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There is no universal recommendation for managing the reactivation of HBV in patients with resolved HBV infection treated with anti-CD20 monoclonal antibodies for B-cell non-Hodgkin lymphoma. This study compared the cost-effectiveness of two commonly used strategies: prophylactic anti-HBV nucleos(t)ide analog therapy (Pro NAT), and HBV DNA monitoring followed by on-demand antiviral therapy (HBV DNA monitoring). Using a decision tree model, the incremental cost-effectiveness ratio (ICER) expressed as cost per quality-adjusted life-year (QALY) gained was calculated. The threshold for cost-effectiveness was set at 5,000,000 JPY, equivalent to 45,662 USD. In a base–case analysis, HBV DNA monitoring was found to be more cost-effective based on the calculation of ICER as 132,048 USD per QALY, a value that far exceeds 45,662 USD. The same results were consistently obtained by a one-way deterministic sensitivity analysis, even after changing each parameter value within the predetermined range. A probabilistic sensitivity analysis with 10,000 simulations also revealed that HBV DNA monitoring is more cost-effective than Pro NAT in 96.8% of cases. Therefore, this study suggests that HBV DNA monitoring is an appropriate managing measure in Japan from a cost-effectiveness perspective.

Background and objective Improved detectability of chronic obstructive pulmonary disease (COPD) using a handheld flow meter (HFM) with symptom-based questionnaires has not been sufficiently evaluated. This study aimed to identify the benefit of using an HFM in COPD screening. Methods A total of 2008 participants, who were ≥ 40 years of age, from Isumi City, Japan, were recruited. We developed two novel point systems for detecting COPD, one incorporated score of HFM alone (sHFM) and the other incorporated the score of International Primary Care Airway Group questionnaire (IPAG) and HFM (sIPAG + HFM). Validation using random sample allocation (split-sample validation) was carried out to assess the predictive performance of these models. Results Participants were assigned to a data set for model creation (n = 1007) or a data set for model assessment (n = 1001) to perform split-sample validation. Decision curve analysis showed that the net benefits of sHFM and sIPAG + HFM were higher than that of the IPAG score (sIPAG) and specificity of the former two were also significantly higher than that of sIPAG. However, the curves of sHFM and sIPAG + HFM were crossing and practically the same with no significant difference in sensitivity and specificity. Conclusion This study confirms that HFM is significantly advantageous in detecting COPD despite the use of a conventional questionnaire.

ObjectivesA sufficient screening rate is indispensable to optimize the positive impact of colorectal cancer (CRC) screening. This study aimed to evaluate the effect of an additional outreach of providing an opportunity to obtain a kit for fecal immunochemical test (FIT) during the general health check-up to increase CRC screening rate.MethodsThis was a longitudinal study using pre-existing data in Kujukuri Town, Japan. The town provided CRC screening in the fiscal year (FY) 2017 using an existing procedure for all beneficiaries of the National Health Insurance, whereas in FY 2018, an additional outreach effort was made to only those with an even number of age (exposed group), who were offered an opportunity to obtain a kit for FIT at the time of general health check-ups but not to those with an odd number of age (control group). To estimate the effectiveness, generalized estimating equation (GEE) with individuals as clusters was performed.ResultsIn total, 3,530 individuals were included (1,708 in the control group and 1,822 in the exposed group). GEE showed significant interaction between the groups (control and exposed) and FYs (2017 and 2018) (pConclusionsAdditional outreach of providing an opportunity to obtain a kit for FIT at the time of the general health check-up improved the CRC screening rate. However, screening rate achieved by this strategy remained low, indicating further efforts is required.

To investigate the predictive capability of insulin resistance surrogate markers for insulin resistance and arterial stiffness based on sex.We assessed the association of triglyceride glucose (TyG) index, triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C), visceral adiposity index (VAI), and lipid accumulation product (LAP) with homeostasis model assessment-insulin resistance (HOMA-IR) and brachial-ankle pulse wave velocity (baPWV) in both sexes.A total of 1720 men and 1098 women were evaluated. HOMA-IR showed good correlation with the TyG index (men: r = 0.47, women: r = 0.45), TG/HDL-C (men: r = 0.45, women: r = 0.41), VAI (men: r = 0.51, women: r = 0.48), and LAP (men: r = 0.55, women r = 0.49) (all p-values 0.001). These markers positively correlated with increased baPWV in both sexes. The standardized partial regression coefficients were 0.11 and 0.14 for the TyG index, 0.13 and 0.16 for TG/HDL-C, 0.14 and 0.19 for VAI, and 0.12 and 0.17 for LAP in men and women, respectively (all p-values 0.01; all p-values for sex interaction 0.05).All insulin surrogate markers showed good correlation with HOMA-IR in both sexes. These indices were also associated with increased baPWV and the associations were stronger in women than in men.

Objectives Our objective was to report initial results of a dose escalation trial of single-fraction carbon ion radiotherapy for peripheral stage I NSCLC. Methods Between April 2003 and February 2012, a total of 218 patients were treated. The total dose was raised from 28 to 50 Gy (relative biological effectiveness [RBE]). There were 157 male and 61 female patients, with a median age of 75 years. Of the tumors, 123 were stage T1 and 95 were stage T2. A total of 134 patients (61.5%) were medically inoperable. By histological type, there were 146 adenocarcinomas, 68 squamous cell carcinomas, three large cell carcinomas, and one mucoepidermoid carcinoma. Results The median follow-up was 57.8 months (range 1.6–160.7). The overall survival rate at 5 years was 49.4%. The local control (LC) rate was 72.7%. A statistically significant difference in LC rate ( p = 0.0001, log-rank test) was seen between patients receiving 36 Gy (RBE) or more and those receiving less than 36 Gy (RBE). In 20 patients irradiated with 48 to 50 Gy (RBE), the LC rate at 5 years was 95.0%, the overall survival rate was 69.2%, and the progression-free survival rate was 60.0% (median follow-up was 58.6 months). With dose escalation, LC tended to improve. As for adverse lung and skin reactions, there were no patients with grade 3 or higher reactions, and less than 2% had a grade 2 reaction. Regarding chest wall pain, only one patient had grade 3 late toxicity. Conclusions We have reported the outcome of a dose escalation study of single-fraction carbon ion radiotherapy for stage I NSCLC, showing the feasibility of obtaining excellent results comparable to those with previous fractionated regimens.

