肺換気・血流シンチは非侵襲的で有用な術前検査である.

It was recently reported that some strains of senescence-accelerated mouse (SAM) including SAMR1 had a spontaneous retroviral insertional mutation in the ATP-binding cassette, sub-family B, member 1A (Abcb1a) gene, while other strains including SAMP8 had not. The Abcb1 gene product, P-glycoprotein, is a representative efflux transporter of cerebral vessels. In this study, using brain samples of SAMR1, Abcb1a gene-mutant mice, and of SAMP8 without that mutation, we examined the gene expression of some representative ATP-binding cassettes, such as Abcb1a, Abcb1b, Abcc, and Abcg2, and the protein expression of P-glycoprotein by real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting, and immunohistochemical techniques. The gene expression of Abcb1a was decreased in the brain samples of SAMR1 compared with those of SAMP8, while that of Abcb1b was increased in the samples of SAMR1 compared with those of SAMP8. There were no differences in the gene expression of Abcc and Abcg2 between the samples of SAMR1 and SAMP8. The protein expression of P-glycoprotein was decreased in the brain samples of SAMR1 compared with those of SAMP8. Immunosignals of P-glycoprotein were seen in vessels walls, mainly CD34-positive endothelial cells and partially astrocytic cells, in both mice. These findings indicate that SAMR1, Abcb1a-mutant mice, showed decreased expression of Abcb1a gene and P-glycoprotein and increased gene expression of Abcb1b, compared with those of SAMP8 without that mutation, suggesting no clear effect of increased gene expression of Abcb1b on decreased expression of P-glycoprotein. The combination of SAMR1 and SAMP8 may be a good tool to investigate which transporter, Abcb1a or Abcb1b, can be used in drug delivery into the brain.

The Wnt gene family is involved in embryogenesis and tumourigenesis. We investigated the clinical significance of Wnt1 expression in non-small cell lung cancer (NSCLC).We studied 216 NSCLC patients. Immunohistochemistry was performed to investigate the Wnt1 expression in relation to the expression of beta-catenin and Wnt-targets, including c-Myc, Cyclin D1, VEGF-A and MMP-7. The Ki-67 proliferation index and the intratumoural microvessel density (IMD) were also evaluated.The ratio of tumours with an aberrant beta-catenin expression was significantly higher in Wnt1-positive tumours than in Wnt1-negative tumours (p0.0001). The Wnt1 expression significantly correlated with the expression of c-Myc (p0.0001), Cyclin D1 (p0.0001), VEGF-A (p=0.0160), MMP-7 (p0.0001), the Ki-67 index (p=0.0048) and the IMD (p=0.0267). Furthermore, the Wnt1 status was a significant prognostic factor for NSCLC patients (p=0.0127).The Wnt1 overexpression is associated with the expression of tumour-associated Wnt-targets, tumour proliferation, angiogenesis and a poor prognosis in NSCLCs.

Cancer of the mediastinum is known to be a relatively rare disease, and clear cell carcinoma in the mediastinum is especially rare. Ectopic thymus is not uncommon, but clear cell carcinoma originating from ectopic thymus has never been reported. We report a case of clear cell carcinoma originating from ectopic thymus in which there was a good response to steroid-supplemented chemoradiotherapy.

Survivin is a member of the inhibitor of apoptosis protein family. Survivin has splice variants with different biological functions associated with tumorigenesis. We investigated 134 non-small cell lung cancers (NSCLCs) to study the clinical significance of wild-type survivin, survivin-2B, and survivin-deltaEx3. Real-time PCR analyses were performed for their gene expressions. The subcellular localisation of survivin proteins was evaluated by immunohistochemistry. The Ki-67 proliferation index and the apoptotic index were also evaluated. The survivin-deltaEx3 gene expression was significantly higher in stage II–III than in stage I (P=0.0174), and significantly correlated with the nuclear pan-survivin expression (P

