Evaluation of Powered ECHELON FLEX for pulmonary lobectomy

肺葉切除における電動式自動縫合器の使用経験

Objective : It has been accepted to use staplers for open and video-assisted thoracic surgery, however there was a risk in stapling of the pulmonary vasculatures. A newly developed stapler, powered ECHELON FLEX (Ethicon) is an electrically-powered stapler. It may reduce tip movement during cutting and stapling, which results in reduction of the risk of trauma to surrounding tissue. The aim of this study was to evaluate powered ECHELON FLEX for pulmonary lobectomy. Methods : We reviewed 16 patients who underwent pulmonary lobectomy with powered ECHELON FLEX in our institution from December, 2013 to April, 2014. Results : There were 25 stapling for the pulmonary artery, 17 stapling for the pulmonary vein, 16 stapling for the bronchus, and 33 stapling for the pulmonary parenchyma. Though two case of oozing from the stamps of a pulmonary artery and pulmonary parenchyma, there were no serious complications related to use of the staplers. Conclusions : The powered ECHELON FLEX can be used for pulmonary lobectomy safely.


Setting of fees for robotic surgery for lung cancer not covered by insurance

肺癌ロボット手術の私費料金設定

In Japan, the only robot surgery covered by health insurance is prostatectomy. Robot surgery for pulmonary cancer has not been approved as advanced health care, and hospitals are required to set out-of-pocket fees for surgery on their own. We calculated the fee not covered by insurance to be 1.28million yen, taking into account expenses for : (1) the use of medical equipment, (2) maintenance, (3) labor costs, and (4) medical materials and drugs. Since the fees for surgery plus hospitalization are actually incurred by patients, whether or not the hospitalization fee should be included in out-of-pocket medical fees is decided by each health care institution. In any case, it is necessary to provide patients with a summary of medical fees prior to surgery. Hospitals are required to collect data on pulmonary robot surgical cases while operating the system with medical fees incurred by individual patients.


Triple assessment of sentinel lymph node metastasis in early breast cancer using preoperative CTLG, intraoperative fluorescence navigation and OSNA.

Use of CTLG and fluorescence navigation made performing SLNB with high accuracy possible in institutions that cannot use the radioisotope method. OSNA provided accurate intraoperative method, allowing for completion of axillary node dissection during surgery and avoidance of second surgical procedure in patients with positive SLNs, thereby reducing patient distress and, finally, saving hospital costs.

SLN were identified by preoperative CTLG and intraoperative SLNB with fluorescence navigation in all patients, the identification rate was 100 %. SLN metastases were detected as positive by OSNA in 9 patients (18 %), 4 were (++), 4 were (+) and 1 was (+I). SLN metastases were detected as positive by histopathology in 10 patients (20 %). The concordance rate between OSNA and permanent sections was 90 %. The negative predictive value of CTLG was 80 %.


特集:Sentinel node navigation surgery Ⅱ．各論 3．肺癌におけるsentinel node navigation surgery


Non-invasive monitoring of anticancer effects of cisplatin on lung cancer in an orthotopic SCID mouse model using [18F] FDG PET-CT.

Positron emission tomography-computed tomography (PET-CT) with [18F] fluorodeoxyglucose (FDG) has recently been applied for evaluating tumor response to anticancer therapy. The aim of the present study was to evaluate the utility of FDG PET-CT in monitoring non-invasively and repeatedly the inhibitory effect of cisplatin (CDDP) on an orthotopic lung cancer model. Validation of in vivo FDG uptake in human lung cancer Ma44-3 cell line in an orthotopic SCID mouse model was carried out. Next, we assessed the use of FDG PET-CT to monitor the response of orthotopic lung cancer to the anticancer effect of CDDP. SCID mice were divided into the CDDP group (7 mg/kg single dose intraperitoneally) and the control group. Tumor volume and maximal standardized uptake value (SUV max) were calculated for all mice. All mice were sacrificed for histopathologic analysis. Validation of FDG PET-CT showed that tumor volume and SUV max were significantly correlated with postmortem tumor length measured in specimens (P=0.023) and (P=0.012), respectively, and there was a significant correlation between SUV max and tumor volume (P=0.048). Response monitoring showed that significant growth inhibition by CDDP in the form of SUV max of the CDDP group was significantly lower than that of the control group on day 8 (P=0.02) and on day 13 (P=0.003). Tumor volume of the CDDP group was significantly lower than that of the control group on day 13 (P=0.03). The present study supports using FDG PET-CT in monitoring tumor progression and therapeutic response of lung cancer in an orthotopic model non-invasively and repeatedly.


Methylation and expression profiles of MGMT gene in thymic epithelial tumors

A key challenge in diagnosis and treatment of thymic epithelial tumors (TET) is in improving our understanding of the genetic and epigenetic changes of these relatively rare tumors. Methylation specific PCR (MSP) and immunohistochemistry were applied to 66 TET to profile the methylation status of DNA repair gene O6-methylguanine DNA methyltransferase (MGMT) and its protein expression in TET to clarify the association between MGMT status and clinicopathological features, response to chemotherapy and overall survival. MGMT methylation was significantly more frequent in thymic carcinoma than in thymoma (17/23, 74% versus 13/44, 29%; P<0.001). Loss of expression of MGMT protein was significantly more frequent in thymic carcinoma than in thymoma (20/23, 87% versus 10/44, 23%; P<0.0001). There is a significant correlation between of MGMT methylation and loss of its protein expression (P<0.0003). MGMT methylation and loss of expression were significantly more frequent in advanced thymic epithelial tumors (III/IV) than in early tumors (I/II). MGMT methylation plays a soul role in development of TET, especially in thymic carcinoma. Therefore, translation of our results from basic molecular research to clinical practice may have important implication for considering MGMT methylation as a marker and a target of future therapies in TET.


Increased number of Hassall's corpuscles in myasthenia gravis patients with thymic hyperplasia.

The thymus is implicated as an organ that contributes to autoimmunity in myasthenia gravis (MG) patients. Hassall's corpuscles (HCs) are assumed to represent the terminally differentiated stage of medullary thymic epithelial cells (mTECs). By using multicolor immunohistofluorescence analysis, we examined HCs in thymuses that were therapeutically excised from MG (+) and MG (-) patients. We found that the number of HCs per unit area of the thymic medulla was significantly elevated in the thymuses of MG (+) patients with thymic hyperplasia. CCL21 expression increased in the hyperplastic MG thymuses. We speculate that the altered differentiation of mTECs is associated with the thymic hyperplasia and the onset of MG.


進行肺癌に合併した続発性気胸に対する胸腔内フィブリン糊注入療法の経験

進行肺癌に合併した続発性気胸に対する胸腔内フィブリン糊注入療法の経験

The Journal of the Japanese Association for Chest Surgery


Actual condition of lymphedema prevention behavior of postoperative breast cancer patients without lymphedema

リンパ浮腫未発症の乳がん術後患者におけるリンパ浮腫予防行動の実態

本研究では，リンパ浮腫未発症の乳がん術後患者におけるリンパ浮腫予防行動の実態調査を行った．対象者は乳房部分切除および腋窩リンパ節郭清を行った乳がん術後患者で，現在外来通院中のリンパ浮腫未発症患者40名に構成的質問紙調査と，その内の21名に面接調査を実施した．結果，リンパ浮腫に関する知識の「リンパ浮腫の病因」，「リンパ浮腫の治療」，「リンパ浮腫の改善方法」，「生活上の注意」，「リンパ浮腫をみた経験」の知識に関して知っているかどうかにより「リンパ浮腫予防法実施状況」で有意差が認められ，継続できるか否かに差があることが示された．また，「リンパ浮腫予防法の数」との間でも有意差が認められ，知識に関して知っているかどうかにより予防法の数に差があることが示された．リンパ浮腫に対する認識および予防行動に対する認識において，それぞれ4つのカテゴリーが抽出された．以上の結果より，未発症患者であるからこそ，自身の体に関心を向け継続していく力をいかにつけていくことが重要となる．そのためにも，患者が体験する日常生活の中から予防法を考案していくことや，実感を伴いながら，知識を意味づけられる予防行動に関する指導を考案していくことが継続の支援に必要である．

JNI : The Journal of Nursing Investigation


Monitoring of exhaled carbon monoxide and carbon dioxide during lung cancer operation

Carbon monoxide (CO) is expelled mainly via the lungs, so that exhaled carbon monoxide (Ex-CO) concentration reflects endogenous production. Recent reports have shown that Ex-CO levels are increased in critically ill patients and after anaesthesia and surgery. However, there has been no investigation of the changes in Ex-CO level during a lung operation. We continuously monitored Ex-CO and exhaled carbon dioxide (Ex-CO2) concentrations during surgery for lung cancer. Eighteen lung cancer patients who underwent elective lung cancer lobectomy were enrolled in this study. All patients were endotracheally intubated and ventilated under general anaesthesia. Ex-CO and Ex-CO2 concentrations were separately monitored and recorded continuously using two sets of Carbolyzer® breath analysers (Taiyo Inc., Osaka, Japan). Ex-CO concentration increased rapidly in response to changes in body position from supine to decubitus and was significantly decreased when patients were once again lying back (supine 2). Upon restarting bilateral ventilation, Ex-CO concentration in the operated lung was significantly higher than that in the breathing lung. In the lateral decubitus position, Ex-CO2 concentration showed the same pattern of increase as seen for Ex-CO. In the operated lung, the Ex-CO2 concentrations changed significantly at clamping, declamping and supine 2. In the re-ventilated, operated lung, the Ex-CO2 concentration was significantly lower than in the breathing lung. In the breathing lung, the Ex-CO2 concentration did not exhibit any significant changes over the course of the operation. When breathing was restarted, the Ex-CO level of the target lung was significantly higher than that of the breathing lung. The Ex-CO concentration was also affected by the surgical body position and this change was marked and transient.

European Journal of Cardio-Thoracic Surgery


18F-fluorodeoxyglucose positron emission tomography/computed tomography and the relationship between fluorodeoxyglucose uptake and the expression of hypoxia-inducible factor-1, glucose transporter-1 and vascular endothelial growth factor in thymic epithelial tumours.

OBJECTIVES: The objective of this study was to evaluate the usefulness of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) and the relationships among the expressions of hypoxia-inducible factor-1 (HIF-1), glucose transporter-1 (Glut-1) and vascular endothelial growth factor (VEGF), histological type, other clinical factors and FDG uptake in thymic epithelial tumours. METHODS: Thirty-three patients who underwent FDG-PET/CT before treatment were reviewed. All types of tumours were reclassified into three subgroups: low-risk thymomas (types A, AB and B1), high-risk thymomas (types B2 and B3) and thymic carcinomas. Tumour contour, pattern of FDG uptake, tumour size and maximum standardized uptake value (SUVmax) were obtained. Expressions of HIF-1, Glut-1 and VEGF were analysed immunohistochemically, and these expressions were evaluated using grading scales. RESULTS: FDG uptake was visually recognized in all (100%) tumours. A homogeneous pattern of FDG uptake was increasingly observed in the order of low-risk thymomas to high-risk thymomas to thymic carcinomas (P = 0.016). SUVmax for thymic carcinomas was significantly higher than that for thymomas (P = 0.008). With the optimal cut-off value of SUVmax of 5.6, the sensitivity, specificity and accuracy for diagnosing thymic carcinoma were 0.75, 0.80 and 0.79, respectively. Regarding the mean scoring of HIF-1, Glut-1 and VEGF, increasing trends were observed in the order of low-risk thymomas to high-risk thymomas to thymic carcinomas. Tumour size revealed a significant correlation with SUVmax (r = 0.60, P < 0.001), and the expression of HIF-1 showed a moderate association, but the expression of Glut-1 showed no correlation with SUVmax. Regarding correlations between the expression of the three markers, there were moderate associations between HIF-1 and Glut-1, and HIF-1 and VEGF, and a significant correlation between Glut-1 and VEGF (r = 0.60, P < 0.001). In type B1 thymoma, HIF-1 and Glut-1 were partly expressed in non-neoplastic immature lymphocytes. CONCLUSIONS: FDG-PET/CT should be performed in patients with tumours in the anterior mediastinum because the pattern of FDG uptake and SUVmax are useful in the differential diagnosis of thymic epithelial tumours. Furthermore, the expressions of HIF-1, Glut-1 and VEGF might be associated with malignancy of thymic epithelial tumours. In contrast, FDG uptake might be dependent on tumour size rather than Glut-1 overexpression.