Purpose In an aging society, many senior citizens want less invasive treatment because of potential medical complications. The National Institute of Radiological Sciences has started to treat stage I lung cancer with single-fraction carbon-ion radiation therapy (CIRT) as a dose escalation prospective phase 1/2 trial. We evaluated the efficacy and safety of CIRT for patients 80 years of age and older, undergoing single-fraction CIRT. Methods and Materials Peripheral non-small cell lung cancer patients who were treated with single-fraction CIRT were prospectively followed. We analyzed the data from among these patients 80 years of age and older. Results There were 70 patients. Median age was 83 years (range: 80-89) and median follow-up period was 42.7 months (range: 12-128 months). Three-year local control, cause-specific survival, and overall survival rates were 88.0%, 81.6%, and 72.4%, respectively. Five-year local control, cause-specific survival, and overall survival rates were 85.8%, 64.9%, and 39.7%, respectively. There were no adverse effects higher than grade 2 either in the acute or late phase in terms of skin and lung. Analgesic agents were necessary for only 5 patients (7.1%), to relieve muscular or rib fracture pain caused by irradiation. Conclusions Single-fraction CIRT was low-risk and effective, even for the elderly.

Aim: One-hour post-load plasma glucose (1h-PG) during an oral glucose tolerance test and smoking are associated with arterial stiffness. However, it remains unknown whether there are synergistic effects of these two factors on arterial stiffness. This study aimed to investigate the interaction between 1h-PG and smoking in relation to brachial–ankle pulse wave velocity (baPWV) in young men with normal glucose tolerance (NGT). Methods: The study included 25-, 30-, 35-, 40-, and 45-year-old non-industrial male workers (n = 2189) who underwent a detailed health check-up. Normotensive participants with NGT and taking no medication were included. Results: A univariate linear regression analysis showed that 1h-PG correlated with baPWV (r = 0.13, p < 0.001), but the correlation was not significant in the multivariate analysis (β = 0.02, p = 0.24). However, we found a significant interaction between 1h-PG levels and smoking status in relation to baPWV (p = 0.048). Therefore, further analyses were conducted in nonsmokers and smokers. A multivariate linear regression analysis revealed that 1h-PG significantly correlated with baPWV in smokers (β = 0.11, p = 0.02), but not in nonsmokers (β = 0.01, p = 0.79). The correlation remained significant even after adjustment for the number of cigarettes smoked per day (β = 0.096, p = 0.048) or the Brinkman index (β = 0.097, p = 0.043). Conclusion: A significant interaction between 1h-PG and smoking in relation to baPWV was found in apparently healthy men younger than 50 years old.

Objectives Carbon ion radiotherapy (CIRT) has been expected to be an alternative for surgery for early-stage non-small-cell lung cancer (NSCLC) and adopted as the second-best choice even in operable patients although local recurrence after CIRT is sometimes experienced. The purpose of this study was to investigate the demographic data, perioperative courses and therapeutic outcomes of patients who underwent salvage resection for local recurrence after CIRT. Methods From November 1994 to February 2012, CIRT was applied for 602 c-T1/T2/T3N0M0 NSCLC lesions of 599 patients at the National Institute of Radiological Science. A total of 95 (16%) patients were diagnosed as having local recurrence, of whom 12 underwent salvage surgeries. The medical records were retrospectively reviewed. Results There were 7 men and 5 women (mean age, 63 ± 7.4 years). The clinical stages upon initial presentation with NSCLC were as follows: 4 IA, 7 IB and 1 IIB. All the patients were operable, but refused surgery and underwent CIRT. The median progression-free survival time after CIRT was 20 months (range, 7.1-77 months), and salvage surgery was performed at a median of 24 months (range, 9-78 months) after CIRT. All surgeries were successfully performed without any significant CIRT-related adhesions during the surgery, resulting in no mortality or Clavien-Dindo grade 3-4 postoperative complications. However, the distribution of pathological stages was as follows: 4 IA, 3 IB, 2 IIB, 2 IIIA and 1 IV, which included 6 upstages from the clinical stages before CIRT. The Kaplan-Meier estimate of overall survival after the salvage surgery showed that the 3-year survival rate was 82%. Conclusions The dose intensity of CIRT spared the hilum of the lungs and parietal pleura, none of the patients developed adhesions outside of the radiation field, such that the salvage surgeries for local recurrence after CIRT were safe and feasible.

BACKGROUND Although concurrent chemoradiotherapy (CCRT) has become the standard approach for unresectable locally advanced non–small cell lung cancer (LA-NSCLC), most patients are not candidates for this treatment because of comorbidities. We evaluated the safety and efficacy of carbon ion radiotherapy (CIRT) in LA-NSCLC patients. METHODS Patients with stage IIA to IIIA (UICC 7th edition) LA-NSCLC were enrolled in a sequential phase I/II trial. For a phase I dose escalation study, the total prescribed dose was increased by 4 Gray equivalents (GyE) in 2 steps, from 68 to 72 GyE and then to 76 GyE, using 16 fractions over 4 weeks. After determining the recommended dose, the phase II trial was started in an expanded cohort. RESULTS Of the 36 patients treated in phase I, 2 grade 3 adverse events (radiation pneumonitis and tracheoesophageal fistula) were observed in the 76 GyE group. Accordingly, for phase II, the next consecutive 26 patients were treated with 72 GyE, with no grade 3 to 5 toxicities resulting. A total of 62 eligible patients were recruited. The majority of patients (49 of 62) were N0 or N1 patients, and the rest (13 of 62) were single-station N2 patients. The median follow-up period was 25.2 months. The 2-year local control rate (LCR) and overall survival (OS) for the entire cohort were 93.1% and 51.9%, respectively. In particular, patients with cT3-4N0 had an excellent prognosis; the 2-year OS and LCR were 69.3% and 100%, respectively. CONCLUSIONS Short-course CIRT monotherapy shows promise as an effective nonsurgical treatment for inoperable LA-NSCLC. Cancer 2015;121:1321–1327. © 2014 American Cancer Society.

