Masatoshi Kakihana

Early detection of bronchial lesions using system of autofluorescence endoscopy (SAFE) 1000

Recently several endoscopic fluorescence detection systems have been developed. In some of them, laser light was used for the excitation of autofluorescence, and sophisticated techniques were also necessary to amplify the fluorescence signal as well. The result of fluorescence diagnosis using a simple system with a conventional Xenon lamp excitation and an image intensifier is reported. The respective results of sensitivity and positive predictive values of cancer plus dysplasia were 66%, and 62% by standard bronchoscopy and 92% and 88% by the newly developed autofluorescence system. In this paper, developed endoscope for detection of tissue/mucosal autofluorescence without the application of any photosensitizing agents or use of any lasers is evaluated.

Pathological Vascular Invasion and Tumor Differentiation Predict Cancer Recurrence in Stage ia Non–Small-Cell Lung Cancer After Complete Surgical Resection

Introduction: The appropriate therapeutic strategy and postoperative management for patients with stage IA non–small-cell lung cancer (NSCLC) still remain a matter of debate because of the prognostic heterogeneity of this population, including the risk of cancer recurrence. The objective of the current study was to identify the clinicopathological factors that affect overall prognosis and cancer recurrence of stage IA NSCLC. Methods: We reviewed the data of 532 patients in whom complete resection of stage IA NSCLC had been performed. Overall survival and recurrence-free proportion (RFP) were estimated using the Kaplan–Meier method. RFP was estimated from the date of the primary tumor resection to the date of the first recurrence or last follow-up. We performed univariate and multivariate analyses to determine the independent prognostic factors. Results: On multivariate analyses, three variables were shown to be independently significant recurrence risk factors: histological differentiation (hazard ratio [HR] = 1.925), blood-vessel invasion (HR = 1.712), and lymph-vessel invasion (HR = 1.751). On subgroup analyses combining these risk factors, the 5-year RFP was 91.3% for patients with no risk factors, 79.5% for those with either poorly differentiated carcinoma or vascular invasion, (p < 0.001 for both), and 62.9% for those with both poorly differentiated carcinoma and vascular invasion (p = 0.068). Conclusion: These results indicated that vascular invasion and tumor differentiation have a significant impact on the prediction of cancer recurrence in patients with stage IA NSCLC. Patients with these predictive factors of recurrence may be good candidates for adjuvant chemotherapy.

Histopathological evaluation of fluorescence bronchoscopy using resected lungs in cases of lung cancer.

Objective evaluation of the performance of autofluorescence bronchoscopy based on analysis of thin sections of the bronchus of resected lungs was performed and compared with the results of preoperative autofluorescence bronchoscopy. Conventional bronchoscopy and autofluorescence bronchoscopy were performed prior to surgery for lung cancer. Thin sections of the bronchus were obtained from the resected specimens. The thin sections were pathologically analyzed and the diagnostic accuracy of endoscopy was calculated. The subjects were 30 consecutive operable lung cancer cases who received white light and autofluorescence bronchoscopy before operation. A total of 163 thin sections of the bronchi in the resected lungs were made. The sensitivity of white light bronchoscopy for cancer was 90 and 31% for dysplasia. The respective figures for autofluorescence bronchoscopy were 97 and 50% for cancer and dysplasia. The specificity of white light and autofluorescence was 88 and 84%, respectively. The diagnostic accuracy of autofluorescence bronchoscopy was objectively confirmed. Autofluorescence examination showed better sensitivity for cancerous/precancerous lesions and the evaluation of the extent of cancer invasion was accurate.

Prognostic impact of number of resected and involved lymph nodes at complete resection on survival in non-small cell lung cancer.

