Yoshikazu Kotani

Predictive value of dose-volume histogram parameters for predicting radiation pneumonitis after concurrent chemoradiation for lung cancer.

PURPOSE To clarify whether the percentage of pulmonary volume irradiated to >20 Gy (V20) is related to the incidence and grade of radiation pneumonitis (RP) in cases of lung cancer treated with concurrent chemoradiation. METHODS AND MATERIALS The subjects comprised 71 patients with lung cancer who were treated with conventionally fractionated definitive concurrent chemoradiation. The chemotherapy agents were carboplatin or cisplatin combined with taxane for most patients. Radiotherapy was delivered at 1.8-2.0 Gy fractions once daily to a total of 48-66 Gy (median 60). We analyzed the relation between RP grade and V20. Univariate and multivariate analyses were performed to assess patient- and treatment-related factors, including age, gender, smoking history, pulmonary function (forced expiratory volume in 1 s), tumor location (upper lobe vs. middle/lower lobe), chemotherapy regimen (platinum + taxane vs. other), total dose, overall radiation periods in addition to V20. RESULTS With a median follow-up of 7.5 months, an RP grade of 0, 1, 2, 3, and 5 was observed in 16, 35, 17, 1, and 2 patients, respectively; the corresponding mean V20 values were 20.1%, 22.0%, 26.3%, 27.0%, and 34.5%. The 6-month cumulative incidence of RP greater than Grade 2 was 8.7%, 18.3%, 51%, and 85% in patients with a V20 of <or=20%, 21-25%, 26-30%, and >or=31%, respectively (p <0.0001). According to both univariate and multivariate analyses, V20 was the only factor associated with RP of Grade 2 or greater. CONCLUSION The incidence and grade of RP are significantly related to the V20 value. Thus, V20 appears to be a factor that can be used to predict RP after concurrent chemoradiation for lung cancer.

Non–Small Cell Lung Cancer: Whole-Body MR Examination for M-Stage Assessment—Utility for Whole-Body Diffusion-weighted Imaging Compared with Integrated FDG PET/CT

PURPOSE To prospectively and directly compare the capability of whole-body diffusion-weighted (DW) imaging, whole-body magnetic resonance (MR) imaging with and that without DW imaging, and integrated fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) for M-stage assessment in non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS The institutional review board approved this study; informed consent was obtained from patients. A total of 203 NSCLC patients (109 men, 94 women; mean age, 72 years) prospectively underwent whole-body DW imaging, whole-body MR imaging, and FDG PET/CT. Final diagnosis of the M-stage in each patient was determined on the basis of results of all radiologic and follow-up examinations. Two chest radiologists and two nuclear medicine physicians independently assessed all examination results and used a five-point visual scoring system to evaluate the probability of metastases. Final diagnosis based on each of the methods was made by consensus of two readers. Receiver operating characteristic (ROC) analysis was used to compare the capability for M-stage assessment among whole-body DW imaging, whole-body MR imaging with and that without DW imaging, and PET/CT on a per-patient basis. Sensitivity, specificity, and accuracy were compared with the McNemar test. RESULTS Area under ROC curve (A(z)) values of whole-body MR imaging with DW imaging (A(z) = 0.87, P = .04) and integrated FDG PET/CT (A(z) = 0.89, P = .02) were significantly larger than that of whole-body DW imaging (A(z) = 0.79). Specificity and accuracy of whole-body MR imaging with (specificity, P = .02; accuracy, P < .01) and that without DW imaging (specificity, P = .02; accuracy, P = .01) and integrated FDG PET/CT (specificity, P < .01; accuracy, P < .01) were significantly higher than those of whole-body DW imaging. CONCLUSION Whole-body MR imaging with DW imaging can be used for M-stage assessment in NSCLC patients with accuracy as good as that of PET/CT.

A metabolomic approach to lung cancer

Lung cancer is one of the most common cancers in the world, but no good clinical markers that can be used to diagnose the disease at an early stage and predict its prognosis have been found. Therefore, the discovery of novel clinical markers is required. In this study, metabolomic analysis of lung cancer patients was performed using gas chromatography mass spectrometry. Serum samples from 29 healthy volunteers and 33 lung cancer patients with adenocarcinoma (n=12), squamous cell carcinoma (n=11), or small cell carcinoma (n=10) ranging from stage I to stage IV disease and lung tissue samples from 7 lung cancer patients including the tumor tissue and its surrounding normal tissue were used. A total of 58 metabolites (57 individual metabolites) were detected in serum, and 71 metabolites were detected in the lung tissue. The levels of 23 of the 58 serum metabolites were significantly changed in all lung cancer patients compared with healthy volunteers, and the levels of 48 of the 71 metabolites were significantly changed in the tumor tissue compared with the non-tumor tissue. Partial least squares discriminant analysis, which is a form of multiple classification analysis, was performed using the serum sample data, and metabolites that had characteristic alterations in each histological subtype and disease stage were determined. Our results demonstrate that changes in metabolite pattern are useful for assessing the clinical characteristics of lung cancer. Our results will hopefully lead to the establishment of novel diagnostic tools.