To investigate the relationship between 1-h post-load plasma glucose, measured during an oral glucose tolerance test, and arterial stiffness, determined by brachial-ankle pulse-wave velocity, in normotensive subjects with normal glucose tolerance.Study subjects were non-industrial workers aged 25-55 years ( n = 8381) who underwent a regular health check-up every 5 years. We included only normotensive subjects with normal glucose tolerance based on the American Diabetes Association criteria. Subjects taking medication and having an abnormal ankle-brachial index (⩽1.0 or ⩾1.3) were excluded. The final sample comprised 4970 participants (mean age: 38.8 ± 9.4 years; women: n = 2048).1-h post-load plasma glucose correlated with brachial-ankle pulse-wave velocity in men ( β = 0.04, p = 0.01), but not women ( β = -0.03, p = 0.13) in multivariate linear regression analysis. We found a significant interaction between 1-h post-load plasma glucose and age in men ( p = 0.04); therefore, a subgroup analysis was performed in each 5-year age group. The correlation between 1-h post-load plasma glucose and brachial-ankle pulse-wave velocity was significant in the 55-year-old age group ( β = 0.12, p = 0.01) and neared significant in 45-year-old ( β = 0.08, p = 0.07) and 50-year-old ( β = 0.09, p = 0.07) age groups.Elevated 1-h post-load plasma glucose levels were associated with arterial stiffness in normotensive, middle-aged men with normal glucose tolerance.

Lung cancer is frequently complicated by interstitial lung disease (ILD). Treatment protocols for lung cancer patients with ILD have not been established; surgery, chemotherapy, and radiotherapy can all cause acute exacerbation of ILD. This study evaluated the toxicity and efficacy of carbon ion radiotherapy (CIRT) in patients with non-small cell lung cancer (NSCLC) and ILD. Between June 2004 and November 2014, 29 patients diagnosed with NSCLC and ILD were treated with CIRT. No patient was eligible for curative surgery or conventional radiotherapy secondary to ILD. Owing to prior symptomology, radiation pneumonitis (RP) and symptom progression pre- and post-treatment were evaluated. The relationships between RP and clinical factors were investigated. Twenty-eight men and one woman, aged 62 to 90 years old, were followed for 2.7–77.1 months (median: 22.8 months). Single-grade symptomatic progression (grade 2–3) was observed in 4 patients, while 1 patient experiencedtwo-grade progression. Two patients experienced radiation-induced acute exacerbation. Local control at 3 years was 63.3% (72.2% for stage I disease); survival at 3 years was 46.3% (57.2% for stage I disease). Eighteen patients had died by the time of this writing, 10 of lung cancer progression. Radiation pneumonitis post-treatment progression correlated with dosimetric factors of the lungs (V5, V10) and a low pre-treatment serum surfactant protein-D. We found that CIRT may be useful as a low-risk, curative option for NSCLC patients with ILD, a population that is typically ineligible for conventional therapy. The DVH analysis showed that minimizing the low-dose region is important for reducing the risk of severe RP. NIRS-9404 . Registered 1 March 1994.

Background and objective Detection of chronic obstructive pulmonary disease (COPD) is crucial in the management of COPD. The aim of this study was to establish the utility of a community-based lung cancer screening for detecting COPD. Methods In Japan, community-based lung cancer screening for residents who are 40 years or older using chest radiography is well established. A screening system in Chiba City, Japan, was used to detect COPD. The criteria to consider COPD at screening included age of 60 years or older, a smoking history and chronic respiratory symptoms. Participants fulfilling these criteria were referred for diagnostic evaluation consisting of pulmonary function testing (PFT) and chest computed tomography (CT). Results Of 89 100 Chiba City residents who underwent lung cancer screening, 72 653 residents were 60 years or older. Among them, 878 (1.0%) were identified with suspected COPD and referred for further evaluation. Of those identified, a total of 567 residents (64.6%, 567/878) underwent further evaluations, and 161 (28.4%) were reported to have COPD, with 38.5% of them requiring COPD treatment. To verify the diagnoses from the secondary evaluation centres, PFT and CT data were collected from 228 study participants, and 24.9% were diagnosed with COPD. CT findings classified according to the Goddard classification revealed that 20.1% of these participants had moderate to severe emphysema. Conclusions COPD screening added to a community-based lung cancer screening programme may be effective in the detection of patients with COPD.

Introduction Carbon ion radiotherapy (CIRT) is a promising modality with excellent localization and significant biologic effects on tumors. Nevertheless, success depends primarily on accurate staging before radiotherapy. Surgical interventions should be avoided in patients considered for CIRT because they usually have multiple comorbidities. The aim of this study was to evaluate the effectiveness of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for lymph node staging in patients with non-small cell lung cancer before CIRT. Methods From April 2005 to December 2007, 49 patients with non-small cell lung cancer considered for CIRT with abnormal positron emission tomography-computed tomography (PET-CT) accumulations in the mediastinum and/or hilum were evaluated by EBUS-TBNA. The convex probe EBUS was used for EBUS-TBNA. Results There were 38 men and 11 women. Their mean age was 75.2 years (range: 55–87). Based on PET-CT, clinical staging was four with N1 disease, 42 with N2 disease, and three with N3 disease. By histology, 26 patients had adenocarcinoma, 19 had squamous cell carcinoma, and four had other histologies. All positive lymph nodes on PET-CT were aspirated (range: 1–5; average 2.55 lymph nodes/patient). EBUS-TBNA diagnosed 43 cases as N0 disease and as a result underwent CIRT. Forty of the 43 cases remained in stable condition without local recurrences (follow-up 6–46 months). The diagnostic accuracy of EBUS-TBNA for lymph node staging was 93.9%. Conclusions EBUS-TBNA offers accurate minimally invasive lymph node staging in patients who are candidates for CIRT. EBUS-TBNA can be safely performed with a high diagnostic accuracy before CIRT.

