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Objectives: Distinguishing solid nodules from nodules with ground-glass lesions in lung cancer is a critical diagnostic challenge, especially for tumors ≤2 cm. Human assessment of these nodules is associated with high inter-observer variability, which is why an objective and reliable diagnostic tool is necessary. This study focuses on artificial intelligence (AI) to automatically analyze such tumors and to develop prospective AI systems that can independently differentiate highly malignant nodules., Materials and Methods: Our retrospective study analyzed 246 patients who were diagnosed with negative clinical lymph node metastases (cN0) using positron emission tomography-computed tomography (PET/CT) imaging and underwent surgical resection for lung adenocarcinoma. AI detected tumor sizes ≤2 cm in these patients. By utilizing AI to classify these nodules as solid (AI_solid) or non-solid (non-AI_solid) based on confidence scores, we aim to correlate AI determinations with pathological findings, thereby advancing the precision of preoperative assessments., Results: Solid nodules identified by AI with a confidence score ≥0.87 showed significantly higher solid component volumes and proportions in patients with AI_solid than in those with non-AI_solid, with no differences in overall diameter or total volume of the tumors. Among patients with AI_solid, 16% demonstrated lymph node metastasis, and a significant 94% harbored invasive adenocarcinoma. Additionally, 44% were upstaging postoperatively. These AI_solid nodules represented high-grade malignancies., Conclusion: In small-sized lung cancer diagnosed as cN0, AI automatically identifies tumors as solid nodules ≤2 cm and evaluates their malignancy preoperatively. The AI classification can inform lymph node assessment necessity in sublobar resections, reflecting metastatic potential., Competing Interests: Disclosure The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Lung squamous cell carcinoma (LUSC) usually shows expansive growth with large tumor nests; few reports on invasive growth patterns (INF) in LUSC have been associated with poor prognosis in gastrointestinal and urothelial cancers. In this study, we examine the association between INF and the prognosis of LUSC., Materials and Methods: We analyzed INF as a potential prognostic factor in 254 consecutive patients with LUSC who underwent complete surgical resection at our hospital between 2008 and 2017. INF was classified into 3 categories based on the structure of the tumor other than the large round solid nest of tumor cells., Results: INF was categorized as INFa in 59 patients (23 %) with only well-demarcated large solid tumor cell nests, INFb in 89 patients (35 %) with medium to small, alongside large solid nests, and INFc in 98 patients (39 %) with cord-like/small nests or isolated cells plus large or medium solid nests. No significant lymph node metastasis differences were observed between INFc and INFa/b tumors. However, in patients with p-stage I, INFc had a poorer prognosis with regard to recurrence-free survival (RFS), with a 5-year RFS rate of 53.3 %, compared to 74.9 % for INFa/b (p = 0.010)., Conclusion: Our study highlights a novel pathological concept of INF in LUSC, and contributed to the proposal that it is a factor indicating an unfavorable prognosis in patients with early-stage LUSC. A prospective multicenter study is warranted for INFc patients, as careful follow-up and adjuvant chemotherapy might lead to the early detection and prevention of recurrence., Competing Interests: Declaration of competing interest Norihiko Ikeda reports a relationship with Astra Zeneca, Chugai pharma, Pfeizer, Taiho pharma, MSD, Boehringer Ingelheim, Eli Lilly, Ono pharma, Teijin, Nihon Mediphysics, Fuji film, Johnson & Johnson, Bristol-Meyers, Olympus, Medtronics that includes: speaking and lecture fees. The other authors declare no competing interests., (© 2024 Elsevier Ltd, BASO ∼ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Even if lung cancer is detected at an early stage, surgery may be difficult in patients with severe comorbidities, like interstitial pneumonia (IP). Radiation therapy cannot be performed due to the high risk of acute IP exacerbation. Therefore, an effective alternative, such as photodynamic therapy (PDT), is required. To prove that acute exacerbation is not induced after PDT in peripheral lung cancer, we investigated the effects of PDT on IP rat models., Methods: Bleomycin (BLM) was administered intratracheally. Seven days after administration, left thoracotomy was performed. Talaporfin sodium was injected, and diode laser irradiation (664 nm, 150mW, 100J/cm 2 ) was performed. Seven days after PDT, the whole blood and left lungs were collected. A total of 23 rats, comprising BLM + PDT (n = 4), BLM + non-PDT (n = 10), non-BLM + PDT (n = 2), non-BLM + non-PDT (n = 5), and two rats that died immediately after PDT were observed. Serum levels of Krebs von den Lungen-6, surfactant protein-D, lactate dehydrogenase, and serum C-reactive protein were measured. Fibrosis and macrophage scorings, and the ​​collagen fibers percentage were examined by staining with hematoxylin and eosin, Elastica van Gieson, anti-α smooth muscle antibody, and anti-CD68 antibodies., Results: There was no remarkable difference in the values of each marker in fibrosis and macrophage scores with or without PDT. In case of