Inhalation of sphingosine kinase inhibitor attenuates airway inflammation in asthmatic mouse model

Sphingosine 1-phosphate (S1P) produced by sphingosine kinase (SPHK) is implicated in acute immunoresponses, however, mechanisms of SPHK/S1P signaling in the pathogenesis of bronchial asthma are poorly understood. In this study, we hypothesized that SPHK inhibition could ameliorate lung inflammation in ovalbumin (OVA)-challenged mouse lungs. Six- to eight-week-old C57BL/6J mice were sensitized and exposed to OVA for 3 consecutive days. Twenty-four hours later, mice lungs and bronchoalveolar lavage (BAL) fluid were analyzed. For an inhibitory effect, either of the two different SPHK inhibitors, N,N-dimethylsphingosine (DMS) or SPHK inhibitor [SK-I; 2-(p-hydroxyanilino)-4-(p-chlorophenyl) thiazole], was nebulized for 30 min before OVA inhalation. OVA inhalation caused S1P release into BAL fluid and high expression of SPHK1 around bronchial epithelial walls and inflammatory areas. DMS or SK-I inhalation resulted in a decrease in S1P amounts in BAL fluid to basal levels, accompanied by decreased eosinophil infiltration and peroxidase activity. The extent of inhibition caused by DMS inhalation was higher than that caused by SK-I. Like T helper 2 (Th2) cytokine release, OVA inhalation-induced increase in eotaxin expression was significantly suppressed by DMS pretreatment both at protein level in BAL fluid and at mRNA level in lung homogenates. Moreover, bronchial hyperresponsiveness to inhaled methacholine and goblet cell hyperplasia were improved by SPHK inhibitors. These data suggest that the inhibition of SPHK affected acute eosinophilic inflammation induced in antigen-challenged mouse model and that targeting SPHK may provide a novel therapeutic tool to treat bronchial asthma.

Dosimetric predictors of radiation esophagitis in patients treated for non-small-cell lung cancer with carboplatin/paclitaxel/radiotherapy

PURPOSE To establish dosimetric predictors of radiation esophagitis (RE) in patients treated with a combination of carboplatin, paclitaxel, and radiotherapy. METHODS AND MATERIALS Three-dimensional radiotherapy plans of 26 patients with non-small-cell lung cancer who received 50-60 Gy of radiotherapy concurrently with weekly administration of carboplatin (AUC 2) and paclitaxel (40-45 mg/m(2)) were reviewed in conjunction with RE. The factors analyzed included the following: percentages of organ volumes receiving >40 Gy (V40), >45 Gy (V45), >50 Gy (V50), and >55 Gy (V55); the length of esophagus (total circumference) treated with >40 Gy (LETT40), >45 Gy (LETT45), >50 Gy (LETT50), and >55 Gy (LETT55); the maximum dose in the esophagus (Dmax); and the mean dose in the esophagus (Dmean). Data were obtained on the basis of superposition algorithm. RESULTS All factors except Dmax showed statistical correlation with RE. Good correlations were shown between RE and LETT45 (rho = 0.714) and V45 (rho = 0.686). CONCLUSIONS LETT45 and V45 appear to be useful dosimetric predictors of RE. It is also suggested that Dmax does not predict RE.

β2-Adrenergic Receptor Polymorphisms Affect Airway Responsiveness to Salbutamol in Asthmatics

We examined the beta2-adrenergic receptor (beta2AR) polymorphisms (Arg16-->Gly, Gln27-->Glu) and clinical status for 117 asthmatics. Airway responsiveness to methacholine and beta2-agonists was evaluated with Astograph. The atopic factors, pulmonary function test, and airway responsiveness to methacholine did not differ significantly among the different beta2AR genotypes. Asthmatics homozygous for Gly16 showed significantly lower airway responsiveness to inhaled salbutamol than those heterozygous for Arg/Gly16 or homozygous for Arg16. Asthmatics heterozygous for Gln/Glu27 had significantly later asthma onsets than those homozygous for Gln27. These results suggest that beta2AR polymorphisms play an important role in the airway responsiveness to inhaled beta2-agonist and the initial asthma onset.

Whole-body MR imaging vs. FDG-PET: Comparison of accuracy of M-stage diagnosis for lung cancer patients†

To conduct a prospective comparison of the accuracy of whole‐body MR imaging and positron emission tomography (PET) with fluorine‐18 deoxyglucose (FDG) (FDG‐PET) to assess the M‐stage in lung cancer patients.