BACKGROUND: The functional criteria for curative surgery for patients with non-small cell lung cancer (NSCLC) and coexisting chronic obstructive pulmonary disease (COPD) remain controversial. We aimed to clarify long-term outcomes after resection. METHODS: Between January 1990 and April 2005, 36 consecutive patients with NSCLC and severe COPD underwent pulmonary resection. All had severe (30-50 % pred FEV1) or very severe COPD (30 % > pred FEV1) preoperatively. Survival, short- and long-term complications were analyzed retrospectively. Prognostic factors were also analyzed. RESULTS: The 5-year survival rate of these patients was significantly worse than that of patients with better pulmonary function (50 % < pred FEV1) ( P < 0.0001). Patients with interstitial pneumonia (IP) had a significantly poorer prognosis ( P = 0.0099). With regard to long-term complications three months after surgery, 30 % of patients reported worsening of dyspnea, and 20 % experienced pneumonia recurrence. No deaths were related to COPD progression. CONCLUSION: Patients with stage IA NSCLC and severe COPD may undergo curative surgical resection; however, postoperative complications and long-term survival remain unsolved problems. IP is a contraindication for surgery in patients with severe COPD.

While lymph node metastasis is a major factor associated with poor prognosis in cancer, little is known of its molecular mechanisms. The aim of this study was to identify genes differentially expressed between non-cancerous and cancerous lung tissues, and to investigate the gene expression profiles of 41 primary lung adenocarcinomas to select sets of gene predictors for lymph node metastasis of lung cancer. Gene expression profiles were obtained using oligonucleotide microarrays, and predictor sets constructed by evaluating the statistical significance of expression levels of selected genes. Gene analysis revealed 15 predictor genes for lymph node metastasis of lung adenocarcinoma. Using the most suitable set of genes, it was possible to predict the lymph node metastasis of patients with lung cancer. The prediction scoring system yielded 71.4% accuracy for forecasting lymph node metastasis in 14 independent test cases. Survival was also significantly better in 18 cases that were pathologically LN negative and predicted to be LN negative according to molecular classification, compared with 23 cases that were pathologically LN positive or predicted to be LN positive according to molecular classification. Gene expression analysis combined with statistical analysis successfully distinguished lymph node metastasis. The findings of this study showed that pathological diagnosis combined with molecular classification clearly distinguished patients with good prognoses from patients with poor prognoses.

To evaluate the safety, immune responses, and antitumor responses after the administration of α-galactosylceramide (αGalCer) KRN7000-pulsed PBMC cultured with IL-2 and GM-CSF (IL-2/GM-CSF-cultured PBMCs), a phase I-II study in patients with non-small cell lung cancer was conducted. Patients with advanced non-small cell lung cancer or recurrent lung cancer refractory to the standard therapy were eligible. αGalCer-pulsed IL-2/GM-CSF-cultured PBMCs (1 × 109/m2) were i.v. administered four times. Immune responses were monitored weekly. Twenty-three patients were enrolled in this study and 17 cases (73.9%) completed. No severe adverse event related to the treatment was observed. After the injection of αGalCer-pulsed IL-2/GM-CSF-cultured PBMCs, an increased number of IFN-γ-producing cells in the peripheral blood were detected in 10 patients (58.8%). Five cases remained as stable disease, and the remaining 12 cases were evaluated as progressive disease. The estimated median survival time (MST) of the 17 cases was 18.6 mo (range, 3.8 to 36.3 mo). Ten patients who displayed increased IFN-γ-producing cells (≥2-fold) showed prolonged MST (31.9 mo; range, 14.5 to 36.3 mo) as compared with poor-responder patients (n = 7) MST (9.7 mo; range, 3.8 to 25.0 mo) (log-rank test, p = 0.0015). The administration of αGalCer-pulsed IL-2/GM-CSF-cultured PBMCs was well tolerated and was accompanied by the successful induction of NKT cell-dependent immune responses. The increased IFN-γ-producing cells that result from αGalCer stimulation in PBMCs were significantly associated with prolonged MST. These results are encouraging and warrant further evaluation for survival benefit of this immunotherapy.

目的．悪性胸膜中皮腫に対する胸膜肺全摘術の意義を明らかにすることを目的として，その手術成績および予後因子について後ろ向きに検討した.対象．われわれの多施設共同研究グループで胸膜肺全摘術を行った悪性胸膜中皮腫32例を対象とした．結果．症例の内訳は，男性31例，女性1例，平均年齢55.4歳であった.術後合併症は膿胸，横隔膜再建パッチの脱落などがみられ，発症率は56.3%であった.術死は2例（6.3%）にみられた.併用療法は胸腔内灌流温熱化学療法，全身化学療法などを13例（40.6%）に行った.全例の術後累積生存率は，2年および3年がそれぞれ40.1%，16.0%で，中間生存期間は16.2ヵ月であった.予後因子に関する多変量解析では，performance status（Eastern Cooperative Oncology Group）0，N0，手術時間600分未満の3因子が独立した有意の予後良好因子であった.これら3因子を全て持った症例の術後2年および3年生存率は，それぞれ64.8%，51.9%であった．結論．悪性胸膜中皮腫に対する胸膜肺全摘術は患者選択によっては良好な成績が期待できる.

Patients with N2 nonsmall cell lung cancer (N2-NSCLC) represent heterogeneous groups. Survivin is a member of the inhibitor of apoptosis family. If N2-NSCLC patients could be stratified, based on survivin expression and/or its relation to cell cycle proteins, into homogeneous subgroups, certain therapies could be selected for those patients. Survivin expression in 78 surgically resected primary pathological N2-NSCLC tumours was evaluated using immunohistochemistry. Relationships of survivin expression to overall survival, clinical features and expression of six cell cycle-related proteins (pRb, cyclin D1, p16 INK4A , p53, p21 Waf1 and Ki-67) were analysed. Nuclear survivin and the number of mediastinal lymph node (LN) stations were independent prognostic factors. The patient group with combined negative survivin/single mediastinal LN station were the most favourable prognostic group, and was related to the clinical nodal factor. Indeed, patients with negative survivin/low Ki-67 labelling indices had the best survival, especially in nonsquamous histopathology. The current authors conclude that nuclear survivin is strongly related to lymph node metastasis and proliferative potentials in pathological N2 nonsmall cell lung cancer patients. Pre-operative N2 nonsmall cell lung cancer patients with combined negative nuclear survivin and a single mediastinal lymph node station, or low proliferative indices, particularly in clinical N0-1 disease and nonsquamous histopathology, respectively, are expected to have a favourable post-operative prognosis and may be candidates for primary resection.