原発性肺癌に対して手術を施行した後, 同側あるいは対側に再発し再度外科治療を試みた再発肺癌について検討した.昭和55年1月より63年12月までの間に再発肺癌切除例は9例あり, この間の手術症例267例の3.4%にあたる.初回手術術式は葉切6例, 部分切除3例で, 臨床病期は1期6例, IIIA期1例, III B期1例で, 残りの1例は他院での手術のため病期を決定でぎなかった.術後同側再発は6例, 対側再発は3例であり, 初回手術から再発肺癌手術までの期間は7～63ヵ月 (平均24.1ヵ月) であった.組織型は腺癌が6例で最も多かった.再発肺癌に対し, 葉切を3例に, 部分切除を6例に施行した.これら9例中4例が死亡 (呼吸不全死1例) し, 4例はdisease freeで, 1例は担癌状態で生存中である.また, limited operationを行うことで再手術後の肺機能温存が可能であった.以上より, 再発肺癌に対して積極的に外科治療を試みることは臨床的意義のあることが示唆された.

The Wnt family genes encode multifunctional signaling glycoproteins that are involved in the regulation of a wide variety of normal and pathological processes including tumorigenesis. In order to clarify the clinical significance of the intratumoral Wnt1 expression in non-small cell lung cancer (NSCLC), we performed an immunohistochemical study on the Wnt1 expression in NSCLCs in relation to the tumor proliferation. The intratumoral Wnt1 protein expression appeared in a cytoplasmic staining pattern. Of the 151 NSCLCs studied, 61 carcinomas (40.4%) were Wnt1-positive. Regarding the tumor biology of the intratumoral Wnt1 expression, the Ki-67 proliferation index was significantly higher in Wnt1-positive than in Wnt1-negative tumors (P=0.0062). Furthermore, regarding the expression of c-Myc, one of the proliferation-regulating Wnt targets, the percentage of c-Myc-positive tumor cells was significantly higher in Wnt1-positive than in Wnt1-negative tumors (P=0.0019). The Ki-67 proliferation index was significantly higher in c-Myc-positive than in c-Myc-negative tumors (P=0.0239). The overall survival was significantly lower in patients with Wnt1-positive NSCLCs than in patients with Wnt1-negative NSCLCs (P=0.0003). A Cox regression analysis demonstrated that the Wnt1 status was a significant prognostic factor for NSCLC patients (hazard ratio 1.983; P=0.0061). Our results revealed that the Wnt1 overexpression affects the tumor proliferation in NSCLCs, partly via the upregulation of c-Myc.

Aims: We previously reported that the blood-brain barrier (BBB) function was deteriorated in vessels located along hippocampal fissures in stroke-prone spontaneously hypertensive rats (SHRSP). In this study, we examined changes of gene expression in the BBB-damaged vessels of SHRSP. Methods: Vascular samples were microdissected from the hippocampi of SHRSP and Wistar-Kyoto (WKY) as a control and the difference in gene expression between the BBB-damaged vessels in SHRSP and vessels without BBB damage in WKY was examined by a microarray. The differences in gene and protein expression between brain tissues in the two strains of rats were examined using real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting and immunohistochemistry. Results: The microarray assay revealed that the ratio of osteopontin gene expression in the vascular tissue of the hippocampi of SHRSP to that of WKY was the highest among 8435 genes. Real-time RT-PCR analysis revealed that the gene expression of osteopontin was significantly increased in the hippocampal samples of SHRSP compared with that in the hippocampal samples of WKY rats or with that in the cortical samples of SHRSP. Immunohistochemical and Western blot analyses showed that the osteopontin protein expression was seen in perivascular ED 1-positive macrophages/microglial cells located around hippocampal fissures and significantly increased in the hippocampi of SHRSP compared with that of WKY. Conclusions: These findings indicate that the expression of osteopontin is increased in BBB-damaged vessels in hypertensive SHRSP compared with that in vessels without BBB impairment in WKY rats, suggesting a role for osteopontin in BBB function.

Spontaneous rupture of the esophagus, Boerhaave’s syndrome, is a rare entity, and is often overlooked at ® rst. Its clinical and pathological features have frequently been described (1). Despite advances in supportive measures, delayed diagnosis and treatment still cause a high mortality rate (2). An early suture of the rupture, with adequate drainage of the mediastinum and pleural cavity, provides the best survival rates (3). Postoperative mediastinitis and empyema carry a grim prognosis. We report a case of Boerhaave’s syndrome, in which postoperative empyema was treated successfully by open chest drainage. The usefulness of open chest drainage is discussed here.