Fluoroscopy-assisted thoracoscopic resection after computed tomography-guided bronchoscopic metallic coil marking for small peripheral pulmonary lesions.

OBJECTIVES: To re-evaluate the efficacy of fluoroscopy-assisted thoracoscopic resection after computed tomography (CT)-guided bronchoscopic metallic coil marking (FATS-CM), which was our original method for small peripheral pulmonary lesions. METHODS: Fifty-eight patients with 63 lesions underwent FATS-CM. A metallic coil was installed in the bronchus nearest to the lesion under CT fluoroscopic guidance with ultrathin bronchoscopy. The virtual bronchoscopic navigation (VBN) system was used in 14 cases. Afterwards, we basically performed wide wedge resection (WWR) using a C-arm-shaped roentgenographic fluoroscope during thoracoscopic surgery initially, and then the final procedure was determined by intraoperative histological diagnosis. Moreover, we prospectively treated ground-glass opacity (GGO) lesions of <20 mm diameter according to our treatment protocol from September 2004. RESULTS: We could install coils in the objective bronchi in all cases. The average time required for the marking procedure was 38.9 (15-120) min. Pneumothorax was recognized in 1 (1.7%) case as a complication, but no fatal complications occurred. We could also install coils for each lesion in 4 cases (9 lesions) with multiple lesions. In 14 cases with the VBN system, the examination time and CT number were significantly reduced (P < 0.05 and <0.001, respectively), compared with those of 40 cases without the VBN system. The average interval between the CM and the operation was 5.6 (0-30) days. We never experienced a case of migration preoperatively. Sixty-two (98.4%) lesions were definitively identified, and WWRs were performed using three trocars in 58 (92.1%) cases during thoracoscopic surgery. Lobectomy was initially performed in only 1 case owing to coil migration. Thirty-seven of 40 cases (92.5%) were in line with the treatment protocol. There were no local-regional recurrences in all cases undergoing WWR. CONCLUSIONS: We could prospectively show that our method was suitable to perform WWR with a sufficient margin for small GGO lesions of <20 mm. Moreover, we reconfirmed that the advantages of our method were safety, permitting flexibility in scheduling operations and a high ability to deal with multiple lesions. Additionally, our method became a minimally invasive and mature technique by using a new VBN system.


Effects of students introduced "Operating Room Visits Observation item List" in a Nursing Practicum

成人看護学実習における「手術室見学実習観察項目表」を導入した実習の学習効果の検討

周手術期看護を体験的に理解することを目標にした成人看護学実習に「手術室見学実習観察項目表」(以下観察項目表とする)を導入して3年になる．この観察項目表は，手術室見学実習時の見学の視点を明確にするために，実習指導に携わる看護師(以下指導者とする)と共同作成したもので，体位固定方法など手術室看護に特有な学習視点としてあげた26項目からなる見学視点ガイドである．学生から研究への使用に同意が得られた観察項目表(学生用)は，2008年は62名(回収率:91%)，2009年は52名(84%)，2010年は56名(95%)であった．指導者から研究への使用に同意が得られた観察項目表(指導者用)は2008年は43名(63%)，2009年は35名(56%)，2010年は58名(98%)であった．これらを分析した結果，26項目のうち，3年間を通して，学生は17項目を80%以上見学できたと答えた．2008年と2010年では[ドレーン挿入]と[出血量の確認]，2009年と2010年では[全身麻酔の導入]と[硬膜外カテーテルの挿入介助]を見学できたと答えた学生の割合が有意に上昇していた(P<0．05)．また，指導者が説明できたと回答した割合が有意に高くなっていた項目は，2008年と2010年では9項目，2009年と2010年では19項目であった．今回の結果から学生が見学できていた項目の割合は3年間で差がない項目がほとんどであったが，指導者が指導できたとする項目は増加していた．また2009年以降観察項目表の導入の効果について5段階評価で確認したところ，約90%の学生が役立ったと回答した．以上のことから，手術室見学実習において，見学する視点を明確にするために「手術室見学実習観察項目表」を導入することは，学生と指導者の双方にとって，手術室見学実習を行う上で見学や指導を行う視点が明確になるため，効果的なツールであるといえる．今後は手術室看護師に分析結果のフィードバックを行い，学生が学習する機会の少ない項目については，ビデオ等の教材などを臨床とともに開発する必要があると考える．


働く世代の肺がん検診受診行動に関する研究

働く世代の肺がん検診受診行動に関する研究

Journal of Shikoku Public Health Society


内科的治療抵抗性の乳児気管支肉芽に対してHo:YAGレーザー焼灼術を施行した1例

The Journal of the Japan Society for Respiratory Endoscopy


当科における気管支鏡検査へのLung pointの経験

当科における気管支鏡検査へのLung pointの経験


YAGレーザー使用時の気管支鏡破損の1例

YAGレーザー使用時の気管支鏡破損の1例


The value of diagnostic imaging in neoadjuvant chemoradiation therapy for non-small cell lung cancer

非小細胞肺癌に対する術前導入化学放射線療法における画像診断の有用性


The effects of smoking prevention education to high-school students, and its ripple effects to their families

高校生を対象とした喫煙防止教育の効果及び家族への波及効果

The aim of this survey was to clarify the effects of smoking prevention education to the highschoolstudents, and its ripple effects to their families. Participants were same group of630students.Questionnaire surveys were conducted, self-reporting and anonymous, immediately beforeand after the lecture meeting, and after8month in2011‐2012fiscal year. As a result, significantfavorable changes were observed in female students regarding the images of smoking and the predictionof behavior associated with smoking in the future. However, favorable outcome was notobserved among both male and female students after eight months. As useful educational contents,to help stop smoking behavior in the future, the causes of vulnerability to cancer and strongdependence on nicotine were pointed out. Significantly high rates were observed : male studentsselected the"economical reasons"", social responsibility"and"transition of smoking rate"; femalestudents selected the"effect on appearance"and"effect on babies". Also, the smoking rate of theparents of targeted students was lower than the national average, which revealed that their parentswere grappling with the problem of smoking abstinence, caused by the chance of having conversationsabout smoking with their family members. We conclude that it is necessary to construct theeducational contents appropriate for the characteristics of each targeted group including familybackground in order to make smoking abstinence a success. Future studies are also necessary todevelop effective educational continuous and periodical approaches of the lecture meeting, whichwill trigger the cessation of smoking and promote conversation within the family unit.


Pemphigus with thymoma improved by thymectomy: report of a case

A 53-year-old female with pemphigus vulgaris received treatment with prednisolone for 3 years. On chest computed tomography performed at follow-up, an anterior-mediastinal tumor (4 cm × 3 cm) was detected and diagnosed as a thymoma. Although amyosthenia was absent, the patient's anti-acetylcholine-receptor antibody level was high, and she was positive for anti-desmoglein 3 antibodies. She underwent extended thymectomy in the same year, following which both the anti-acetylcholine receptor antibody and the anti-desmoglein 3 antibody levels were normalized. The patient's skin symptoms improved, and the steroid dose was gradually lowered and finally discontinued 4 years postoperatively. Extended thymectomy may be an effective therapy for treating patients with pemphigus.


A CASE OF CONGENTIAL ESOPHAGOBRONCHIAL FISTULA IN AN ADULT WITH IMPAIRED PULMONARY FUNCTION WHO WAS TREATED USING FISTULECTOMY AND RIGHT MIDDLE AND LOWER LOBECTOMY

右中下葉・瘻管切除を施行した低肺機能の成人先天性食道気管支瘻の1例


Computed tomography lymphography by transbronchial injection of iopamidol to identify sentinel nodes in preoperative patients with non-small cell lung cancer : A pilot study

The objective of the present study was to assess the safety and feasibility of computed tomography lymphography by transbronchial injection of a water-soluble extracellular computed tomography contrast agent. From April 2010 to May 2011, patients with clinical stage I non-small cell lung cancer who were candidates for lobectomy were enrolled in the present study. An ultrathin bronchoscope was inserted to the target bronchus under the guidance of virtual bronchoscopic navigation images. Computed tomography images of the chest were obtained 0.5 and 5 minutes after 2 or 3 mL of iopamidol was injected through a microcatheter. Sentinel nodes were identified when the maximum computed tomography attenuation value of the lymph nodes on the postcontrast computed tomography images increased by 30 Hounsfield units or more compared with the precontrast images. Patients underwent lobectomy with standard lymph node dissection. The ultrathin bronchoscope could access the targeted bronchus, and iopamidol was delivered into the peritumoral area in all 13 patients without any complications. Sentinel nodes were identified in 12 (92.3%) of the 13 patients. The average number of sentinel nodes was 1.5 (range, 1-2). Pathologic examination revealed metastatic lymph nodes in 2 patients. Metastatic nodes were included with the sentinel nodes. Computed tomography lymphography by transbronchial injection of iopamidol was a safe and feasible method to identify the sentinel nodes in patients with clinical stage I non-small cell lung cancer.

Journal of Thoracic and Cardiovascular Surgery


A Pediatric Case of Removal of a Bronchial Foreign Body Using a Laryngeal Mask Airway

摘出時にラリンジアルマスクを使用した小児気管支異物の1例

Background. We report a pediatric case of remove of bronchial foreign body using a laryngeal mask airway and flexible bronchoscopy. Case. A 18-month-old girl accidentally inhaled a peanut. Afterwards she entered another hospital with a chief complaint of wheezing and received antibiotic treatment. On the next day, an abnormal shadow was pointed out, which was suspected to indicate a foreign body, in the left main bronchus. Chest computed tomography (CT) scan was carried to our hospital. On the same day, after the airway was cleared using a laryngeal mask airway (LMA size 2.0) under general anesthesia, a flexible bronchoscope (external diameter 4.0 mm) was inserted. The foreign body was successfully removed with a balloon-tip catheter. The foreign body was a peanut. Conclusion. By using a laryngeal mask airway, we could maintain available ventilation and enable a smooth procedure using a flexible bronchoscope while removing a pediatric bronchial foreign body.

背景.摘出時にラリンジアルマスクを使用した小児気管支異物の1例を経験したので報告する.症例.1歳6カ月の女児.ピーナッツを食べた際に誤嚥.その後,喘鳴が出現し,前医に入院.抗菌薬を投与されていたが,翌日施行された胸部CTにて気管支異物を疑われ,当院に搬送された.CTにて左主気管支に異物と思われる陰影を認め,気管支異物と診断し,同日全身麻酔下に異物除去を施行した.ラリンジアルマスク(サイズ2.0)を使用して気道を確保した後,外径4.0mmの軟性気管支鏡を挿入し,バルーン付きカテーテルにて摘出した.異物はピーナッツであった.結論.小児気管支異物に対して,ラリンジアルマスクの使用により,異物摘出時の有効な換気と軟性気管支鏡のスムーズな操作性を担保することができた.