death, fibrosis was mild, and PDT was not affected., Conclusions: In IP rat models, PDT did not induce lung fibrosis or acute exacerbation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: We aimed to clarify clinical profiles of patients with adenocarcinoma presenting as multifocal ground-glass opacities (MGGOs) to assess their prognosis and the optimal management method for residual satellite lesions., Methods: We identified 190 patients with cN0 MGGOs (MGGO cohort) and 1426 patients with solitary lung adenocarcinoma (control cohort) who underwent complete resection between 2004 and 2016. Propensity score matching was performed to adjust for differences in baseline characteristics of both cohorts for survival analyses. MGGOs consist of a main tumor and satellite lesions and were subdivided into 3 groups: the PG group, with multifocal pure GGOs; the GD group, in which the main tumor presented as GGO dominant; and the SD group, where the main tumor presented as solid dominant., Results: No significant differences in recurrence-free survival were observed between the 2 cohorts before and after the propensity score matching. For patients with MGGOs, 22 were in the PG group, 47 in the GD group, and 121 in the SD group. Type of MGGOs was a significant factor for recurrence-free survival recurrence-free survival both in the entire population (SD vs PG-GD, P = .008) and in p-stage I cohorts (P = .004) on multivariable analysis. Among 116 patients (61.1%) with residual satellite lesions, 38 patients had progressed lesions and 69 stable lesions. Although the emergence of new lesions during the follow-up period was an independent predictor for satellite lesion progression, neither progressed lesions nor the emergence of new lesions influenced survival., Conclusions: Patients with MGGOs and solitary adenocarcinoma had a similar prognosis. The biologic behavior of main tumors dominates clinical outcomes in patients with MGGOs., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Quantitative computed tomography (CT) histogram analysis of tumors is reported to help distinguish between invasive and less invasive lung cancers. This study aimed to clarify whether CT histogram analysis of tumors can be used to classify patients with clinical stage 0 to IA non-small cell lung cancer according to pathologic lymph node (pN) status., Methods: Predictive factors associated with pN metastasis were identified from the derivation dataset including 629 patients with clinical stage 0 to IA non-small cell lung cancer who underwent complete resection with lymph node dissection (surgeries between 2008 and 2013). The validation dataset including 238 patients (surgeries between 2014 and 2015) were subsequently reevaluated. Clinicosurgical factors, including CT histogram analysis of tumors (CT value percentiles 2.5, 25, 50, 75, and 97.5, skewness, and kurtosis) were assessed., Results: Seventy-three patients (12%) in the derivation cohort and 35 patients (15%) in the validation cohort had positive nodes. The pN status significantly affected survival in the entire population: 5-year overall survival of 93.1% vs 71.1% and 5-year disease-free survival of 85.9% vs 43.1% for negative vs positive (both P < .001). On multivariate analysis in the derivation cohort, the 75th percentile CT value (P < .001), age (P = .003), and comorbidities (P = .006) were significantly associated with pN metastasis. The area under the curve and the cutoff level of the 75th percentile CT value relevant to pN metastasis were 0.729 and 1.5 HU, respectively, and the threshold value provided accuracy of 71% for the validation cohort., Conclusions: Histogram analysis of CT imaging metrics of tumors contributes to noninvasive prediction of pN metastasis in patients with clinical stage 0 to IA non-small cell lung cancer., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The second-generation photosensitizer NPe6 has strong anti-tumor effects with a much shorter photosensitive period than the first-generation photosensitizer Photofrin. Although photosensitive period has been reduced, skin photosensitivity is still a major side effect of photodynamic therapy (PDT). Therefore, we conducted a prospective study to investigate whether the NPe6 fluorescence intensity in skin after PDT could be measured effectively in human patients to improve the management of a patient's photosensitive period., Methods: The NPe6 fluorescence measurements using a constructed fluorescence sensing system at the inside of the arm were acquired prior to and 5 and 10min after NPe6 administration as well as at the time of PDT (4-5h after administration), at discharge (2 or 3days after PDT), and at 1 or 2 weeks after PDT. Participants were interviewed as to whether they had any complications at 2 weeks after PDT., Results: Nine male patients and one female patient entered this study. Nine patients were inpatients and one patient was an outpatient. All of the measurements of NPe6 fluorescence in the skin could be obtained without any complications. The spectral peak was detected at the time of discharge (2-3days after administration) in most cases and it decreased at 1 or 2 weeks after PDT., Conclusions: The fluorescence of NPe6 in the skin could be detected feasibly using the fluorescence sensing system in human patients. Measuring the relative concentration of NPe6 in the skin indirectly by measuring fluorescence intensity might be useful to predict the period