This work investigated how wearing a new design of back belt affects erector spinae activity, hand force, and body stability. The belt was first tested with static holding tasks and found to significantly decrease the back muscle activity. Actual lifting tasks were further carried out to test the effect of the belt. Ten male subjects performed a symmetric lifting task of low-lying loads (11 and 16 kg) at natural toting velocity, using either a squat or stoop lifting posture, both with and without a belt. The study measured various independent variables using electromyography (EMG), load cells, and motion capture device. The results demonstrated that the belt reduced the load on the erector spinae, as well as the triceps brachii and biceps brachii. The overall mean values of the peak (hand) force did not appear significantly affected while wearing the belt, but the force peaks appeared postponed. The belt did not alter body stability while lifting. From the present findings, the belt effectively changed the force distribution during lifting, at least reducing the muscle load on the back. The belt may be a potentially useful device for symmetric industrial lifting tasks.

Recent studies have reported that mutations of the epidermal growth factor receptor (EGFR) gene are associated with the responsiveness of tyrosine kinase inhibitors (TKIs), which are molecular targets for non-small cell lung cancer (NSCLC). To provide genetic analyses for NSCLC patients, a simple and reliable method using paraffin-embedded materials is needed. The DEXPAT DNA extraction kit was used for DNA extraction from paraffin-embedded materials. DNA was amplified using the nested PCR technique, then analyzed by direct sequencing for EGFR mutations (exons 18 to 21). The phenol/chloroform extraction for DNA was also performed for comparison. When the DEXPAT kit was used, distinct bands were observed in all products after nested PCR assays of paraffin-embedded materials. Distinct sequencing signals were obtained. Results from the sequencing analysis of paraffin-embedded materials and frozen materials were completely concordant. The current study suggests that DNA extraction with the DEXPAT kit followed by nested PCR is a simple and reliable technique for analyzing the EGFR gene status with paraffin-embedded samples.

Motility-related protein-1 (MRP-1/CD9) is involved in cell motility. We studied the change in the actin cytoskeleton, and the expression of actin-related protein (Arp) 2 and Arp3 and the Wiskott–Aldrich syndrome protein (WASP) family according to MRP-1/CD9 gene transduction into HT1080 cells. The frequency of cells with lamellipodia was significantly lower in MRP-1/CD9-transfected HT1080 cells than in control HT1080 cells (P

The selection of the most effective chemotherapy treatment based on evaluation of biomarkers, that is, ‘tailor-made chemotherapy’, can improve the clinical outcome of non-small cell lung cancer patients, including early-stage tumors with a high metastatic potential and advanced-stage tumors with a low proliferation rate. Therefore, treatment would be chosen according to which drugs would be most effective in combating specific tumors. For example: 5-fluorouracil-derived agents would be used for tumors with a low expression of thymidylate synthase; gefitinib and erlotinib for tumors with epidermal growth factor receptor (EGFR) mutations or increased EGFR gene copy numbers; cisplatin and carboplatin for tumors with a low expression of excision repair cross complementing-1; and gemcitabine for tumors with a low expression of ribonucleotide reductase. The remaining populations of non-small cell lung cancers require chemotherapy using other drugs based on an evaluation of other targeted molecules.

We experienced a surgical case of large cell carcinoma with neuroendocrine morphology (LCCNM) of the lung. A 76-year-old man was admitted to our hospital because a routine chest X-ray examination had revealed a nodular shadow in the left lung field. 18F-fluorodeoxyglucose positron emission tomography showed accumulation of fluorodeoxyglucose in an area corresponding to the shadow. Transbronchial lung biopsy failed to give a definitive diagnosis, therefore open lung biopsy was performed because of suspected lung cancer. Needle biopsy was performed, and the tumor was diagnosed as large cell neuroendocrine carcinoma by rapid intraoperative pathological examination. As sampling of hilar lymph nodes revealed no metastasis, left upper segmentectomy was performed for severe obstructive pulmonary disease. Immunohistochemical examination finally diagnosed the tumor as LCCNM. The patient is doing well without recurrence at ten months after surgery.