During a recent investigation of LKB1 gene abnormality in lung lesions, strong expression of LKB1 protein in normal neuroendocrine (NE) cells of the bronchial epithelium was found. Because LKB1 functions as a tumor suppressor gene, the question of whether alteration of LKB1 expression is related to the development of pulmonary NE tumors of various grades was investigated. LKB1 immunohistochemistry was examined in a total of 68 primary pulmonary NE tumors consisting of 30 specimens of small cell lung carcinoma (SCLC), 23 large cell neuroendocrine carcinomas (LCNEC), two atypical carcinoids, and 13 typical carcinoids. Loss or low expression (

Although the histogenesis of sclerosing hemangioma (SH) of the lung is now thought to be respiratory epithelial in origin, the genetic abnormalities that mediate its development are not known. Because pathophysiology of several syndromes associated with benign tumors may converge on the tuberous sclerosis complex (TSC), serine/threonine kinase 11 (STK11), and mammalian target of rapamycin (mTOR) pathways, the purpose of the present paper was to investigate their roles in the development of SH. Semiquantitative immunohistochemical analysis was done to assess the expression of phospho-mTOR, phospho-S6 ribosomal protein, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), phospho-Akt, STK11, tuberin, hamartin, vascular endothelial growth factor (VEGF), and hypoxia-inducible factor-1alpha (HIF-1alpha) in 19 cases of typical SH. To determine whether genetic alteration of STK11 is involved in the development of SH, all encoding exons of STK11 were analyzed by polymerase chain reaction (PCR) amplification and direct sequencing of genomic DNA of six specimens. The six specimens were also investigated for whether promoter hypermethylation exists as an alternative inactivating mechanism for STK11. All specimens showed moderate to marked reaction to phospho-S6 ribosomal protein and PTEN; 16 specimens (84%) showed slight to moderate reaction to phospho-mTOR, negative reaction to STK11, and slight to moderate reaction to hamartin; 11 (58%) showed slight to moderate reaction to phospho-Akt; 18 (95%) showed slight to moderate reaction to tuberin and positive reaction for HIF-1alpha; and 17 (90%) showed moderate reaction to VEGF. No somatic mutation of STK11 was found and the six specimens were unmethylated in the promoter region. These data imply that aberrant mTOR signaling may play a role in the development of SH, and its vascular nature may be due partially to high levels of VEGF caused by dysregulation of mTOR signaling.

Background A phase I/II study was first conducted for the treatment of stage I non-small cell lung cancer (NSCLC) from 1994 to 1999 to determine the optimal dose. On the basis on the results, a phase II study using a regimen of four fractions during 1 week was performed. The purpose of the present study was to determine the local control and 5-year survival rates. Methods From December 2000 to November 2003, 79 patients with 80 primary lesions were treated. Using a fixed dose of 52.8 GyE for stage IA NSCLC and 60.0 GyE for stage IB NSCLC in four fractions during 1 week, the primary tumors were irradiated with carbon beams alone. The average age of the patients was 74.8 years. Sixty-two (78.5%) of these patients were medically inoperable. Local control and survival were determined using the Kaplan-Meier method. The data were statistically processed using the log-rank test. Results All patients were observed for a minimum of 3 years or until death, with a median follow-up time of 38.6 months, ranging from 2.5 to 72.2 months. The local control rate for all patients was 90% (T1: 98%, T2: 80%). The patients' 5-year lung cancer-specific survival rate was 68% (IA: 87%, IB: 42%). The overall survival was 45% (IA: 62%, IB: 25%). Half of the deaths were attributable to intercurrent diseases. No toxic reactions in the lung greater than grade 3 were detected. Conclusion Carbon ion beam radiotherapy with a regimen of four fractions during 1 week has been proven as a valid alternative to surgery for stage I NSCLC and to offer particular benefits, especially for elderly and inoperable patients.

Endobronchial ultrasonography (EBUS) has emerged as a new diagnostic tool that allows the bronchoscopist to see beyond the airway. The radial probe EBUS was first introduced to evaluate the airway structure, which has been shown to be useful for identifying the extent of tumor invasion in the central airway. With advance in technology, smaller radial probes are now available that are capable of visualizing peripheral lung nodules. EBUS is also used as a tool to assist in a biopsy in respiratory diseases. The radial probe EBUS–guided transbronchial needle aspiration (TBNA) increases the yield of TBNA of mediastinal processes. By the use of the ultra-miniature probe EBUS along with the guide sheath, peripheral lung lesions can be accessed without the exposure to radiation. However, it is still not a real-time procedure with target visualization. The newest development is the convex probe EBUS (CP-EBUS) with a curvilinear electronic transducer on the tip of a flexible bronchovideoscope. CP-EBUS allows real-time EBUS-guided TBNA. Although the main indication for EBUS-TBNA is lymph node staging, it can also be used for diagnosis of intrapulmonary tumors, of unknown hilar and/or mediastinal lymphadenopathy, and of mediastinal tumors. To date, there are no reports of complications related to EBUS-guided TBNA. It is a novel approach that has a good diagnostic yield with excellent potential in assisting safe and accurate diagnostic interventional bronchoscopy. The aim of this review is to highlight the current status of the different EBUS techniques available and to discuss the future direction of EBUS.

Using cultured and nude mouse tumor cells (IA) derived from a human lung cancer, we previously demonstrated their radiosensitivity by focusing attention on the dynamics of tumor clonogens and the early and rapid survival recovery (potential lethal damage repair: PLD repair) occurring after X-ray irradiation. To the authors' knowledge, this is the first study demonstrating gene expression in association with PLD repair after carbon-ion beam or X-ray irradiation to cancer cells. In this study we tried to detect the mechanism of DNA damage and repair of the clonogens after X-ray or carbon-ion beam irradiation. At first, colony assay method was performed after irradiation of 12 Gy of X-ray or 5 Gy of carbon-ion beam to compare the time dependent cell survival of the IA cells after each irradiation pass. Second, to search the genes causing PLD repair after irradiation of X-ray or carbon-ion beam, we evaluated gene expressions by using semi-quantitative RT-PCR with the selected 34 genes reportedly related to DNA repair. The intervals from the irradiation were 0, 6, 12 and 24 hr for colony assay method, and 0, 3, 18 hr for RT-PCR method. From the result of survival assays, significant PLD repair was not observed in carbon-ion beam as compared to X-ray irradiation. The results of RT-PCR were as follows. The gene showing significantly higher expressions after X-ray irradiation than after carbon-ion beam irradiation was PCNA. The genes showing significantly lower expressions after X-ray irradiation rather than after carbon-ion beam irradiation were RAD50, BRCA1, MRE11A, XRCC3, CHEK1, MLH1, CCNB1, CCNB2 and LIG4. We conclude that PCNA could be a likely candidate gene for PLD repair.