Interventional study for improvement of lung cancer screening rate

The aim of this study is to evaluate whether leaflet distribution affects lung screening rate, and what factor affects the motivation of consultation. Men and women aged 40 to 59 were targeted to improve screening rate of ages for cancer screening, especially in their prime. Each 1,000 subject, a total of 2,000 were selected and divided into 8 groups in consideration of age group by random sampling method. This group was further divided into two groups, an intervention group including subjects distributed a leaflet and a non-intervention (control) group. A survey was conducted by postal self-administered survey forms. Collection rate was 21.6% for the intervention and 17.6% for the control group. The numbers of respondents who answered that this leaflet was effective for motivation of consulting lung cancer screening and the leaflet was ineffective, were 120 (60.0%) and 80 (40.0%), respectively. This indicated that the leaflet was clearly effective (p<0.01). Actual cancer screening rate was 38.8% for the intervention group and 37.7% for the control group. It was shown that distribution by mail of even a single leaflet made by National Cancer Center was effective for motivation of consultation of lung cancer screening.

The Journal of Medical Investigation : JMI


Hepatocyte growth factor expression in EGFR mutant lung cancer with intrinsic and acquired resistance to tyrosine kinase inhibitors in a Japanese cohort.

High-level HGF expression was detected more frequently than EGFR T790M secondary mutation or MET amplification in tumors with intrinsic and acquired EGFR-TKI resistance in EGFR mutant lung cancer in Japanese patients. These observations provide a rationale for targeting HGF in EGFR-TKI resistance in EGFR mutant lung cancer.


Follow-up using fluorescence bronchoscopy for the patients with photodynamic therapy treated early lung cancer.

To evaluate the accuracy of fluorescence bronchoscopy by precise histological analysis of the photodynamic therapy (PDT) treated lesions.


5-Aminolevulinic acid-induced fluorescence diagnosis of pleural malignant tumor.

BACKGROUND: It is known that endogenously synthesized protoporphyrin IX (PpIX) following the administration of 5-aminolevulinic acid (5-ALA) is an effective photosensitizer for photodynamic diagnosis (PDD). We tested in vivo and in vitro susceptibility of human lung cancer and mesothelioma cells to photodynamic diagnosis (PDD) using 5-aminolevulinic acid (5-ALA) as a photosensitizer. METHODS: Human lung cancer cell lines A549, Ma44-3, FT821 and human mesothelioma cell lines MSTO-211H, NCI-H290, Y-MESO-14 were incubated with 0.03% 5-ALA for 4h. After incubation, protoporphyrin IX (PpIX) fluorescence was detected using a fluorescence microscope. Pleural carcinosis was induced in severe combined immunodeficiency disease mice using the previous cell lines to test the efficacy of PDD in vivo. The mice were sacrificed 4h after oral administration of 400mg/kg of 5-ALA. We counted the visible tumors under white light then fluorescence light. RESULTS: In vitro, clear red fluorescence was observed in all cell lines. The mean fluorescence intensity was stronger in A549 and FT821 cells than Ma44-3 cells (165.59±26.49, 157.62±18.93 vs. 104.01±17.58). Also, MSTO-211H and NCI-H290 cells had stronger fluorescence intensity than Y-MESO-14 cells (142.51±26.85, 165.16±12.91 vs. 92.31±8.69). In vivo, the tumor detection rate of fluorescence diagnosis was 1.1-4.5 times higher than that of white light. The mean number of metastases detected by the PDD was significantly higher than that of white light for FT821 (p=0.004), Ma44-3 (p=0.006) and Y-MESO-14 cell lines (p=0.005), but not for A549, NCI-H290 and MSTO-211H cell lines. Small lesions were detected by fluorescence diagnosis even though the lesions were invisible macroscopically under white light. CONCLUSION: Our results suggest the possibility of clinical application of fluorescence diagnosis with intrapleural malignant tumors.


Aberrant DNA methylation of some tumor suppressor genes in lung cancers from workers with chromate exposure.

Our previous studies revealed a variety of genetic changes in lung cancers from chromate-exposed workers (chromate lung cancer). In the present study, we examined epigenetic changes in chromate lung cancers. Nested-methylation-specific PCR was employed in studying the methylation of CpG islands in the APC, MGMT, hMLH1 genes in 36 chromate lung cancers and 25 nonchromate lung cancers. Methylation in chromate lung cancers was detected at 86% for APC, 20% for MGMT, and 28% for hMLH1. Whereas, it occurred at lower frequencies in nonchromate lung cancers, particularly in APC (44%) and hMLH1 (0%) genes. Our previous study showed that methylation of p16 gene in chromate lung cancer and nonchromate lung cancer was 33% and 26%, respectively. The mean methylation index (MI), a reflection of the overall methylation status, was significantly higher in chromate lung cancers than nonchromate lung cancers (0.41 vs. 0.21, P=0.001). Methylation of multiple genes (particularly hMLH1, p16, and APC genes) had experienced more than 15 yr of chromate exposure in chromate lung cancer (MI: <15 yr; 0.19, ≥ 15 yr, 0.42). There is a significant correlation of p16 and hMLH1 methylation with the expressional decrease or loss of the corresponding gene products (P=0.037 and 0.024) respectively, and an inverse correlation between APC and MGMT methylation (P = 0.014). This study provides a novel evidence for the chromium carcinogenesis that chromate lung cancer is linked to the progressive methylation of some tumor suppressor genes, which may be related to genomic instability.


[Lung cancer in patient with a common trunk of left pulmonary veins; report of two cases].

左上下肺静脈が共通幹を形成していた肺癌の2例

A 69-year-old man and a 53-year-old man with lung cancer of left upper lobe underwent pulmonary resection. A preoperative chest computed tomography (CT) scan showed the left superior and inferior pulmonary veins forming a common trunk. In the former case, the common trunk was misidentified as the superior pulmonary vein. The latter was recognized preoperatively by using 3-dimensional CT, and successfully performed left superior segmentectomy. This variation type is surgically important because of a potential risk of intraoperative bleeding and damage to pulmonary circulation during pulmonary resection.

The Japanese Journal of Thoracic Surgery


The relation between the cancer screening rate and the cancer mortality rate in Japan

The aim of this research was to clarify the relation between the screening rates for five cancers (lung cancer, stomach cancer, colorectal cancer, uterus cancer, and breast cancer) and their mortality rate by using publicly accessible databases. The used information materials were those prepared by the Ministry of Health, Labour and Welfare, the Center for Cancer Control and Information Services, and the National Cancer Center. Our results were as follows: 1) regarding stomach and colorectal cancers, a positive correlation was found between the screening rate and the mortality rate (p<0.001); 2) in the relation between the screening rate and the mortality rate according to administrative divisions, the mortality rate decreased significantly when the lung cancer screening rate improved (p<0.005); 3) the mortality rate for breast cancer increased in those aged 50 or over; 4) the mortality rate for uterus cancer had been slightly increasing since 1990; and 5) regarding the screening rate, a positive correlation was found between breast cancer and uterus cancer (p<0.001). In future, improvement in lifestyle and in the knowledge of cancer should be promoted to enhance the screening rates.


Epidemiological and clinical features of lung cancer patients from 1999 to 2009 in Tokushima Prefecture of Japan

Lung cancer is the leading cause of malignancy-related death worldwide. In the present study, we reviewed the epidemiologic and clinical features of lung cancer in Tokushima Prefecture, Japan. Between January 1999 and December 2009, 2,183 patients with lung cancer were enrolled in this study. One thousand five hundred ninety-one (73%) patients were male and 592 (27%) patients were female. Median age was 70 years, with a range of 15-93 years. Seventy-six percent of patients had smoking history. One thousand nine hundred five (87%) patients were non-small cell lung cancer and the predominant histological type was adenocarcinoma (51%). Among all 2,183 patients, 702 (32%) belonged to elderly population. Four hundred seventy-one (22%), 213 (10%), 24 (1%), 116 (5%), 238 (11%), 370 (17%) and 678 (31%) patients had stage IA, IB, IIA, IIB, IIIA, IIIB and IV lung cancer, respectively. In Tokushima University Hospital, 516 (29%), 191 (11%), 58 (3%), 755 (43%) and 216 (12%) patients were initially treated with chemotherapy, chemo-radiotherapy, thoracic radiotherapy, operation and best supportive care, respectively. The median time to progression (TTP) and the median survival time (MST) of patients treated with chemotherapy and chemo-radiotherapy were 3.5 months, 13.0 months and 7.0 months, 18.0 months, respectively. The median TTP and the MST of 33 elderly patients treated with chemotherapy were 3.3 months and 18.0 months, respectively, which were comparable with those of total population. These results indicated the benefit of chemotherapy in elderly patients with advanced lung cancer by proper selection.


Diagnosis of the presence of lymph node metastasis and decision of operative indication using fluorodeoxyglucose-positron emission tomography and computed tomography in patients with primary lung cancer.

PET/CT is superior to CT scan in lymph node staging. However, because the false-positive rate is high in PET-positive lymph nodes measuring less than 1 cm in diameter, we think that clinical background should be considered and other modalities or histological examinations should be undertaken if necessary. J. Med. Invest. 57: 305-313, August, 2010.

The Journal of Medical Investigation : JMI


[Clinical analysis of elderly patients with primary lung cancer].

胸部外科の指針 高齢者原発性肺癌における臨床的検討

We clinically reviewed 33 surgery patients and 15 non-surgery patients aged 80 years or older with primary lung cancer treated at our hospital. The surgery group consisted of 21 males and 12 females (82.0 +/- 1.9 years old). The surgical procedures were 1 pneumonectomy, 19 lobectomies (1 bronchoplasty), 4 segmentectomies and 9 partial resections. The cancer types were 17 adenocarcinomas, 14 squamous cell carcinomas and 2 others. The stagings were 24 in stage I, 4 in stage II and 5 in stage III. There were no direct surgical deaths within 30 days post operatively. There have been 9 other disease-related deaths to date (27%). The non-surgery group consisted of 9 males and 6 females (81.7 +/- 1.5 years old). Treatment procedures consisted of radiationtherapy in 11, chemotherapy in 2 and best supportive care in 3. The cancer types were 2 adenocarcinomas, 11 squamous cell carcinomas and 2 others. The stagings were 7 in stage I, 4 in stage II and 4 in stage III. There have been 3 other disease-related deaths to date (20%). We must carefully select the therapeutic approach for elderly lung cancer patients, because the other disease-related death rates of both groups were high. The 5-year survival rate of stage I patients in the surgical group was relatively good (60.2%). There were long-term survival (7 5-year survivors) in the surgical group. Since there were some cases of radiation pneumonia in the group receiving radiation therapy, it would be better to perform surgery for elderly patients with lung cancer, especially those with stage I disease. For elderly patients, it is important to consider quality of life as well as the survival rate.


Undiminished regulatory T cells in the thymus of myathenia gravis patients

The thymus has been implicated as a possible site of origin that triggers autoimmunity in myasthenia gravis (MG). Although several groups have suggested that the decrease in the number of regulatory T (Treg) cells contributes to the onset of MG, the exact role of Treg cells in MG remains unclear. To address this point, we examined the number and distribution of Treg cells in a large number of patients with MG. Immunohistofluorescence analysis of Foxp3 along with CD4 and CD8 was performed in thymic sections of MG (+) (n = 24) and MG (-) patients (n = 27). Circulating CD4(+)CD25(+) cells in the peripheral blood of patients with MG (n = 15) and age-matched healthy subjects (n = 15) were also analyzed. Foxp3(+)CD4(+)CD8(-) cells were predominantly found in the thymic medulla and their number declined with age. There was no significant difference in the number or the distribution of Foxp3(+)CD4(+)CD8(-) cells in the thymus between MG (+) and MG (-) patients. The number of circulating CD4(+)CD25(+) cells in the peripheral blood of patients with MG was not significantly altered compared to that in healthy subjects. The cellularity of Treg cells in the thymus and circulation is not diminished in patients with myasthenia gravis.