Background: Lymph node (LN) status is a major determinant of stage and survival in patients with lung cancer. In the 7th edition of the TNM Classification of Malignant Tumors, the number of involved LNs is included in the definition of pN factors in breast, stomach, esophageal, and colorectal cancer, and the pN status significantly correlates with prognosis. Methods: We retrospectively investigated the prognostic impact of the number of resected LNs (RLNs) and involved LNs in the context of other established clinical prognostic factors, in a series of 928 consecutive patients with non-small cell lung cancer (NSCLC) who underwent complete resection at our institution between 2000 and 2007. Results: The mean number of RLNs was 15. There was a significant difference in the total number of RLNs categorized between less than 10 and ≥10 (p = 0.0129). Although the incidence of LN involvement was statistically associated with poor prognosis, the largest statistically significant increase in overall survival was observed between 0 to 3 and ≥4 involved LNs (hazard ratio = 7.680; 95% confidence interval = 5.051–11.655, p < 0.0001). On multivariate analysis, we used the ratio between the number of involved LNs and RLNs. The number of RLNs was found to be a strong independent prognostic factor for NSCLC (hazard ratio = 6.803; 95% confidence interval = 4.137–11.186, p < 0.0001). Conclusion: Complete resection including 10 or more LNs influenced survival at complete NSCLC resection. Four involved LNs seemed to be a benchmark for NSCLC prognosis. The number of involved LNs is a strong independent prognostic factor in NSCLC, and the results of this study may provide new information for determining the N category in the next tumor, node, metastasis classification.

Klotho predicts good clinical outcome in patients with limited-disease small cell lung cancer who received surgery

BACKGROUND The important role of surgery in early-stage small cell lung cancer (SCLC) has been recognized, and curative surgical resection is recommended. However, the role of adjuvant chemotherapy for stage I SCLC has not yet been evaluated, and novel approaches focusing on the specific genomic characteristics of SCLC may be invaluable for customized therapy. In this study, we focused on the Klotho gene, which is an anti-aging gene known to be a potential tumor suppressor. We investigated whether the expression of Klotho, assessed by immunohistochemistry, can predict survival in patients with resected SCLC. METHODS The medical records of patients diagnosed as having limited-disease (LD) SCLC and treated by surgical resection (n=30) at Tokyo Medical University Hospital were retrospectively reviewed. The expression status of Klotho, and of the ATP-binding cassette (ABC) transporters MRP1, MDR and breast cancer resistant protein (BCRP), which can cause resistance to anticancer drugs, including irinotecan, was assessed by immunohistochemical analysis in resected surgical specimens of patients with early-stage SCLC. RESULTS Of the 30 patients, Klotho expression was seen in the specimens from 18 patients (60.0%), but not in those of the remaining 12 patients (40.0%). The immunostaining for Klotho was mostly localized in the cytoplasm. The expression of Klotho was significantly associated with the overall survival (OS) (ratio 0.088; 95% confidence interval 0.019-0.409; P=0.002). The administration of perioperative chemotherapy had no significant effect in improving the survival, as assessed by the Kaplan-Meier method. However, the patients showing Klotho expression in the resected specimens in p-stage I and II, may have benefited from perioperative chemotherapy. A multivariate analysis revealed no significant association between the expression status of MRP1, MDR or BCRP and the OS. CONCLUSION Expression of Klotho was predictive of a favorable outcome following resection in limited-disease SCLC patients, and the Klotho expression status may serve as a new biomarker for the need of additional therapies to be developed in the future.

Impact of visceral pleural invasion on the survival of patients with non-small cell lung cancer.