Congenital bronchial atresia (CBA) is an infrequent pulmonary anomaly characterized, in general, by a blindly terminating bronchus, mucoid impaction, and hyperinflation of the peripheral pulmonary parenchyma. We herein report an adult case of lobar bronchial atresia who showed no hyperinflation of the peripheral pulmonary parenchyma.

The aim of this study was to clarify the mechanism of apoptosis seen in the cortex of neural cell-specific hypoxia inducible factor-1alpha (HIF-1alpha)-deficient embryos. A previous study showed that the neural cells in the cortical area of the mutant embryos underwent apoptosis coincident with vascular regression. Through histological, immunohistochemical, and electron microscopic technique, two kinds of apoptotic cells were detected in the mutant embryonal cortex. Apoptotic cells of one type were clustered in small round structures, 10-20 mum in diameter, whereas the others, present in large numbers, were distributed in a group at the cortical plate located more to the outer side than the round structures. The histochemical and electron microscopic findings indicate that the former represented the appearance of macrophages, in which cellular fragments including vascular cells underwent oxidative stress-related, TNF receptor-mediated, caspase-2-induced apoptosis, while the latter showed c-Myc-related, caspase-3-activated apoptosis of the neural cells. These results suggest that two pathways of apoptosis are induced in neuronal and vascular cells of the cortex in the neural cell-specific HIF-1alpha-deficient mouse.

Primary lung carcinomas showing features of salivary gland-type neoplasms are rare. Many are mucoepidermoid carcinomas and adenoid cystic carcinomas. Myoepithelial carcinoma of the lung is extremely rare, and in the WHO classification is classified as 'Others' among carcinomas of the salivary gland. The pertinent literature is restricted to a few pathological reports, and hardly any clinical examinations have been performed. Here we report a resected case of myoepithelial carcinoma of the lung, including details of clinical examination, with a review of previously documented cases.

Background Oxidative stress in diabetes mellitus has recently received increasing attention as it has been proven to be associated with the development of diabetic vascular complications. Our aim was to examine whether microvascular changes, including oxidative damage, were induced in the brains of diabetic animals. Methods The expression of 8-hydroxy-2′-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, the binding of cationized ferritin, a marker for evaluating endothelial glycocalyx, to the endothelial cells of capillaries and vascular permeability of intravenously injected horseradish peroxidase were examined in the cortices of 12- and 20-week-old db/db and db/+m mice. Results Immunostaining for 8-OHdG was clearly seen in the vessels of the cortex of 20-week-old db/db mice, but was hardly seen in those of mice in the other groups. The immunopositive area of 8-OHdG was significantly increased in the cortex of 20-week-old db/db mice compared with that of 20-week-old db/+m mice. No extravasated leakage of horseradish peroxidase was seen in any groups of mice, while the numbers of cationized ferritin particles binding to the endothelial cells was significantly decreased in 12- and 20-week-old db/db mice compared with that of db/+m mice at the same age, respectively. Conclusion These findings suggest that changes in endothelial glycocalyx are induced in db/db mice and, in addition, the long-term diabetic condition of these mice induces oxidative DNA damage to the cerebral vessels. Copyright © 2005 John Wiley & Sons, Ltd.

Vascular permeability and endothelial glycocalyx were examined in young adult spontaneously hypertensive rats (SHR), stroke-prone SHR (SHRSP), and Wistar Kyoto rats (WKY) as a control, in order to determine earlier changes in the blood-brain barrier (BBB) in the hypothalamus in chronic hypertension. These rats were injected with horseradish peroxidase (HRP) as an indicator of vascular permeability. Brain slices were developed with a chromogen and further examined with cationized ferritin, a marker for evaluating glycocalyx. Staining for HRP was seen around vessels in the hypothalamus of SHR and SHRSP, but was scarce in WKY. The reaction product of HRP appeared in the abluminal pits of endothelial cells and within the basal lamina of arterioles, showing increased vascular permeability in the hypothalamus of SHR and SHRSP, whereas there were no leaky vessels in the frontal cortex of SHR and SHRSP, or in both areas of WKY. The number of cationized ferritin particles binding to the capillary endothelial cells was decreased in the hypothalamus of SHR and SHRSP, while the number decreased in the frontal cortex of SHRSP, compared with those in WKY. Cationized ferritin binding was preserved in some leaky arterioles, while it was scarce or disappeared in other leaky vessels. These findings suggest that BBB disruption occurs in the hypothalamus of 3-month-old SHR and SHRSP, and that endothelial glycocalyx is markedly damaged there without a close relationship to the early changes in the BBB.