Background The presence of somatic mutations in epidermal growth factor receptor (EGFR) predicts the effectiveness of EGFR tyrosine kinase inhibitors (TKIs). It would be ideal if an EGFR mutation could be detected in biopsy samples, since the majority of non-small cell lung cancer patients are inoperable at the time of presentation. We have reported the usefulness of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for the lymph node staging of lung cancer. EBUS-TBNA enables the sampling of histologic cores, which can be used for genetic analysis. Methods The purpose of this study was to develop and analyze the feasibility of detecting EGFR mutations in samples obtained by EBUS-TBNA. Forty-six patients with primary lung cancer in whom metastatic adenocarcinoma in the hilar and/or mediastinal lymph node was diagnosed by EBUS-TBNA were enrolled into the study. DNA was extracted from paraffin-embedded samples, and the EGFR mutation was analyzed in exons 19 and 21 using a newly developed loop-hybrid mobility shift assay. The results were confirmed by direct sequencing. Results Forty-three cases were eligible for analysis and in 11 cases, EGFR mutation (25.6%) was detected; one case was an in-frame deletion (E746-A750del) of exon 19, nine cases were point mutations (L858R) of exon 21, and one case was a double point mutation (L858R+L861V). All cases with EGFR mutations were confirmed by direct sequencing. Conclusions EGFR mutation can easily be detected in metastatic lymph nodes sampled by EBUS-TBNA. EBUS-TBNA allows genetic evaluations of tumor cells within the lymph node and may provide us with indications for EGFR-TKI therapy in the near future.

Interleukin-12 receptor beta2 (IL-12Rbeta2) knock-out mice develop lung adenocarcinoma, and epigenetic silencing by CpG methylation leads to loss of this gene in B-cell malignancies. The aim of this study was to determine whether IL-12Rbeta2 methylation is a common feature in human lung cancer.We examined mRNA expression of IL-12Rbeta2 in lung cancer cell lines, and normal bronchial, and tracheal epithelial cells using RT-PCR, and we examined the methylation status of IL-12Rbeta2 in primary lung cancers.Loss of expression was found in 10 of 13 (77%) NSCLC cell lines, and 2 of 5 (40%) SCLC cell lines compared with normal bronchial or tracheal cells. Treatment of 11 expression-negative cell lines with a demethylating agent restored expression in all cases. Aberrant methylation status of IL-12Rbeta2 gene was reversely concordant with its mRNA expression. IL-12Rbeta2 methylation was detected in 96 of 230 primary NSCLCs (42%) and 3 of 6 primary SCLCs (50%). IL-12Rbeta2 methylation correlated with poorer prognosis in lung adenocarcinomas (hazard ratio = 2.33, P = 0.0059).We conclude that epigenetic silencing of IL-12Rbeta2 is a frequent event in lung cancers. Aberrant methylation of this gene seems to be a useful predictor of long-term outcome for adenocarcinoma of the lung.

BACKGROUND. Patients who have pathologic N2 (pN2) nonsmall cell lung cancer (pN2 NSCLC) represent a heterogeneous group with regard to prognosis and treatment. Molecular features of NSCLC seem to be of interest. For the current study, to select an appropriate therapeutic strategy for each patient, patients with N2 NSCLC were stratified into homogenous subgroups according to the expression profiles of cell cycle-related markers. METHODS. The expression levels of retinoblastoma protein (pRb), cyclin D1, p16, p53, and p21 proteins and values of the Ki-67 labeling index were evaluated in 61 primary surgically resected tumor specimens from patients with pN2 NSCLC using immunohistochemistry. The prognostic impact of these markers on overall survival was analyzed in both univariate and multivariate analyses. RESULTS. In univariate analysis, p21, p16, and Ki-67 were correlated significantly with survival. In multivariate analysis, only p21 and p16 influenced survival. Indeed, the group of patients with pN2 NSCLC who were positive for p21 and p16 had the most favorable overall survival (P = .001) and were correlated significantly with the clinical lymph node (cN) status (cN2 disease; P = .008). Moreover, no significant difference in survival was observed between patients with cN0/cN1 disease and patients with cN2 disease within the group (P = .4333). CONCLUSIONS. Loss of control of cell-cycle checkpoints is a common occurrence in pN2 NSCLC. Functional cooperation between different cell-cycle regulators constitutes another level of regulation in cell growth control and tumor suppression. Preoperative patients with pN2 NSCLC, even those with cN2 disease, who have positive p21 and p16 protein expression in their primary tumors are expected to have a favorable postoperative prognosis and may be candidates for primary resection. Cancer 2007. © 2007 American Cancer Society.

A 53-year-old woman was referred to Matsudo City Hospital for palliative care of stage IVb invasive thymoma with multiple pulmonary metastases and dissemination. Moderate doses of corticosteroid were administered for palliative effects during the preterminal stage of the disease for 2 years. The thymoma progressed slowly but continuously. At age 55, she was admitted to our hospital for a whole-body eruption and high body temperature. We could not identify the pathogen or allergen. Based on the results of a skin biopsy, with the exception of corticosteroid we stopped administering all suspicious medications, including folk medicines. After 1 month of antipyretic therapy, whole-body eruption disappeared and we encountered rapid regression of the thymoma. Unfortunately she died of interstitial pneumonitis only 2 months after the regression.