Postoperative Lung Function in Lung Cancer Patients: Comparative Analysis of Predictive Capability of MRI, CT, and SPECT

OBJECTIVE The purpose of this study was to prospectively compare the utility of dynamic contrast-enhanced perfusion MRI in the prediction of postoperative lung function in patients with lung cancer with the utility of quantitative and qualitative assessment of CT and perfusion SPECT. SUBJECTS AND METHODS One hundred fifty lung cancer patients (87 men, 63 women) underwent dynamic perfusion MRI, MDCT, perfusion SPECT, and measurement of preoperative and postoperative forced expiratory volume in the first second of expiration (FEV1) expressed as percentage of predicted value. Postoperative FEV1 was predicted with dynamic perfusion MRI by semiquantitative assessment of the perfusion of whole lungs and resected segments of lungs, with quantitative assessment of functional lung volume on CT with commercially available software, with qualitative assessment of CT on the basis of the number of segments of total and resected lung, and with perfusion SPECT by assessment of uptake of microaggregated albumin particles in whole lungs and resected segments of lungs. Correlation and limits of agreement between actual and predicted postoperative FEV1 values were statistically evaluated. RESULTS Actual postoperative FEV1 had stronger correlation with postoperative FEV1 predicted from perfusion MRI (r = 0.87, p < 0.0001) and quantitative CT (r = 0.88, p < 0.0001) than with postoperative FEV1 predicted from qualitative CT (r = 0.83, p < 0.0001) and perfusion SPECT (r = 0.83, p < 0.0001). The limits of agreement between the actual postoperative FEV1 and postoperative FEV1 predicted from perfusion MRI (5.3% +/- 11.8% [mean +/- 2 SD]) were smaller than the values for postoperative FEV1 predicted from qualitative CT (6.8% +/- 14.4%) and perfusion SPECT (5.1% +/- 14.0%) and was almost equal to the value for postoperative FEV1 predicted from quantitative CT (5.0% +/- 11.6%). CONCLUSION Dynamic perfusion MRI is more accurate in prediction of the postoperative lung function of patients with lung cancer than are qualitative CT and perfusion SPECT and may be at least as accurate as quantitative CT.

Phase III Study Comparing Amrubicin Plus Cisplatin With Irinotecan Plus Cisplatin in the Treatment of Extensive-Disease Small-Cell Lung Cancer: JCOG 0509

PURPOSE This randomized phase III trial was conducted to confirm noninferiority of amrubicin plus cisplatin (AP) compared with irinotecan plus cisplatin (IP) in terms of overall survival (OS) in chemotherapy-naive patients with extensive-disease (ED) small-cell lung cancer (SCLC). PATIENTS AND METHODS Chemotherapy-naive patients with ED-SCLC were randomly assigned to receive IP, composed of irinotecan 60 mg/m(2) on days 1, 8, and 15 and cisplatin 60 mg/m(2) on day 1 every 4 weeks, or AP, composed of amrubicin 40 mg/m(2) on days 1, 2, and 3 and cisplatin 60 mg/m(2) on day 1 every 3 weeks. RESULTS A total of 284 patients were randomly assigned to IP (n = 142) and AP (n = 142) arms. The point estimate of OS hazard ratio (HR) for AP to IP in the second interim analysis exceeded the noninferior margin (HR, 1.31), resulting in early publication because of futility. In updated analysis, median survival time was 17.7 (IP) versus 15.0 months (AP; HR, 1.43; 95% CI, 1.10 to 1.85), median progression-free survival was 5.6 (IP) versus 5.1 months (AP; HR, 1.42; 95% CI, 1.16 to 1.73), and response rate was 72.3% (IP) versus 77.9% (AP; P = .33). Adverse events observed in IP and AP arms were grade 4 neutropenia (22.5% v 79.3%), grade 3 to 4 febrile neutropenia (10.6% v 32.1%), and grade 3 to 4 diarrhea (7.7% v 1.4%). CONCLUSION AP proved inferior to IP in this trial, perhaps because the efficacy of amrubicin as a salvage therapy was differentially beneficial to IP. IP remains the standard treatment for extensive-stage SCLC in Japan.

Inhalation of urokinase-type plasminogen activator reduces airway remodeling in a murine asthma model

The airway remodeling that occurs in asthma is characterized by an excess of extracellular matrix deposition in the submucosa, hyperplasia/hypertrophy of smooth muscle, goblet cell metaplasia, and accumulation of fibroblasts/myofibroblasts. The urokinase-type plasminogen activator (uPA)/plasmin system participates in pericellular proteolysis and is capable of directly degrading matrix components, activating latent proteinases, and activating growth factors. In a mouse ovalbumin (OVA) asthma model, we increased plasminogen activator activity in the lung by administering exogenous uPA or by using mice genetically deficient in the uPA inhibitor plasminogen activator inhibitor-1 (PAI-1) to assess the role of this system in asthma pathogenesis. After intraperitoneal OVA sensitization, mice inhaled OVA plus uPA (500 IU/mouse) or saline by ultrasonic nebulization for 3 wk. When studied 24 h after the final exposure, the groups with upregulated plasmin activity had significantly reduced subepithelial fibrosis within the airway walls and had decreased airway hyperresponsiveness (AHR) to methacholine. Morphometric analysis showed that subepithelial wall thickening of the bronchi (subepithelial area ratio) was also reduced, as were collagen and alpha-smooth muscle actin. Upregulation of plasmin activity also increased the level of hepatocyte growth factor activity in bronchoalveolar lavage fluid, whereas the release of transforming growth factor-beta was decreased. The administration of uPA 1 wk after the last OVA inhalation also significantly reduced lung hydroxyproline content and AHR. These results show that enhancing uPA/plasmin activity lessens the airway remodeling in a murine asthma model.