A 61-year-old man was referred to our hospital because of rapid growth of a mass shadow revealed by chest radiography. The mass was diagnosed as pure small cell carcinoma by CT-guided needle biopsy, and the patient underwent chemotherapy. However, as the tumor showed no response, we considered the possibility of some other form of malignancy and performed surgery. Postoperatively, the mass was diagnosed as small cell carcinoma combined with small cell, spindle cell and squamous cell carcinoma. We report this case in view of the rarity of this combination of morphologic patterns in a primary bronchogenic carcinoma.

Objectives We investigated whether bone morphogenetic protein 2, released slowly from a gelatin sponge, could induce cartilage regeneration in a canine model of tracheomalacia and evaluated the long-term results. Methods A 1 × 5-cm gap was made in the anterior cervical trachea by removing 5-cm long strips of 10 sequential cartilagines. In the control group (n = 5), the gaps were left untreated. In the gelatin sponge group (n = 5), a gelatin sponge soaked in a buffer solution was implanted in each defect. In the bone morphogenetic protein group (n = 5), a gelatin sponge soaked in a buffer solution containing 12 μg bone morphogenetic protein 2 was implanted in each defect. Results Tracheomalacia was observed in the control and gelatin sponge groups but not in the bone morphogenetic protein group. No regenerated cartilage was detected in the control or gelatin sponge groups, even 6 months after surgery. In contrast, regenerated cartilage, which had developed from the host perichondrium, was observed around the stumps of the resected cartilagines in the bone morphogenetic protein group. This regenerated cartilage maintained the integrity of the internal lumen for longer than 6 months. A compressive fracture test revealed that the tracheal cartilage in the bone morphogenetic protein group was significantly more stable than that in the gelatin sponge and control groups ( P = .0015 and P = .0001, respectively). Conclusions In this canine model of tracheomalacia, cartilage regeneration was induced around the stumps of tracheal cartilagines by bone morphogenetic protein 2 released slowly from a gelatin sponge. This regenerated cartilage was not reabsorbed for longer than 6 months and was strong enough to maintain the integrity of the internal lumen of the trachea.

Understanding and controlling angiogenesis and lymphangiogenesis could lead to effective strategies for cancer treatment. The aim of our study was to clarify the clinical value of vascular endothelial growth factor-A (VEGF-A) and VEGF-C in non-small cell lung cancer (NSCLC).One hundred and fifty-three patients with NSCLCs were studied to investigate intratumoral expression of VEGF-A and VEGF-C by immunohistochemistry. Simultaneously, we evaluated tumor angiogenesis using CD34 immunostaining.Seventy-eight carcinomas (51.0%) were VEGF-A-positive, and 64 carcinomas (41.8%) were VEGF-C-positive. There was no correlationship between VEGF-A expression and VEGF-C expression in NSCLCs. The frequency of hypervascular tumors was significantly higher in VEGF-A-positive NSCLCs than in VEGF-A-negative NSCLCs (p=0.0442), while there was no correlation between intratumoral VEGF-C expression status and tumor vascularity. Concerning survival of NSCLC patients, intratumoral expression of VEGF-A was one of the significant prognostic factors in NSCLC patients (relative risk=2.012, p=0.0101), especially in patients with adenocarcinomas (relative risk=3.816, p=0.0025). On the other hand, intratumoral expression VEGF-C was one of the significant prognostic factors in patients with squamous cell carcinomas (relative risk=3.946, p=0.0143).The present study demonstrated that intratumoral VEGF-A expression is one of the significant prognostic factors in patients with adenocarcinomas, and that intratumoral VEGF-C expression is one of the significant prognostic factors in patients with squamous cell carcinomas. These different functions of the VEGF family in relation to tumor histology might reflect the clinical behaviors of NSCLCs.