Gefitinib耐性後に切除した肺腺癌術後肺転移の1例

Gefitinib耐性後に切除した肺腺癌術後肺転移の1例

The Journal of the Japanese Association for Chest Surgery


Late pulmonary metastases from malignant melanoma of the left planta.

We report a patient treated for malignant melanoma of the left planta who developed pulmonary metastases after a disease-free interval of 10 years. Metastatectomy was performed after observing progress for 12 months. However, 18 months later, pretracheal and right axillary lymph node metastases occurred. Because pulmonary metastasis from malignant melanoma may occur after 10 years or more, we observe patients carefully. If it does occur, an operation should be considered under limited indications. We should also recognize that recurrence may occur within a short interval after metastatectomy as well.

General Thoracic and Cardiovascular Surgery


Increasing incidence of elderly onset patients with myasthenia gravis in a local area of Japan

As the number of elderly patients with myasthenia gravis (MG) has recently increased in Europe and the USA, a retrospective survey of Japanese MG patients was conducted in a single neurological centre over several decades. The study consisted of 112 consecutive MG patients with onset of the disease from 1971 to 2006 from an area of approximately 0.8 million inhabitants in Japan. Patients were classified into three subgroups according to age at onset: young onset (39 years old), middle aged onset (40-59 years old) and elderly onset (60 years old). The trends in incidence rate and clinical features were examined: disease severity, seropositivity for antiacetylcholine receptor antibody, occurrence of other autoimmune diseases, occurrence of thymoma and therapeutic response. The onset adjusted age specific average annual incidence per 100,000 of the elderly onset MG patients increased 20-fold from 1981-1990 (0.06; 95% CI 0.00 to 0.36) to 2001-2006 (1.30; 95% CI 0.77 to 2.05). Clinical features of the elderly onset MG patients included low antiacetylcholine receptor antibody titres (mean 24.6 nmol/l), less frequent autoimmune overlaps (8.0%) and nearly no complete stable remission with or without thymectomy. The increasing incidence of elderly onset MG in Japanese patients similar to that reported in Caucasians has been confirmed. The clinical features suggest different immunological backgrounds between young onset and elderly onset MG patients, irrespective of the ethnic background.

Journal of Neurology, Neurosurgery, and Psychiatry


Fluorescence diagnosis of lymph node metastasis of lung cancer in a mouse model.

Fluorescence diagnosis of lymph node metastasis of non-small cell lung cancer has not been reported previously. This study was conducted to evaluate the feasibility of fluorescence detection using 5-aminolevulinic acid and mono-L-aspartyl chlorine e6 for lymph node metastasis in a lung cancer mouse model. Human lung cancer cell line Ma44-3, which forms metastatic lymph nodes in the mediastinum, was injected into the left lungs of 6 severe combined immunodeficiency disease mice. Two weeks after implantation, 2 groups of 3 mice received oral administration of 5-aminolevulinic acid (100 mg/kg) or intraperitoneal administration of mono-L-aspartyl chlorine e6 (5 mg/kg). Both lungs and mediastinal organs were removed en-bloc and illuminated with blue light (405 nm) to evaluate the detectability of lung tumors and metastatic lymph nodes in the mediastinum. These organs were evaluated histopathologically. Clear red fluorescence was observed in the lung tumors of all mice. Metastatic lymph nodes had formed in 5 of 6 mice and were detected by fluorescent detection in all 5 mice even though one of the lymph nodes was invisible macroscopically under white light. In conclusion, fluorescence diagnosis of lymph node metastasis is possible in a mouse model. The successful result with small lymph node metastasis suggests the possibility of clinical application.


Functional evaluation of pallid mice with genetic emphysema.

Studies on pallid mice models of genetic emphysema have conventionally focused on morphological or biochemical evaluations. However, it is important to consider the functional aspects. We evaluated the exercise capacity and respiratory function in male pallid mice and male C57BL/6J mice at 3, 6, 12, and 15 months of age. The functional evaluations were conducted using a treadmill and a pulmonary function analysis device. The morphology of the lungs was analyzed on the basis of mean linear intercept (Lm) values. The body weights of the pallid mice at 12 and 15 months were significantly lower than those of the age-matched C57BL/6J mice. The pallid mice showed deterioration in exercise capacity from 6 months, as indicated by the trends in running distance. At 6, 12, and 15 months, the pallid mice showed significantly higher pulmonary compliance and significantly lower forced expiratory volume in 20 ms (FEV(20 ms))/vital capacity (VC) values in comparison with the corresponding values for the C57BL/6J mice. In the morphological analysis of the pallid mice, emphysema was detected from 12 months, and the mice showed a significantly larger Lm at 12 months. The exercise capacity and lung function in the pallid mice significantly deteriorated from 6 months, at which time no pathological changes in the lung were detected. The deterioration in the exercise capacity and pulmonary function preceded the microscopic morphological changes.Laboratory Investigation advance online publication, 20 April 2009; doi:10.1038/labinvest.2009.34.

Laboratory Investigation; a Journal of Technical Methods and Pathology


Triterpenes augment the inhibitory effects of anticancer drugs on growth of human esophageal carcinoma cells in vitro and suppress experimental metastasis in vivo.

The antineoplastic effects of combinations of anticancer drugs (5-fluorouracil, irinotecan and cisplatin) and triterpenes (ursolic acid, betulinic acid, oleanolic acid and a Japanese apricot extract (JAE) containing triterpenes) on esophageal squamous carcinoma cells were examined by the WST-8 (2-(2-methoxy- 4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt) assay in vitro and by an animal model in vivo. Triterpenes and JAE showed additive and synergistic cytotoxic effects, respectively, on esophageal squamous carcinoma cells (YES-2cells) by combinational use of 5-fluorouracil. JAE and 5-fluorouracil induced cell cycle arrest at G2/M phase and at S phase, respectively, and caused apoptosis in YES-2 cells. A new animal model of esophageal cancer causing tumor colonization of the peritoneal cavity and producing bloody ascites was made by injecting YES-2 cells into the peritoneal cavity of a severe combined immunodeficiency mouse. In this model, 5-fluorouracil inhibited colonization of tumor cells in the peritoneum. The addition of JAE to 5-fluorouracil augmented the suppression of experimental metastasis of the peritoneum. The numbers of peritoneal nodules of more than 2 mm in diameter in mice treated with 5-fluorouracil and JAE were less than those in mice treated with 5-fluorouracil alone or JAE alone. These results suggest that triterpenes, especially JAE, are effective supplements for enhancing the chemotherapeutic effect of 5-fluorouracil on esophageal cancer. (c) 2009 UICC.


Recurrent thymoma with a pleural dissemination invading the intervertebral foramen.

We report a rare case of recurrent thymoma with pleural dissemination invading the intervertebral foramen. A woman with Masaoka's stage IVa thymoma with myasthenia gravis (MG) underwent macroscopically complete resection. After 45 months, she developed back pain. Computed tomography (CT) of the chest demonstrated a mass in the right thoracic cavity invading the intervertebral foramen between thoracic vertebrae 10 and 11. She underwent complete resection of the tumor and postoperative radiotherapy. The resected specimen was histologically diagnosed as a pleural dissemination from thymoma. There has been no local recurrence.

European Journal of Cardio-Thoracic Surgery


Surgically treated pleomorphic carcinoma of the lung

We experienced 3 resected cases of pleomorphic carcinoma of the lung. Each cases were 74-year-old man (case 1), 74-year-old woman (case 2) and 69-year-old man (case 3). Two patients (case 1 and 2) were histologically diagnosed as pleomorphic carcinoma composed of spindle cell carcinoma with giant cell carcinoma. One patient (case 3) was similarly diagnosed as pleomorphic carcinoma composed of spindle cell carcinoma with adenocarcinoma and squamous cell carcinoma. Although lymph nodes metastasis were not recognized in all patients, invasion to vessels were recognized in 2 patients (case 1 and 3). In one patient (case 1), recurrence was recognized at contralateral side 1 month after surgery and he died of other disease 2 months after surgery. The other 2 patients were alive without recurrence 24 and 5 months after surgery. Recently it is reported that recurrence is recognized at early phase after surgery and prognosis is poor in a case with vessel invasions in spite of pathological NO state. Since one patient (case 3) had nonmetastatic lymph nodes with vessel invasions, careful observation is considered to be necessary.

The Japanese Journal of Thoracic Surgery


Clinical analysis of tracheoplasty and bronchoplasty in primary lung cancer

気管・気管支形成手術の現況 2．気管・気管支形成 原発性肺癌における気管・気管支形成手術の臨床的検討

In our department, there were 482 thoracic surgeries for primary lung cancer between 1994 and 2007. We clinically reviewed cases that underwent tracheoplasty or bronchoplasty (n = 22, 4.6%). The patients consisted of 21 males and 1 female (66.5 +/- 12.0 years-old). All patients were smokers. The tissue forms were 19 squamous cell carcinomas, 2 adenocarcinomas, 1 large cell carcinoma, 1 adenoid cystic carcinoma and 1 carcinoid, including 2 multiple carcinomas. Sleeve resections involved the trachea in 1, upper lobes in 13, lower lobes in 3, upper-middle lobes in 2 and intermediate bronchus in 1. Wedge resections were performed in the upper lobes in 2. Fourteen reconstructions were performed. We ordinarily sutured the trachea and bronchus in any case, using a single outside knot. There was no leakage at the anastomosis. There were 2 hospital deaths. There were 4 cancer deaths, including 2 local recurrences. There were 4 patients demonstrating stenosis post operatively. There were 3 stenoses among 4 preoperative radiation therapies. We considered that radiation therapy disturbed the repair of the anastomosis. There were 8 pneumonia patients who developed post operatively. There were 2 operative hospital deaths among 3 angio-bronchoplasties without coverage. Recently, we have routinely covered the anastomosis at the reconstruction site and have not experienced any major complications.


Aberrant methylation of tumour-related genes in thymic epithelial tumours.

BACKGROUND: Thymoma is an uncommon neoplasm derived from epithelial cells of the thymus. Few studies have addressed the genetic alterations that occur in the tumourigenesis of thymoma. METHODS: We examined aberrant DNA methylation of DAP-K, p-16, MGMT and HPP1 genes in 26 thymomas and 6 thymic carcinoma to clarify the association between aberrant DNA methylation and clinicopathological features. RESULTS: Fifteen (47%) of 32 thymic epithelial tumours showed aberrant methylation. Aberrant methylation was more frequent in thymic carcinoma (86%) than in thymoma (29%). Moreover, the frequency of tumours with methylation of multiple genes in thymic carcinoma was higher than in thymoma (60% vs 20%). In thymoma, the frequency of tumour methylation, including the type A tumour component (28%), was lower than that of tumours with type B tumour component (42%). MGMT methylation was detected in 23% of thymoma and in 83% of thymic carcinoma. The frequency of methylation of the MGMT gene in both tumours was high compared with the other 3 genes. CONCLUSIONS: Aberrant DNA methylation was more frequent in thymic carcinoma than in thymoma, and the frequency of DNA methylation in thymic epithelial tumours is roughly parallel to their malignant behaviour.