BACKGROUND In this study, we investigated visceral pleural invasion (VPI) as a poor prognostic factor in patients with non-small cell lung cancer (NSCLC) according to the 7th edition of the TNM classification. METHODS Between January 2000 and December 2007, 886 consecutive patients with pathological T1a-T2b NSCLC underwent complete resection with systematic lymph node dissection in Tokyo Medical University. We statistically analyzed the association between VPI and clinicopathologic factors, or clinical outcomes. RESULTS The 5-year overall survival (OS) rates of the pl0, pl1, and pl2 patients were 80.8%, 63.7%, and 49.6%, respectively, with significant differences between pl0 and pl1 (p=0.002), pl1 and pl2 (p=0.03). Thus, the pl1 and pl2 patient groups were defined as patients with VPI. VPI was found to be a significant independent prognostic factor by multivariate survival analysis (p=0.0002). In patients with tumors ≤3 cm, especially with tumors ≤2 cm, VPI was significantly associated with an increased rate of lymph node metastasis, compared with non-VPI (p=0.0003 and p=0.015, respectively). Analysis of the OS of patients stratified by tumor size (≤3 cm, 3.1-5 cm, 5.1-7 cm) and VPI status showed that in any nodal status, patients with 3.1-5 cm/VPI tumors had significantly worse survival than patients with ≤3 cm/VPI tumors (p=0.019) and patients with 3.1-5 cm/non-VPI tumors (p=0.001). On the other hand, there was no significant difference in the OS between patients with 3.1-5 cm/VPI tumors and patients with 5.1-7 cm tumors regardless of lymph node metastasis (T2b tumors). Similar relationships were observed among these groups with N0 disease. CONCLUSION We identified the presence of VPI as an independent poor prognostic factor in patients with NSCLC of ≤7 cm. Tumors 3.1-5cm with VPI should be upstaged to T2b tumors in the future in the TNM classification of the Union of International Cancer Control staging system. In addition, the surgical strategy involving more extensive lymph node dissection for patients with ≤3 cm/VPI tumors, especially ≤2 cm/VPI, is warranted owing to more frequent lymph node metastasis.

Prognostic Factors and the Significance of Treatment After Recurrence in Completely Resected Stage I Non-small Cell Lung Cancer

OBJECTIVE The objective of this study was to identify the clinicopathologic factors influencing postrecurrence survival (PRS) in and the effect of postrecurrence therapy (PRT) on patients with completely resected stage I non-small cell lung cancer (NSCLC). METHODS We reviewed the data of 919 patients in whom complete resection of stage I NSCLC had been performed. RESULTS Of the 919 patients, 170 (18.5%) had recurrent disease. Initial PRT was performed in 118 patients (69.1%) (surgery in eight, chemotherapy in 79, radiotherapy in 10, and chemoradiotherapy in 21). On multivariate analyses, PRT (hazard ratio [HR], 0.542; 95% CI, 0.344-0.853; P = .008), female sex (HR, 0.487; 95% CI, 0.297-0.801; P = .005), and differentiation (HR, 1.810; 95% CI, 1.194-2.743; P = .005) demonstrated a statistically significant association with favorable PRS. Bone metastasis (HR, 3.288; 95% CI, 1.783-6.062; P < .001), liver metastasis (HR, 4.518; 95% CI, 1.793-11.379; P = .001), chemotherapy (HR, 0.478; 95% CI, 0.236-0.975; P = .040), epidermal growth factor receptor-tyrosine kinase inhibitors treatment (EGFR-TKIs) (HR, 0.460; 95% CI, 0.245-0.862; P = .015), and nonadenocarcinoma (HR, 2.136; 95% CI, 1.273-3.585; P = .004) were independently and significantly associated with PRS in the 118 patients who underwent any PRT. Subgroup analysis with a combination of these five PRS factors in the patients who underwent any PRT revealed median PRS times of 42.4 months for 20 patients lacking all five risk factors and 18.8 months for 98 patients with at least one of these risk factors (P = .001). CONCLUSIONS PRT, sex, and differentiation were independently associated with PRS. In the patients who underwent any PRT, PRS was related to EGFR-TKIs, chemotherapy, histology, and initial recurrence sites. One challenge for the future will be to create systematic treatment strategies for recurrent NSCLC according to the risk factor status of individual patients.

A proposal for combination of total number and anatomical location of involved lymph nodes for nodal classification in non-small cell lung cancer.