Purpose: A phase I/II study on carbon ion radiotherapy for Stage I non–small-cell lung cancer (NSCLC) was first conducted between 1994 and 1999 and determined the optimal dose. Second, a Phase II study using the optimal dose was performed. The purpose of the present study was to clarify the local control and 5-year survival rates. Methods and Materials: Between April 1999 and December 2000, 50 patients with 51 primary lesions were treated. Using a fixed dose of 72 GyE in nine fractions over 3 weeks, the primary tumors were irradiated with carbon ion beams alone. The average age of the patients was 74.5 years. Thirty-three (66%) of these were medically inoperable. Local control and survival were determined by using the Kaplan-Meier method and the data were statistically processed by using the log–rank test. Results: All patients were observed for a minimum of 5 years or until death with a median follow-up time of 59.2 months (range, 6.0–83.0 months). The local control rate for all patients was 94.7%. The patients’ 5-year cause-specific survival rate was 75.7% (IA: 89.4; IB: 55.1), and overall survival 50.0% (IA: 55.2; IB: 42.9). No toxic reactions in the lung greater than Grade 3 were detected. Conclusions: Carbon ion radiotherapy, a new treatment modality with superior benefits in terms of quality of life and activity of daily living, has been proven as a valid alternative to surgery for Stage I NSCLC and to offer particular benefits, especially for elderly and inoperable patients.

A diagnosis of sarcoidosis should be substantiated by pathological means in order to thoroughly exclude other diseases. The role of real-time endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the diagnosis of sarcoidosis has not been reported. The purpose of the present study is to evaluate the diagnostic yield of EBUS-TBNA in demonstrating the pathological features of sarcoidosis. In total, 65 patients with suspected sarcoidosis, with enlarged hilar or mediastinal lymph nodes on computed tomography, were included in the study. Patients with a suspected or known malignancy or previously established diagnosis of sarcoidosis were excluded. Convex probe endobronchial ultrasonography integrated with a separate working channel was used for EBUS-TBNA. Surgical methods were performed in those in whom no granulomas were detected by EBUS-TBNA. Patients were followed up clinically. EBUS-TBNA was performed on a total of 77 lymph node stations in 65 patients. A final diagnosis of sarcoidosis was made for 61 (93.8%) of the patients. The remaining four patients were diagnosed as having Wegener9s granulomatosis (n = 1) or indefinite (n = 3). In patients with a final diagnosis of sarcoidosis, EBUS-TBNA demonstrated noncaseating epithelioid cell granulomas in 56 (91.8%) of the patients. No complications were reported. Endobronchial ultrasound-guided transbronchial needle aspiration proved to be a safe procedure with a high yield for the diagnoses of sarcoidosis.

蛍光気管支内視鏡の開発により，白色光観察単独では発見が困難であった，preinvasive bronchial lesionの検出が容易になった．蛍光気管支内視鏡技術はさらなる発展を遂げ，気管支ファイバースコープの観察から気管支ビデオスコープを用いた観察に移行しており，高画質，多機能化が図られただけでなく，操作性も向上している．蛍光気管支内視鏡は，preinvasive bronchial lesionの早期発見のみならず，光線力学的治療や手術を目的とした悪性病変の進展範囲の正確な判定にも使用される．蛍光気管支内視鏡が多くの施設で使用されるようになってきたことから，内視鏡画像所見についての所見分類の必要性が高まっている．本稿では現在市販されている気管支ビデオスコープを使用する2機種について，代表的な画像所見を挙げ解説する．蛍光気管支内視鏡検査の実施にあたっては，使用する機器の特徴を十分にふまえたうえで，施行することが望ましい．本報告をもとに次回の肺癌取扱い規約では，蛍光気管支内視鏡画像所見分類（案）を追加する予定である．

気管支squamous dysplasiaや上皮内癌(CIS)も含む肺門部早期肺癌など微小病変の早期診断や気管支粘膜表面の毛細血管を明瞭に描出する新たな呼吸器内視鏡領域における特殊光観察—蛍光観察AFIと狭帯域観察NBIを行っている。気管支ビデオスコープを使用するAFIでは，高画質，高解像度の鮮明な画像が得られ，肺門部早期肺癌に加えsquamous dysplasiaの早期診断が可能となった。腫瘍の進展範囲の詳細な把握も可能で，光線力学的治療の照射部位や手術症例の正確な切除範囲の決定に有用である。NBIは青色光へのHbの強い吸収特性を利用し，気管支粘膜表面の微細構造，特に毛細血管を明瞭に描出する。dysplasiaにおける血管網の増生，蛇行，錯綜に加え点状血管が確認され，dysplasia, CIS, micro invasive cancer, invasive cancerと進展するにつれて点状血管，ループ状の腫瘍血管増生が明らかになった。これらは癌の進展に比例し増大している。扁平上皮癌の多段階発癌におけるangiogenesisが内視鏡的に捉えられた。

背景．胸腺癌は比較的稀な腫瘍であり，特に進行期症例では，その治療法は未だ確立されていない．症例．55歳男性．職場健診にて胸部異常影を指摘され当科紹介となった．胸部X線写真では左肺門部に巨大な腫瘤影を認め，CTでは前縦隔から左胸腔内に大きく突出する長径9.5 cmの腫瘤影を認めた．腫瘤は左腕頭静脈，大動脈，肺動脈起始部と接して存在しており，各々への浸潤を疑った．また腫瘍マーカーはAFP：24.9 ng/ml，NSE：26.0 ng/ml，CYFRA：34.0 ng/mlと高値を示しており前縦隔腫瘍の診断にて入院となった．入院後，経皮的吸引細胞診及び組織診を行い，胸腺癌（正岡III期）と診断した．CDDP＋VNRによる化学療法を2コース施行したところ著明な腫瘍の縮小を認め，腫瘍マーカーも正常範囲となったため，腫瘍を左肺上葉とともにen blocに摘出した．病理診断は胸腺未分化癌であった．術後放射線治療及び化学療法を施行し，現在術後12ヶ月が経過したが再発なく，元気に社会復帰している．結論．進行期胸腺癌症例では，術前化学療法に外科切除術の併用が治療の1選択肢となる可能性が示唆された．

RRAD, a small Ras-related GTPase, is highly expressed in human skeletal muscle, lung, and heart. Although loss of expression of RRAD in breast cancer cells has been reported and it may act as an oncogene, the mechanism of silencing is unknown. We examined (1) mRNA expression of RRAD in lung and breast cancer cell lines using RT-PCR and (2) methylation status of lung and breast cancers. Loss of RRAD expression was found in 14 of 20 (70%) NSCLC cell lines, 11 of 11 (100%) SCLC cell lines, and 8 of 10 (80%) breast cancer cell lines; expression was not affected in normal bronchial and mammary epithelial cells. Treatment of 23 expression-negative cell lines with a demethylating agent restored expression in all cases. We developed a methylation-specific assay from the analysis of bisulfite sequencing of the 5′ region of RRAD in expression-negative and positive cell lines, which resulted in good concordance between methylation and expression. Primary lung and breast cancers showed hypermethylation in 89 of 214 (42%) and 39 of 63 (62%) cases, respectively. RRAD hypermethylation correlated with smoking history and poorer prognosis in lung adenocarcinomas. We conclude that epigenetic silencing of RRAD is a frequent event in lung and breast cancers, and analysis of it may provide novel opportunities for prognosis and therapy of these cancers.