Approach by clamshell incision for bilateral pulmonary metastasis

手術の工夫 両側転移性肺腫瘍に対するclamshell incisionによるアプローチ

In recent years thoracotomy by "clamshell incision" has frequently been chosen for heart-lung transplantation, bilateral lung tumors and mediastinal tumor merging into lung tumor because this approach provides very good visibility to access the whole bilateral lung including the lower lobe and mediastinal organs. In our hospital, 4 patients underwent bilateral thoracotomy by clamshell incision for pulmonary metastasectomy between 2001 and 2005. All cases had bilateral pulmonary metastases, and multiple wedge resection was performed. All lesions that were planned for resection on preoperative computed tomography (CT) could be resected. Regarding the surgical approach to bilateral pulmonary metastases that did not need lobectomy, clamshell incision is one of the useful approaches that can allow wedge resection anywhere in the whole lung. In cases that are expected multiple procedures, bilateral thoracotomy by clamshell incision is recommended because it allows another route for thoracotomy at reoperation.


Clinical experience with 16 cases of mediastinal lymphoma

縦隔悪性リンパ腫の臨床的検討

Sixteen cases of mediastinal lymphoma in our hospital were reviewed clinically. There were 7 men and 9 women, whose mean age is 35 years old. The histological types were non-Hodgkins' disease in 12 (B-cell type in 6 and T-cell type in 6), Hodgkins' disease in 2, mucosa-associated lymphoid tissue (MALT) lymphoma in 2. All cases except 1 in which percutaneous needle biopsy was performed were diagnosed histologically. Even small specimens by percutaneous needle biopsy can be helpful in diagnosing histological type and subtype with immunohistlogy, recommending percutaneous needle biopsy as an mitial step for diagnosis. When histological diagnosis can not be made by needle biopsy, open biopsy should be done.


Effect of mediastinal lymph nodes sampling in patients with clinical stage I non-small cell lung cancer

Systematic nodal dissection has been recommended for patients with resectable non-small cell lung cancer because of its staging accuracy. However, in patients with clinical stage I non-small cell lung cancer whether systematic nodal dissection provides more benefits than mediastinal lymph node sampling or not is controversial. In this retrospective study, we evaluated the effect of mediastinal lymph node sampling in patients with clinical stage I NSCLC. One hundred and nineteen consecutive patients with clinical stage I NSCLC, who underwent curative operation between January 1994 and December 2000, were retrospectively reviewed (dissection group = 58: sampling group= 61). Systematic nodal dissection was defined as complete removal of mediastinal lymph node, and mediastinal lymph node sampling was defined as removal of lymph node levels 3, 4, and 7 for right-sided tumors and levels 5, 6, and 7 for left-sided tumors. The total number of removed mediastinal lymph nodes in patients who underwent systematic nodal dissection was 22.1 +/- 9.7, which was significantly higher than that in patients who underwent mediastinal lymph node sampling of 11.4 +/- 7.0 (p < 0.001). Postoperatively N2 disease was detected in 8 patients (13.8%) in the dissection group and 7 (11.5%) in the sampling group. After the median follow up of 79 months, the cancer specific survival rate at 5 year was 78.0% in the dissection group and 76.2% in the sampling group (p = 0.60). Mediastinal lymph node sampling showed the similar effect to systematic nodal dissection in patients with clinical stage I non-small cell lung cancer.

The Journal of Medical Investigation : JMI


Thymoma is the most common tumor of the anterior mediastinum. This tumor is associated with unique paraneoplastic syndromes (myasthenia gravis, pure red cell aplasia, hypogammaglobulinemia, and other autoimmune diseases). The rarity of this tumor has somewhat obscured the optimal treatment. Although the histologic classification of thymoma has remained a subject of controversy for many years, the WHO classification system, published in 1999, appeared to be an advance in our understanding of thymoma. The optimal treatment for thymoma depends on its clinical stage. Surgery remains the mainstay of treatment for thymic epithelial tumors. Thymomas also have a high response rate to chemotherapy or radiotherapy. Only surgical resection is performed for patients with stage I (non-invasive) thymoma. The value of postoperative radiotherapy in completely resected stage II or III tumors is questionable. Multimodality therapy involving surgery, chemotherapy and radiotherapy appears to increase the rate of complete resection and survival in advanced (stage III and IV) thymomas.


Postprocessing technique with MDCT data improves the accuracy of the detection of lung nodules

The aim of this study was to determine whether postprocessing techniques could improve the accuracy of detecting lung nodules. A total of 154 segmented lung volumes of multidetector-row computed tomography (MDCT) data were the subject of the study. Lung nodules were present in 88 volumes and absent in 66 volumes. We prepared four groups: (1) 7- or 10-mm thick-section axial images; (2) 1-mm thin-section axial images; (3) sliding slab maximum intensity projection (MIP) images with a slab thickness of 15 mm; and (4) sliding slab volume rendering (VR) images with a slab thickness of 15 mm. Sixteen physicians reviewed each group in interactive cine mode. The observers' performance in the detection of lung nodule was evaluated by receiver operating characteristic (ROC) analysis. The observers' performance of the MIP and VR groups was significantly better than in other two groups. There was no significant difference statistically between the thin and thick groups. The detectability of lung nodules is improved with the use of sliding slab MIP and VR using thin-section image data. Thin-section volume data are essential for improving diagnostic accuracy, but observation of thin-section images without utilization of image-processing techniques dose not improve diagnostic accuracy.


Photodynamic therapy using a second generation photosensitizer, Talaporfin

Background: Photodynamic therapy (PDT) using Talaporfin is an attractive treatment for centraltype early lung cancer. It was noted that some patients had altered levels of arterial oxygen saturation as indicated by pulse oximeter (SpO2) and arterial oxygen saturation levels in blood gas analysis (SaO2) during PDT. The present experiments were designed to provide an explanation for these findings. Methods: The influence of Talaporfin on SpO2 using in vitro and in vivo experiments, and clinically, was examined. Results: Our in vitro and in vivo experiments showed a linear relationship between Talaporfin concentration in the plasma and the SpO2 level (R = 0.9957 and 0.9837). The apparent SpO2 level decreased according to the increase of Talaporfin concentration in the plasma. In two patients with PDT, SpO2 levels at 4 6 h and 24 h after Talaporfin administration were 93% and 97%, respectively. Conclusions: Talaporfin raised blood absorbance at 660nm with a pulse oximeter. It appeared that the presence of the drug falsely decreased the level of SpO2 since SpO2 did not actually change.


Two cases of bronchogenic cyst with severe adhesion to the trachea

We experienced two bronchogenic cysts with severe adhesion to the trachea. Both cysts were located on the right side of the trachea. The surgical procedure was changed to thoracotomy from thoracoscopic surgery due to strong adhesion to the trachea. In case 1, sharp separation of the cystic wall from the trachea led to tracheal wall damage. In case 2, the cystic wall except a portion which was adhered to the trachea was resected. The inner side of the residual cystic wall underwent dull curettage to remove the epithelial component. There were no postoperative complications in either case.


Predictive Value of Thymidylate Synthase and Dihydropyrimidine Dehydrogenase Expression in Tumor Tissue, Regarding the Efficacy of Postoperatively Administered UFT(Tegafur+Uracil) in Patients with Non-small Cell Lung Cancer

UFT (tegafur + uracil) has been reported to be effective as an adjuvant in postoperative chemotherapy for non-small cell lung cancer (NSCLC) in a randomized prospective study. Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) expression were investigated in resected tumors and the relationship between their expression and clinical factors in NSCLC patients was examined. Fifty-four NSCLC patients had undergone complete surgical resection and lymph node dissection, and had been administered UFT post-surgery. The TS and DPD expression in the tumor tissues was evaluated by immunohistochemical staining. The relationship between TS and/or DPD expression and clinicopathological factors was examined. There were 38 TS-negative and 16 TS-positive cases, and 22 DPD-negative and 32 DPD-positive cases. There was no significant difference between the patients with TS or DPD and those without TS or DPD in age, gender, histological type or p-stage. The 5-year survival rates of patients positive and negative for TS were 50.0 and 89.5%, while 10-year survival rates were 23.3 and 79.7%, respectively (p<0.001). The 5-year survival rates of TS-positive and TS-negative patients in p-stage I were 54.6 and 95.5%, while 10-year survival rates were 22.7 and 95.5%, respectively (p<0.001). There was no significant difference between DPD-positive and DPD-negative patients in prognosis. The oral administration of UFT after surgery might improve the survival of NSCLC patients when TS levels in tumor tissues are low. Immunohistochemical evaluation of TS and DPD expression may be useful for predicting the efficacy of UFT after complete resection in NSCLC.


The reduced expression and aberrant methylation of p16(INK4a) in chromate workers with lung cancer.

STUDY OBJECTIVES: It is known that chromium is one of the important inhaled carcinogens that cause lung cancer. Our previous studies revealed a variety of genetic changes in lung cancers from chromate-exposed workers (chromate lung cancer). However, the epigenetic effects of chromium are not understood. MATERIALS AND METHODS: We investigated the methylation of the p16 gene using a methylation-specific PCR method in 30 chromate lung cancers and 38 non-chromate lung cancers, and the expression of the p16 protein using immunohistochemistry in 25 chromate lung cancers. RESULTS: Ten (33%) chromate lung cancers showed methylation of the p16 promoter region. On the other hand, 10 (26%) of the non-chromate lung cancers also showed it. The frequency of p16 methylation in non-chromate lung cancer was 0%, 33% and 30% for low (< or =600), moderate (<600, >1000) and high (> or =1000) Brinkman indexes, respectively. However, the frequency of p16 methylation in chromate lung cancer was constant, irrespective of the Brinkman index. In chromate lung cancer, patients with chromate exposure of less than 15 years never had p16 methylation, while 40% (> or =25 years) or 43% (> or =15, <25 years) of patients with chromate exposure of more than 15 years did. In chromate lung cancer, chromate exposure, not smoking, mainly influenced the p16 methylation. Most of the chromate lung cancers with p16 methylation (85.7%) showed repression of the p16 protein. CONCLUSIONS: We speculate that not only genetic but also epigenetic alterations are involved in the carcinogenesis due to chromium.


The balance of VEGF-C and VEGFR-3 mRNA is a predictor of lymph node metastasis in non-small cell lung cancer.

A positive association between vascular endothelial growth factor-C (VEGF-C) expression and lymph node metastasis has been reported in several cancers. However, the relationship of VEGF-C and lymph node metastasis in some cancers, including non-small cell lung cancer (NSCLC), is controversial. We evaluated the VEGF-C and vascular endothelial growth factor receptor-3 (VEGFR-3) expression in NSCLC samples from patients who had undergone surgery between 1998 and 2002 using real-time quantitative RT-PCR and immunohistochemical staining. We failed to find a positive association between VEGF-C and VEGFR-3 mRNA expression and lymph node metastasis in NSCLC. An immunohistological study demonstrated that VEGF-C was expressed not only in cancer cells, but also in macrophages in NSCLC, and that VEGFR-3 was expressed in cancer cells, macrophages, type II pneumocytes and lymph vessels. The VEGF-C/VEGFR-3 ratio of the node-positive group was significantly higher than that of the node-negative group. Immunohistochemical staining showed that VEGFR-3 was mainly expressed in cancer cells. The immunoreactivity of VEGF-C and VEGFR-3 was roughly correlated to the mRNA levels of VEGF-C and VEGFR-3 in real-time PCR. VEGF-C mRNA alone has no positive association with lymph node metastasis in NSCLC. The VEGF-C/VEGFR-3 ratio was positively associated with lymph node metastasis in NSCLC. This suggests that VEGF-C promotes lymph node metastasis while being influenced by the strength of the VEGF-C autocrine loop, and the VEGF-C/VEGFR-3 ratio can be a useful predictor of lymph node metastasis in NSCLC.