BACKGROUND We previously reported the prognostic impact of the number of involved lymph nodes (LNs) on survival in non-small cell lung cancer (NSCLC). However, it remains unknown whether the total number or anatomic location of involved LNs is a superior prognostic factor. METHODS A total of 689 patients with NSCLC who underwent complete resection involving dissection of the hilar and mediastinal LNs with curative intent of ≥ 10 LNs were enrolled. The association between the total number of LNs (nN) involved and survival was assessed by comparison with the anatomic location of LN involvement (pathologic lymph node [pN]), the present nodal category. RESULTS We classified the patients into five categories according to the combined pN and nN status as follows: pN0-nN0, pN1-nN1-3, pN1-nN4-, pN2-nN1-3, and pN2-nN4. Although there was no statistically significant difference between the pN1-nN4- and pN2-nN1-3 categories, pN2-nN1-3 had better prognoses than pN1-nN4-. On multivariate analysis, the nN category was an independent prognostic factor for overall survival and disease-free survival (vs nN4-; the hazard ratios of nN0 and nN1-3 for overall survival were 0.223 and 0.369, respectively, P < .0001 for all), similar to the pN category. We propose a new classification based on a combination of the pN and nN categories: namely, N0 becomes pN0-nN0, the N1 category becomes pN1-nN1-3, the N2a category becomes pN2-nN1-3 + pN1-nN4-, and the N2b category becomes pN2-nN4. Each survival curve was proportional and was well distributed among the curves. CONCLUSIONS A combined anatomically based pN stage classification and numerically based nN stage classification is a more accurate prognostic determinant in patients with NSCLC, especially in the prognostically heterogeneous pN1 and pN2 cases. Further large-scale international cohort validation analyses are warranted.

In situ telomerase activity in pleural effusions: A promising marker for malignancy

Telomerase activity in 16 pleural effusions was studied using an in situ telomerase repeat amplification protocol (TRAP) assay on cytospin preparations. Six of nine cytologically malignant specimens contained telomerase‐positive cells (67%), and in two further specimens, suspicious positive cells were seen. Two of four atypical specimens contained telomerase‐positive cells, whereas two benign cases were telomerase‐negative. No mesothelial cells showed telomerase reactivity. Thus, telomerase activity was specific for malignancy and it was always found only in malignant cells. The results suggest that telomerase activity measured with this in situ method can be a valuable complement in the assessment of malignancy in pleural effusions. Diagn. Cytopathol. 2001;24:11–15.

High-quality 3-dimensional image simulation for pulmonary lobectomy and segmentectomy: results of preoperative assessment of pulmonary vessels and short-term surgical outcomes in consecutive patients undergoing video-assisted thoracic surgery

OBJECTIVES The aim of this study was to evaluate the effectiveness of 3-dimensional computed tomography (3D-CT) software in short-term surgical outcomes and the assessment of variations of pulmonary vessel branching patterns on performing video-assisted thoracic surgery (VATS). METHODS The study included 179 consecutive patients who had undergone VATS anatomical lung resection, of which 172 were lobectomies (96%) and 7 were segmentectomies (4%), from May 2011 through January 2013. There were 124 patients (69%) in whom 3D-CT was performed and 55 patients (31%) who had not undergone 3D-CT. Observed actual pulmonary vessel branching patterns by intraoperative findings or footage were compared with the 3D image findings. Various surgical outcomes, including the occurrence of postoperative complications, in this study defined as those of Grade 2 or above under the Clavien-Dindo classification system, and total operative time, were retrieved from available clinical records. RESULTS Among the 124 patients with preoperative 3D imaging, there were 5 (4%) conversions from VATS to thoracotomy. The incidence rate of patients with postoperative complications was 8% (n = 10), and there were no 30-day or 90-day mortalities. Pulmonary artery (PA) branches were precisely identified for 97.8% (309 of 316) of branches on 3D images, and the sizes of the seven undetected branches (five in the right upper lobe, two in the left upper lobe) ranged from 1 to 2 mm. The 3D images accurately revealed 15 cases (12%) of anomalous or unusual PA branches and 5 cases (4%) of variant pulmonary veins. Multivariate logistic regression analysis of the association with postoperative complications and operative time in 165 lung cancer patients demonstrated that male gender was the only statistically significant independent predictor of complications (risk ratio: 5.432, P = 0.013), and patients without 3D imaging tended to have operative complications (risk ratio: 2.852, P = 0.074), whereas conducting the 3D-CT (risk ratio: 2.282, P = 0.021) as well as intraoperative bleeding amount (risk ratio: 1.005, P = 0.005) had significant association with operative time. CONCLUSIONS High-quality 3D-CT images clearly revealed the anatomies of pulmonary vessels, which could play important roles in safe and efficient VATS anatomical resection.