Background Patients with pulmonary large cell neuroendocrine carcinoma (LCNEC) have a very poor prognosis, but the benefit of adjuvant chemotherapy for these patients has not been established. We performed a prospective analysis of adjuvant chemotherapy for patients with completely resected pulmonary LCNECs to assess the effect of adjuvant chemotherapy. Methods The adjuvant mixture consisted of cisplatin and VP-16 and was administered after surgery to 15 patients with LCNECs from 2000 to 2005. We compared patient survival with historical data for LCNEC patients treated without platinum-based adjuvant chemotherapy after surgery. Results There were no differences in age, gender, surgical methods, and staging between the adjuvant chemotherapy group and the control group. Median follow-up was 33 months for the adjuvant group and 42 months for the control group. Of the 15 patients in the adjuvant chemotherapy group, 2 patients had disease recurrence and 1 died of interstitial pneumonia. The overall survival rate at 2 and 5 years of patients with adjuvant chemotherapy was 88.9%. The overall survival rate between patients with adjuvant chemotherapy and the historical control group was significantly different. Conclusions Adjuvant chemotherapy consisting of cisplatin and VP-16 after surgery appears promising for the improvement of the prognosis for patients with completely resected LCNECs, and it should be evaluated further in larger multi-institutional trials.

Purpose: Human Vα24 natural killer T (Vα24 NKT) cells bearing an invariant Vα24JαQ antigen receptor are activated by a glicolipid ligand α-galactosylceramide (αGalCer; KRN7000) in a CD1d-dependent manner. The human Vα24 NKT cells activated with αGalCer and interleukin-2 have been shown to produce large amounts of cytokines, such as IFN-γ, and also exerting a potent killing activity against various tumor cell lines. We did a phase I study with autologous activated Vα24 NKT cell therapy.Experimental Design: Patients with advanced or recurrent non–small cell lung cancer received i.v. injections of activated Vα24 NKT cells (level 1: 1 × 107/m2 and level 2: 5 × 107/m2) to test the safety, feasibility, and clinical response of this therapeutic strategy. Immunomonitoring was also done in all cases.Results: Six patients were enrolled in this study. No severe adverse events were observed during this study in any patients. After the first and second injection of activated Vα24 NKT cells, an increased number of peripheral blood Vα24 NKT cells was observed in two of three cases receiving a level 2 dose of activated Vα24 NKT cells. The number of IFN-γ-producing cells in peripheral blood mononuclear cells increased after the administration of activated Vα24 NKT cells in all three cases receiving the level 2 dose. No patient was found to meet the criteria for either a partial or a complete response.Conclusions: The clinical trial with activated Vα24 NKT cell administration was well tolerated and carried out safely with minor adverse events even in patients with advanced diseases.

The purpose of this study was to clarify the clinical benefits of perioperative administration of high-dose prednisolone (PSL) combined with extended thymectomy on the long-term outcomes of 116 consecutive patients with generalized myasthenia gravis (MG).A retrospective review was conducted on 116 patients diagnosed with generalized MG who received alternate-day oral administration of high-dose PSL (100 mg/alternate days) and had undergone transsternal extended thymectomy. Incidences of postoperative myasthenic crisis, adverse effects of steroid, long-term outcomes, such as complete stable remission (CSR), pharmacologic remission (PR) or improvement (Imp), and disease recurrence after CSR were evaluated.Six patients (5.2%) experienced post-thymectomy myasthenic crisis. Crude cumulative CSR and PR + CSR rates were 44.8 and 62.7%, respectively. Life table analysis showed that 41.8, 52.8 and 63.4% of the patients were in CSR at 3, 5 and 10 years, respectively. Multivariate analysis revealed that age and pretreatment classification according to the Myasthenia Gravis Foundation of America (MGFA) criteria tended to be independent predictors of CSR. There were 6.9% with compressive vertebral fracture, 13.8% with cataract, and 5.2% with steroid-induced diabetes. Life table analysis revealed that recurrence rates after CSR were 36.8 and 46.0% at 3 and 5 years, respectively. Patients with thymoma had a significantly higher rate of recurrence than those without thymoma (p = 0.001).Alternate-day administration of high-dose prednisolone reduced the risk of post-thymectomy myasthenic crisis. Presence of thymoma was a risk factor for MG recurrence after CSR.

Purpose. The characteristics of tumor extension determine whether pneumonectomy or lobectomy with bronchoplasty should be performed for central lung cancer. We investigated how the characteristics of tumor extension determined the operative methods and the surgical outcomes. Methods. We conducted a retrospective chart review of 151 patients with positive bronchoscopic findings who underwent lung cancer operations between January 1995 and March 2002. Twenty-five patients underwent pneumonectomy, 88 underwent lobectomy/segmentectomy (Lob/Seg), and 38 underwent Lob/Seg with bronchoplasty. Results. Pathologic staging was higher in the pneumonectomy group than in the Lob/Seg groups, with or without bronchoplasty (P = 0.002). Interlobar extension and hilar lymph node involvement were more frequent, and mucosal invasion was less frequent, in the pneumonectomy group than in the Lob/Seg with bronchoplasty group. The frequencies of all specific pulmonary complications and 30-day mortality were similar among the three groups. The 5-year overall survival rates were 23.7%, 51.5%, and 72.8% for the pneumonectomy, Lob/Seg, and Lob/Seg with bronchoplasty groups, respectively (P = 0.0004). There was a significant difference in survival between patients with mucosal and those with submucosal types of lung cancer (P = 0.0114). Conclusions. Lob/Seg with bronchoplasty was feasible without a higher risk of operative complications or poorer long-term survival. The nature of tumor extension was important in the selection of operative methods and in predicting survival.