Clinical analysis of operative and hospital deaths in primary lung cancer

胸部外科の指針 原発性肺癌における手術死亡および在院死亡

In our department, there were 313 thoracic surgeries for primary lung cancer from January 1994 to December 2003. We clinically reviewed for the operative and hospital death (n=18, 5.8%). The patients were 16 males and 2 females (70.6 +/- 5.6 years old). The surgical procedures were 4 pneumonectomies, 13 lobectomies (3 bronchoplasties) and 1 partial resection. The mean interval until postoperative death was 122.5 +/- 156.1 days. There were 5 direct operative deaths within 30 days (1.6%). There were 4 cancer deaths, 2 hemoptyses, 2 operative bleeding, 2 thromboses, 2 cerebral hemorrhages, 1 pyothorax, 1 pneumonia, 1 respiratory failure, 1 multiple organ failure after chemotherapy and 2 unexplained deaths. The patients with pneumonectomy or aged significantly had high mortality. For postoperative complications such as hemoptysis or bleeding, perioperative management that takes these issues into consideration is needed. Furthermore, we must carefully review the preoperative evaluation and combined treatment, because there were many cancer deaths among cases showing early recurrence and metastasis.

The Japanese Journal of Thoracic Surgery


Lung regeneration: implantation of fetal rat lung fragments into adult rat lung parenchyma.

OBJECTIVE: The capability of regeneration of lung tissues in adults is limited after chronic destruction. Bone marrow-derived stem cells, retinoic acid, growth factors, and other approaches have been attempted to promote or facilitate this process. We hypothesized that fetal lung tissues, with great potential for growth and differentiation, could be used for lung regeneration. METHODS: Day 17 fetal lung tissue fragments at the pseudoglandular stage of lung development from Lewis rats were implanted into adult Lewis rat lungs. For group 1, fetal lung fragments were injected into the adult left lung parenchyma; for group 2, fetal fragments were injected with the left lung partially resected; for group 3, adult fragments were injected; and for groups 4 and 5, fetal fragments were implanted into the omentum and subcutaneous tissue, respectively. RESULTS: The grafts implanted into pulmonary parenchyma were differentiated with opening of the alveolar space after 4 weeks and were advanced further with morphologic features similar to those of neonatal lungs after 8 and 12 weeks. The implants were connected with pulmonary circulation determined by means of perfusion with India ink. These changes appeared to be further enhanced in animals with partial lung resection that might have facilitated the maturation of implanted fetal lung tissues through mechanical factors, soluble factors, or both. Fetal lung tissues did not mature when implanted into the omentum or subcutaneous tissue. Adult lung fragments did not expand after being reimplanted back into the same animal. CONCLUSIONS: Fetal lung tissue might be an option for further investigation into lung regeneration.

Journal of Thoracic and Cardiovascular Surgery


Fluoroscopy-assisted thoracoscopic resection of pulmonary nodules after computed tomography--guided bronchoscopic metallic coil marking.

OBJECTIVE: To localize small and deeply situated pulmonary nodules during thoracoscopy with roentgenographic fluoroscopy, we developed a marking procedure that uses a metallic coil. METHODS: Nine patients underwent video-assisted thoracoscopic surgery for the removal of 11 pulmonary lesions. Fluoroscopy-assisted thoracoscopic surgery after computed tomography-guided bronchoscopic metallic coil marking was performed with an ultrathin bronchoscope, with simulation by means of virtual bronchoscopy. During thoracoscopy, a C-arm-shaped roentgenographic fluoroscope was used to detect the radiopaque nodules. RESULTS: The marking procedure took 15 to 60 minutes from insertion to removal of the bronchoscope. There were no complications from the marking, and all 11 nodules were easily localized by means of thoracoscopy. The metallic coil showed the nodules on the fluoroscopic monitor, which aided in nodule manipulation. Nodules were completely resected under thoracoscopic guidance, except in one case in which a minithoracotomy was performed at an early stage of the trial. The pathologic diagnosis was primary adenocarcinoma in 9 patients, pulmonary metastasis from colon cancer in 1 patient, and pulmonary lymph node in 1 patient. Two cases of bronchioloalveolar adenocarcinoma with an invasive component and a well-differentiated adenocarcinoma were converted to open thoracotomy to perform curative lobectomy. CONCLUSIONS: In this pilot study computed tomography-guided transbronchial metallic coil marking with an ultrathin bronchoscope with virtual bronchoscopic simulation might be a useful method for the fluoroscopy-assisted thoracoscopic resection of pulmonary nodules.


Matrix metalloproteinase inhibitor MMI-166 inhibits lymphogenous metastasis in an orthotopically implanted model of lung cancer

Matrix metalloproteinases (MMP) are considered to be critically involved in tumor invasion and the metastasis of various cancers. MMI-166 is a selective inhibitor of matrix metalloproteinase (MMP-2, MMP-9, and MMP-14). The purpose of this study was to evaluate the effects of MMI-166 on both the growth of the implanted tumor and the lymph node metastasis of the mediastinum and prolonging the life span, using an orthotopic implantation model of the Ma44-3 cancer cell line. We examined the anti-invasive effect of MMI-166 in lung cancer cell lines using an in vitro invasion assay. Next, we examined the anticancer effect of MMI-166 in vivo. MMI-166 (200 mg/kg body weight) or a vehicle was administered orally to the orthotopically implanted lung cancer model. MMI-166 dose-dependently inhibited the invasion of cancer cell lines with expressions of MMP-2 and/or MMP-9 in vitro. In vivo, MMI-166 significantly inhibited mediastinal lymph node metastasis in this orthotopic model (weight of the mediastinum: control, 0.089 +/- 0.009 versus MMI-166, 0.069 +/- 0.008 mg; P = 0.005; metastatic area: control, 93,495 +/- 55,747 versus MMI-166, 22,747 +/- 17,478 pixels; P = 0.045). MMI-166 prolonged the life span by 6 days in median survival time in the orthotopically implanted model (P = 0.039). These results showed that MMI-166 could possibly inhibit lymph node metastasis and prolong the life span in lung cancer patients.


Photodynamic therapy for submucosal tumor of the central bronchus

A 75-year-old man was referred to our hospital because of the emphysema and tumor of the right intermediate bronchus. Thoracic CT scan and bronchoscopic examination demonstrated a spherical tumor of the right intermediate bronchus covering a normal mucosa. The biopsy specimen obtained from this tumor was histologically diagnosed as "glandular type of adenocarcinoma in the bronchus". Surgical treatment was not feasible because of poor pulmonary function. Therefore, the patient underwent Photodynamic therapy (PDT) using porfimer sodium (Photofrin) and an excimer dye laser. After 4 months, the tumor disappeared and there has been no recurrence for 3 years 3 months. PDT can affect a submucosal tumor of the central airway, and is safe for patients with poor pulmonary function. Our report recommends that PDT should be applied not only to early lung cancer but also submucosal tumor of the central bronchus.

The Journal of Medical Investigation : JMI


Revised GMDH-type Neural Networks using AIC or PSS Criterion and Their Application to the Medical Image Recognition

Journal of Advanced Computational Intelligence and Intelligent Informatics


Extramedullary plasmacytoma immunoglobulin D (λ) in the chest wall and the subglottic region


Thymidylate Synthase and Dihydropyrimidine Dehydrogenase in Non-small Cell Lung Cancer: Relationship between mRNA Expression and Activity

UFT (Tegafur + Uracil) has been reported to be effective for postoperative adjuvant chemotherapy of non-small cell lung cancer (NSCLC) in a randomized prospective study. Recently, many clinical studies have demonstrated that UFT is effective for cancer with a low activity of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD). In the present study, we investigated TS and DPD activity in resected tumors and corresponding normal lungs and the relationship between the activity and the mRNA expression of TS and DPD in NSCLC. Seventy-seven patients underwent complete surgical resection and lymph node dissection for NSCLC. The activity of TS was determined by the FdUMP binding assay combined with gel filtration. The activity of DPD was determined by radio-enzymatic assay. Tumor tissues and their paired non-cancerous tissues were assayed. Furthermore, the mRNA expressions of TS and DPD were examined by real-time RT-PCR. The mean TS and DPD activities in NSCLC were approximately 2.4-fold and 5-fold of those in normal lungs. The mean TS and DPD activities of NSCLC were 0.099 pmol/mg and 407 pmol/mg/min, respectively. Although both TS and DPD activities showed a tendency to be high for adenocarcinoma, there was no significant difference between TS and/or DPD activities and any clinical findings (age, gender, stage and histological type). The mRNA expression of DPD was correlated with DPD activity (rs=0.846, p<0.001). The mRNA expression of TS was weakly correlated with TS activity (rs=0.757, p<0.001). TS and DPD activities in NSCLC were higher than those in normal lungs. Assay of DPD mRNA and TS mRNA by real-time RT-PCR can be used as an indicator for the use of UFT.


Orthotopically implanted SCID mouse model of human lung cancer suitable for investigating metastatic potential and anticancer drug effects

To evaluate the effects of drugs in clinical settings, an animal model of lung cancer similar to clinical cancer is necessary. Our previous studies described an SCID mouse model using orthotopic implantation of the human lung cancer cell line which mimicked the lymph node metastasis of patients with lung cancer. In this study, we made animal models that reflected various metastatic forms of lung cancer in humans. We applied our procedure to 6 lung cancer cell lines. Suspensions of 2.0 x 10(4) cancer cells were injected into the left lung of SCID mice. We evaluated the mRNA expressions of 52 proteins related to the metabolism of and resistance to anticancer drugs of each tumor cell line and its orthotopically implanted tumor using a customized cDNA array. Three lung cancer cell lines had the potential of lymphogenous metastasis and 3 cell lines had the potential of hematogenous metastasis in this model system. The A549 line showed multiple metastases, and Ma2 line showed solitary metastasis. The expression of 52 genes in each implanted tumor was closely correlated with that in each cell lines (correlation coefficients: 0.8883-0.9533), and the gradient of the regression line was more than 0.9. This model was similar to the metastatic form in patients with lung cancer. The similar expression of proteins in each tumor cell line in vitro and implanted tumor in vivo gives an advantage in evaluating the effects of molecular-targeted drugs and the relationship between specific genes and tumor potential in preclinical studies.


Betulinic acid augments the inhibitory effects of vincristine on growth and lung metastasis of B16F10 melanoma cells in mice

We examined the antitumour effect of a combination of betulinic acid (BA) and vincristine (VCR) on murine melanoma B16F10 cells in vitro and in vivo. Betulinic acid, a pentacyclic triterpene, showed a synergistic cytotoxic effect on melanoma cells by combinational use of VCR. Betulinic acid and VCR induced cell cycle arrest at different points (BA at G1 phase and VCR at G2/M phase) and caused apoptosis in B16F10 melanoma cells. In the in vivo study, VCR inhibited metastasis of tumour cells to the lung. The addition of BA to VCR augmented suppression of the experimental lung metastasis of melanoma cells in C57BL/6 mice. The number of lung nodules of more than 1 mm in diameter in mice treated with BA and VCR was less than that in mice treated with VCR alone. These results suggest that BA is an effective supplement for enhancing the chemotherapeutic effect on malignant melanoma.


WHO histologic classification is a prognostic indicator in thymoma

The histologic classification of thymoma has remained a subject of controversy for many years. In 1999, the World Health Organization Consensus Committee published a histologic typing system for tumors of the thymus. We reclassified a series of 100 thymomas resected at Tokushima University Hospital and four affiliated hospitals in Japan between 1973 and 2001 according to the World Health Organization histologic classification and reported its clinicopathologic relationship and prognostic relevance. There were 8 type A, 17 type AB, 27 type B1, 8 type B2, 12 type B3, and 28 type C thymomas. The frequency of invasion to neighboring organs increased according to tumor subtype in the order A (0%), AB (6%), B1 (19%), B2 (25%), B3 (42%), and C (89%). There was no recurrence in patients with type A, AB, or B2 thymoma. The recurrence rates of patients with B1, B3, or C thymoma were 15%, 36%, and 47%, respectively. The disease-free survival rates were 100% for types A and AB, 83% for types B1 and B2, 36% for type B3, and 28% for type C thymoma at 10 years. There were significant differences in disease-free survival between types A and AB and types B1 and B2 (p = 0.0436), and between type B3 and type C (p = 0.042). By multivariate analysis, only Masaoka clinical stage (p = 0.002) showed significant independent effects on disease-free survival. The 10-year survival rates of types A and AB, types B1 and B2, type B3, and type C thymoma were 100%, 94%, 92%, and 58%, respectively. The current study confirmed the World Health Organization histologic classification as a good prognostic factor.


Green fluorescent protein expression and visualization of mediastinal lymph node metastasis of human lung cancer cell line using orthotopic implantation

Suppression of lymphatic metastasis improves survival in lung cancer patients. We have reported a patient-like model of lung cancer metastasis based on orthotopic implantation in severe combined immunodeficiency (SCID) mice and demonstrated the lymphogenous spread histologically using human NSCLC cell lines. To visualize micrometastases, we transfected the Aequorea Victoria jellyfish green fluorescent protein (GFP) gene to the cancer cell line. The tumor cell lines were able to stably express GFP at high levels both in vitro and in vivo. Fluorescent tumors and metastasis of the mediastinum could be visualized at microscopic levels after transplantation. This model demonstrated that GFP gene-transfected tumor cells represent a new tool for evaluating the metastatic process and are very useful for developing chemotherapy to inhibit metastasis.


Establishment of patient-like SCID mouse model by orthotopically implanting primary cultured cells from surgically-resected lung cancer tissues

In our previous studies, we established a lymphogenous metastatic SCID mouse model using orthotopic implantation of human lung cancer cell lines. However, the lymphogenous metastatic potential of each cell line in our models does not reflect that of a primary tumor. In this study, we made orthotopic implanted models using primary cultured cells from surgically-resected lung cancer tissues. Tissues of 5 patients with non-small cell lung cancer (NSCLC) were applied to a primary culture method using a collagen gel coated flask. Suspensions of 2.0x10(4) cancer cells were injected into the left lung of SCID mice. We could maintain primary culture cells from 2 (FM205 and FT821 cells) of 5 lung cancers, and made orthotopically implanted SCID mouse models. The size of both tumors in implanted sites of the lung increased with time. The FM205 cells microscopically were metastasized to the mediastinum by 4 weeks after implantation and macroscopically metastasized by 16 weeks. The FT821 cells were microscopically metastasized to the mediastinum by 4 weeks after implantation and macroscopically metastasized by 6 weeks. The lymphogenous metastatic potential of these primary culture cells was similar to that of clinical tumors. As the lymphogenous metastatic potential of this model reflects that of the clinical tumor, it is useful for elucidating the mechanism of lymphogenous metastasis and selecting anticancer drugs suitable for an individual patients.


Microscopic analysis of chromium accumulation in the bronchi and lung of chromate workers

It is known that chromium is an inhaled carcinogen and an important risk factor in the development of lung carcinoma. The authors used a microscopic X-ray fluorescence analyzer with transmitted X-ray mapping imaging (Horiba, Kyoto, Japan) to measure the accumulation of chromium in 10 resected lung tissue specimens and 90 biopsy specimens from chromate workers. The maximum chromium accumulation (mean +/- standard deviation) in 10 resected lung tissue specimens was 197 +/- 238 counts per second (cps)/mili ampere (mA) (range, 4-649 cps/mA). Chromium accumulation was scattered in six tissue specimens and diffuse in one specimen. Chromium accumulation in the proximal bronchi was less than in the bronchioles or subpleural regions of the lung. Chromium accumulation was detectable in 63 (70%) of 90 biopsy specimens, and the mean accumulation was 6.5 +/- 9.2 cps/mA (range, 0-46.5 cps/mA). Chromium detected in bronchial tissue specimens was deposited in the bronchial stroma but not in the epithelium. The maximum chromium accumulations in dysplasic (n = 3), squamous metaplastic (n = 10), and normal bronchial epithelia (n = 9) in chromate workers and in normal bronchial epithelia (n = 3) in non-chromate workers were 20.2 +/- 5.4, 18.3 +/- 12.2, 13.2 +/- 13.4, and 3.0 +/- 1.8 cps/mA, respectively. The amount of chromium accumulation significantly increased according to the progression of malignant change of the bronchial epithelium (P = 0.003). Previous studies found that lung carcinoma with chromate exposure exhibited a variety of genetic abnormalities. Considering genetic aberrations and chromium accumulation in these premalignant lesions is useful for elucidating the process of carcinogenesis in chromium-induced lung carcinoma.


Fatal air embolism during computed tomography guided pulmonary marking with a hook-type marker

Journal of Thoracic and Cardiovascular Surgery


Increased expression of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 is correlated with poor prognostic variables in patients with thymic epithelial tumors

A distinction between noninvasive, invasive, and metastatic thymoma on the basis of the cytologic features is difficult. The current study investigated whether the expression of MMP and TIMP was correlated with tumor invasiveness and prognosis in patients with thymoma. Tumor tissue samples were obtained from 42 patients with thymic epithelial tumors between 1974 and 2001 at Tokushima University Hospital. Three-micrometer-thick, formalin-fixed, paraffin-embedded tissue sections were immunostained using specific antibodies against MMP-2, MMP-9, TIMP-1, and TIMP-2. MMP-2 expression was detected in 30 tumors (71%), and TIMP-2 expression was detected in 31 tumors (74%). MMP-9 expression was detected in 22 of 36 tumors (61%), and TIMP-1 expression was detected in only 7 tumors (19%). MMP-2 and TIMP-2 expression levels were very low (10% and 0%, respectively) in noninvasive tumors but were very high (91% and 97%, respectively) in invasive tumors. In thymic epithelial tumors, the more progressive the clinical stage of tumor, the higher the strongly positive rate of MMP-2 and TIMP-2 expression. There was no correlation between positivity for MMP-9 and stage. Twenty-five percent of Type AB thymomas and 50% of Type B1 thymomas expressed MMP-2 and TIMP-2. Most of Type A, Type B2, Type B3, and Type C thymomas expressed MMP-2 and TIMP-2. There were significant differences in disease-free survival at 5 years between patients without and with MMP-2 expression (91% vs. 55%, respectively) and patients without and with TIMP-2 expression (100% vs. 53%, respectively). MMP-2 and TIMP-2 are key enzymes for invasiveness of thymic epithelial tumors. The expression of these proteins can predict a poor outcome in patients with thymoma.


Progressive increase of CD4+/CD45RC- lymphocytes after allograft rat lung transplantation: a marker of acute rejection

Acute rejection remains one the most serious problems in lung transplantation. Although biopsy has been used for assessing the dysfunction of grafts, it is difficult to determine rejection at an early stage. Lymphocyte infiltration and activation play an important role in acute rejection of transplanted organs, and the dynamic change of lymphocyte subpopulations might be a marker to determine graft rejection after lung transplantation. A rat lung transplant model was used. Graft-infiltrating lymphocytes in lung tissues were examined by means of histology, and isolated cells were analyzed by means of flow cytometry. Phenotypes of lymphocytes in the regional and remote lymph nodes, spleen, peripheral blood, and bronchoalveolar lavage fluid were also measured by means of flow cytometry. After allograft transplantation, increased lymphocytes were seen in allografts but not in isografts. In allografts the percentage of T cells increased from day 1 to day 5, whereas that of B cells was decreased. The CD4(+)/CD8(+) ratio decreased in allografts. The proportion of CD4(+)/CD45RC(-) cells increased in the allografts, which was mainly due to the increase of CD45RC(-) cells in the total CD4(+) cells. Similar changes were found in regional mediastinal lymph nodes but not in the mesenteric lymph nodes, spleen, or peripheral blood. Thus this is a specific response to lung allografts. Importantly, CD45RC(-) cells were significantly increased in the bronchoalveolar lavage fluid. Significant change of lymphocyte subpopulations is a sign of lymphocyte activation. Increased CD4(+)/CD45RC(-) cells in lung allografts could be an early marker of acute rejection, which can be examined by means of lung lavage and flow cytometry.


Suppression of mediastinal metastasis by uracil-tegafur or cis-diamminedichloroplatinum(II) using a lymphogenous metastatic model in a human lung cancer cell line

The extent of lymphatic metastasis is the most important factor in the prognosis for non-small cell lung cancer (NSCLC). Therefore, suppression of lymphatic metastasis provides an improvement in survival time in lung cancer patients. We established a new patient-like model for lung cancer metastasis by orthotopic implantation in severe combined immunodeficiency (SCID) mice and demonstrated the lymphogenous spread histologically using human NSCLC cell lines. The cardinal features of this model are a simple procedure and a similarity to the metastatic form of human lung cancer. The purpose of this study is to assess the inhibitory action of uracil-tegafur (UFT) and cis-diamminedichloroplatinum(II) (CDDP) on lymphatic metastasis and life span prolongation in our lymphogenous metastatic model system using SCID mice. The inhibition ratios of mediastinal lymph node metastasis were 86.2, 94, and 92.1% for 12 mg/kg body UFT, 17 mg/kg body UFT, and 10 mg/kg body CDDP, respectively. The administration of anticancer drugs prolonged the life span by 4.6 days (17 mg/kg body UFT) and 8 days (10 mg/kg body CDDP) in MST. We demonstrated that UFT alone and CDDP alone suppressed mediastinal metastasis and prolonged the life span in our lymphogenous metastatic model. Regardless of the administration route and characteristics of anticancer drugs, cytostatic or cytotoxic, our model is capable of evaluating the inhibitory effect of drugs on lymphatic metastasis. This model should make an important contribution to our understanding of the mechanism and selection of drugs for antilymphatic metastasis in lung cancer.


Multilocular thymic cyst associated with Sjögren's syndrome

A 61-year-old woman, who had been diagnosed as having Sjögren's syndrome, developed an anterior mediastinal mass. She was diagnosed with Sjögren's syndrome with thymoma, preoperatively. Extended thymectomy was performed. Macroscopically, the mediastinal mass showed thick-walled multiloculated cavities filled with turbid yellow fluid. Microscopically, the cyst lining was continuous with thymic lobules in the wall with inflammatory process, cholesterol granuloma formation, and prominent lymph follicular hyperplasia. She was diagnosed with multilocular thymic cysts associated with Sjögren's syndrome.


Intralobar sequestration associated with increased serum CA19-9 and CA125

血中CA19-9およびCA125上昇を認めた肺葉内肺分画症の一例


SCID mouse lymphogenous metastatic model of human lung cancer constructed using orthotopic inoculation of cancer cells

An animal model of metastasis with features similar to those of lung cancer metastasis in humans is required for an understanding of the cellular and molecular mechanisms of human lung cancer metastasis. Ma-44 cell lines derived from human squamous cell lung cancer were percutaneously injected (2-3 x 10(4)) into the left lung of SCID mice. After orthotopic implantation, Ma-44 cell lines formed tumors in the left lung at a high rate (17/25, 68%), and many of those metastasized to mediastinal lymph nodes (13/17, 76%) by the 14th day, but not to other organs. After the ectopic implantation, the Ma-44 cell line inoculated subcutaneously (2-3 x 10(5)) formed a tumor at the inoculation site by the 28th day (all mice), but did not metastasize to any organs. The Ma-44 cell line inoculated intravenously (2-3 x 10(5)) formed metastases in the lungs (37/50, 74%), and these pulmonary metastases metastasized to the mediastinal lymph nodes at low rate (3/37, 8%) by the 14th day. The orthotopic sites of implantation are critical for the metastatic ability of transplanted tumors in SCID mice. Since non-small cell lung cancer (NSCLC) grows at the primary site in humans, lymphogenous metastasis occurs frequently, and blood-born metastasis occurs at moderate rate, our orthotopic SCID mice model was similar to the metastatic behavior of NSCLC in humans. Thus, this model may be useful for elucidating the mechanism of lymphogenous metastasis in human lung cancer, and testing the anti-metastatic efficacy of therapeutic agents in vivo.


The expression of the CD44 variant exon 6 is associated with lymph node metastasis in non-small cell lung cancer


High frequency of p53 protein expression in thymic carcinoma but not in thymoma.

Thymic epithelial tumours are broadly classified into thymomas and thymic carcinomas. Although both tumours occasionally show invasive growth, they exhibit different clinical and biological findings. The oncogene and anti-oncogene in thymic epithelial tumours have not been evaluated fully. We investigated the expression of p53 protein by immunohistochemical analysis using the anti-p53 polyclonal antibody (CM-1) in 17 thymomas and 19 thymic carcinomas. We also examined p53 gene (exon 5-8) mutation in 18 thymic carcinomas by using polymerase chain reaction-single-strand conformation polymorphism methods and direct sequencing. Of the thymoma cases, only one invasive thymoma showed focal nuclear staining. Fourteen of the 19 thymic carcinomas (74%) showed nuclear staining. Point mutations of the p53 gene were recognized in only 2 of the 18 thymic carcinomas (11%). One was the mutation C to T transition in the first letter of codon 222 in exon 6, which results in the amino acid substitution from proline to serine. Another was a silent mutation. p53 protein accumulation is highly frequent in thymic carcinomas but not in thymomas, and gene mutation is uncommon in thymic carcinomas.


Invasive thymoma with endobronchial polypoid growth.

A rare case of invasive thymoma with endobronchial polypoid growth is presented. A 68-year-old woman presented with coughing and sputum. The chest X-ray and computed tomography (CT) findings demonstrated a large mass with a calcified lesion in the left hilar region. A bronchoscopic examination showed a polypoid tumor in the left B3b bronchus. The tumor was surgically resected and revealed a unique polypoid endobronchial extension. This tumor was pathologically diagnosed to be invasive thymoma.


骨外性粘液型軟骨肉腫に対する遊離植皮術後に発症した肺塞栓の1例

骨外性粘液型軟骨肉腫に対する遊離植皮術後に発症した肺塞栓の1例


A dose-response relationship between the frequency of p53 mutations and tobacco consumption in lung cancer patients.

Mutations of the p53 tumor suppressor gene are frequent in lung cancers. It is suggested that p53 mutations are associated with smoking-induced lung carcinogenesis. We examined p53 mutations in 53 lung cancers by analyzing reverse transcription-polymerase chain reaction-single strand conformation polymorphism (RT-PCR-SSCP) to ascertain the association between p53 mutations and smoking. Twenty-five (47%) of 53 lung cancers carried p53 mutations. A discriminant analysis showed that the Brinkman index (0.156) and gender (0.140) significantly influenced p53 mutations. Furthermore, there was a dose-response relationship between the quantity of cigarettes consumed and the frequency of p53 mutations in lung cancer patients (P < 0.001). In patients with adenocarcinoma, the frequency of p53 mutations correlated with the amount of the tobacco smoked (P < 0.05). We suggest that the p53 gene is a target of particular carcinogen in tobacco smoke.


p53 alteration correlates with negative ER, negative PgR, and high histologic grade in breast cancer.

Seventy tumors of invasive ductal carcinoma of the breast were examined for p53 alteration by the RT-PCR-SSCP method. Sixty-five samples (92.9%) were investigated in the regions of codons 101-200 and 201-300. In total, 16 samples (24.6%) showed p53 gene alteration. We found that p53 gene alteration showed a correlation with (1) a negative ER status, (2) a negative PgR status, and (3) a high histologic grade (especially numerous mitotic figures) of the tumor. However, we found no correlation between p53 gene alteration and the lymph node status or clinical stage. Thus, p53 gene alteration in breast cancer may occur in highly malignant breast cancer other than advanced clinical stage cancer or node-positive cancer.


Frequency of spontaneous p53 mutations (CpG site) in breast cancer in Japan.

Sixty-five tumors of invasive ductal carcinoma of the breast were examined for p53 alteration by the reverse transcription-polymerase chain reaction-single strand conformation polymorphism (RT-PCR-SSCP) method and sequencing analysis. In total, 16 samples (24.6%) showed p53 gene alteration. Sixteen of these alterations were evaluated by sequencing analysis, and 15 showed missense point mutations while one showed a 9-base pair deletion. In the 15 point mutations, G:C to A:T transitions constituted the majority (53%), and five tumors (33%) had a transition at the CpG site, which are mutational patterns not commonly found in breast tumors from Europe and America. On the other hand, there were no G:C to T:A transversions in our cases, which were frequently observed transversions in Europe and America. These p53 mutation patterns in breast cancer in Japan are not similar to those in Europe and America reported by Hollstein et al. and Coles et al.. These findings suggest that there are some differences between mechanisms of breast cancer in Japan and in Europe and America.


Mutations in the P53 tumour suppressor gene in primary lung cancer in Japan.

The reverse transcription-polymerase chain reaction-single strand conformation polymorphism (RT-PCR-SSCP) analysis and sequencing were used to examine p53 gene alterations in 18 surgical specimens of primary lung cancers obtained in Japan. Somatic mutations resulting in amino acid changes were found in eight of the 18 cases (44%). Seven missense mutations were located in amino acid-conserved domains or their vicinities (codons 110 to 307). Most mutations were found at G-C pairs, suggesting that specific carcinogens are involved in the etiology of lung cancer. The p53 mutations showed a significant association with a history of smoking (P = 0.0294). We suggest that the p53 mutations may be associated with smoking-induced lung carcinogenesis.

Biochemical and Biophysical Research Communications


An immunohistochemical study of thymic epithelial tumors. III. The distribution of interdigitating reticulum cells and S-100 beta-positive small lymphocytes.

We report an immunohistochemical study of the distribution and number of interdigitating reticulum cells (IDC) and S-100 beta-positive small lymphocytes (S-100 beta + lymphocytes) in 53 thymomas and 11 thymic carcinomas. All 53 thymomas showed the presence of IDC in the tumor parenchyma. In most cases of predominantly lymphocytic and mixed-type thymoma, IDC clustered in areas, that corresponded to locations that had medullary differentiation and contained accumulated mature lymphocytes. By contrast, in most of the predominantly epithelial-type thymomas, IDC were scattered rather than forming clusters. The distribution and number of IDC were correlation with the histological type of thymoma but not with invasiveness. In thymic carcinomas, IDC were scattered in tumor nests. In 47 of the 53 thymomas (89%), infiltrating S-100 beta + lymphocytes were readily recognized. The remaining six cases without S-100 beta + lymphocytes were noninvasive thymoma. We conclude that the degree of S-100 beta + lymphocyte infiltration is correlated with the stage of thymoma and may be a marker of thymoma malignancy.

The American Journal of Surgical Pathology


Transferrin receptor expression in adenocarcinoma of the lung as a histopathologic indicator of prognosis.

Immunohistochemical reactivity with OKT9 (antitransferrin receptor) monoclonal antibody was studied in 58 surgically resected adenocarcinomas of the lung. The cell surface and cytoplasm of the tumor cells were stained in 44 cases (76 percent). The expression of the transferrin receptor (TrfR) in tumor cells was compared with histopathologic prognostic factors, such as TNM factors, degree of histologic differentiation, degree of nuclear atypia, and frequency of mitotic figures. The expression of TrfR showed significant correlation with the degree of histopathologic differentiation (p less than 0.025), degree of nuclear atypia (p less than 0.025), and frequency of mitotic figures (p less than 0.001). However, there was no definite correlation with TNM factors. These results indicate that the expression of the TrfR in pulmonary adenocarcinoma corresponds to the elevated proliferative activity of the tumor cells, and that immunohistochemical reactivity with OKT9 can be used as one of the histopathologic indicators of prognosis of pulmonary adenocarcinoma.


Pulmonary Resection in Renal Cell Carcinoma Metastasis : the Influence of Histologic Atypia of the Metastatic Focus on Preoperative or Perioperative Diagnosis

臨床と研究 腎癌肺転移巣の組織学的異型度が画像診断に及ぼす影響

The Japanese Journal of Thoracic Surgery


Changes in high school students' attitudes towards smoking habits before and after the smoking prevention education

喫煙防止教育前後における高校生の喫煙に対する態度と意識の変化

In order to prevent the smoking habit, it is important to start a smoking prevention education (SPE)earlier. Implementing educational intervention with appropriate timing and content is necessary during and after the high school years when a smoking habit is easily formed. The purpose of this research was to clarify high school students' attitudes and beliefs towards smoking before and after SPE and to examine how to provide optimal SPE in the future. The subjects were 680 high school students in the A prefecture. The SPE was implemented, their attitudes and beliefs towards smoking habit were measured using a scale of``belief and attitude towards smoking habits'', and its changes were assessed before and after the education and eight months later. The scores showed significant change in negative attitude toward smoking habit immediately after the SPE. However, the survey after eight months showed the SPE effects were not maintained except one item. Gender and the presence or absence of smokers in their family was involved in the continuation of the effects of SPE. It was suggested that it is necessary to have an appropriate intervention method to the subjects' characteristics and the optimal intervention timing should be discussed and an approach to reinforce the continuance of effects of SPE are required for the SPE in the future.


Novel bronchofiberscopic catheter spray device allows effective anesthetic spray and sputum suctioning

To evaluate how serum lidocaine concentrations (SLC) rise when lidocaine is administered by a Bronchofiberscopic Catheter Spray Device (BCSD), and to demonstrate the effect on the aspiration speed of a substitute for sputum when a catheter spray remains in the channel of the bronchofiberscope (BF). This is a prospective randomized clinical study. After lidocaine ultrasonic nebulizer, the BF was inserted orally. During the procedure patients received 4% lidocaine by two methods. In Group 1, 11 patients received lidocaine by bronchofiberscopic (BF) injection. In Group 2, 15 patients received lidocaine by spraying from the diameter 1.06 mm catheter through the BF channel. SLC were measured at 40 min from onset of nebulization. Separately, we examined how effectively sputum was aspirated through the BF channel with a catheter. Total lidocaine dose (TLD) is the total dose used for nebulization and for the BF injection or spray. The TLD for Groups 1 and 2 were 698.2+/-162.1 mg (mean+/-SD) and 498.7+/-103.8 mg, respectively (P = 0.03). The SLC for Groups 1 and 2 were 1.28+/-0.72 and 1.48+/-0.70 mg/l, respectively (P = 0.49). Using BCSD allows easier in administration of lidocaine and is not associated with a significant increase in SLC in comparison with BF injection. Although sputum aspiration using the BF inserted with our catheter was somewhat slow, we did not feel inconvenient so much. Compared to the conventional method, using BCSD may be preferable for patients and bronchoscopists.