of skin photosensitivity after PDT., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: In this study, we investigated the responsiveness of the Self-Administered Foot Evaluation Questionnaire (SAFE-Q) for patient's assessment before and after hallux valgus surgery., Methods: Patient-reported answers on the SAFE-Q and Short Form-36 (SF-36) before and at a mean of 3-4 and 9-12 months after hallux valgus surgery were analyzed. Data of 100 patients (92 women, eight men) from 36 institutions throughout Japan were used for analysis., Results: In all subscales of the SAFE-Q, the trend of increased scores after surgery was statistically significant (P < 0.001). Among the patients with available scores both before and at 9-12 months after surgery (n = 66), the largest effect sizes (ESs) were observed for shoe-related (1.60), pain and pain-related (1.05), and general health and well-being (0.84) scales. In the SF-36 (n = 64), the largest ES was observed for the bodily pain scale (0.86). Less notable changes were observed for the remaining SF-36 domains., Conclusion: The SAFE-Q is the first patient-reported outcome measure which includes a quality of life assessment of shoes. In our cohort, the most remarkable responsiveness was observed for the shoe-related subscale. Based on its responsiveness, the SAFE-Q appears to be sufficient for evaluation of foot-related quality of life before and after surgery., (Copyright © 2017 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: Microscopic vascular invasion (MVI) in patients with non-small cell lung cancer (NSCLC) has been reported to be a strong predictor of poor outcomes but it has not been a descriptor of the TNM classification. The purposes of this study were to determine whether the presence of MVI is related to a predictor of poor outcomes and to explore the degree of MVI according to tumor size., Methods: A total of 1,884 patients with stage pT1-4N0-2 NSCLC who underwent complete resection comprised the study sample. Overall survival (OS) and recurrence-free proportion were estimated using the Kaplan-Meier method. The Cox proportional hazards model was used to assess independent predictors of poor outcomes., Results: Of 1,884 patients, 1,097 (58.2%) had MVI. Multivariate analysis showed MVI was a significant independent predictor of unfavorable OS (hazard ratio, 1.666; P < .001) and recurrence (hazard ratio, 2.268; P < .001). The frequency of MVI varied according to tumor size, and in each cohort of tumor sizes ≤ 2 cm, > 2 to 3 cm, and > 3 to 5 cm, there were significant differences in survival outcome by MVI status. The proportions of patients with a 5-year recurrence-free period with tumor sizes ≤ 2 cm, > 2 to 3 cm, and > 3 to 5 cm between MVI (+) and MVI (-) were 93.0% and 72.5% (P < .001), 90.8% and 63.3% (P < .001), and 86.4% and 59.9% (P < .001), respectively., Conclusions: This study demonstrated that MVI was a strong predictor of poor outcomes and that the effect is more prominent in patients with tumor sizes ≤ 5 cm. Further analysis of survival and MVI should be collected for future revision of the TNM system., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Epidermal growth factor receptor (EGFR) status and pathological stage (p-stage) were shown to be essential prognostic factors for estimating survival after recurrence of lung adenocarcinoma. In patients with EGFR mutations, those with early p-stage tumors showed better survival after disease recurrence than those with advanced p-stage tumors. The EGFR mutation status and p-stage could also prompt the design of clinical trials on adjuvant therapy for patients after complete surgical resection., Background: The current staging system and epidermal growth factor receptor (EGFR) mutation status are key factors for predicting survival. However, the significance of these factors as predictors of survival after disease recurrence (PRS) has not been sufficiently elucidated. The objective of this study was to investigate the clinicopathological factors, particularly the EGFR mutation status and pathological stage (p-stage), which affect PRS in patients with completely resected lung adenocarcinoma., Patients and Methods: We retrospectively reviewed the data of 198 consecutive lung adenocarcinoma patients with disease recurrence who previously underwent complete surgical resection in our hospital., Results: Of the 198 patients, 117 were examined for EGFR mutations (mutants). Mutants were detected in 57 patients (28.7%). The patients with mutants had a significantly better 3-year PRS (3y-PRS) rate (68.6%) than those with an EGFR wild type (WT) status (51.7%) or an unknown (UN) status (27.0%). The 3y-PRS rates for p-stage I to II (p-I-II) and p-stage III (p-III) were 52.5% and 29.3%, respectively. Multivariate survival analysis showed that the EGFR mutation status and p-stage had significant associations with favorable PRS. The 3y-PRS rate for mutants/p-I-II (81.4%) was significantly better than that for mutants/p-III (48.0%). Conversely, there was no significant difference between mutants/p-III and WT/UN/p-I-II (3y-PRS: 40.7%) or between mutants/p-III and WT/UN/p-III (3y-PRS: 24.4%)., Conclusion: EGFR status and p-stage were shown to be essential prognostic factors for estimating PRS. In patients with mutants, those with early p-stage tumors showed better PRS than those with advanced p-stage tumors., (Copyright © 2015 Elsevier Inc. All rights reserved.)

We used a high-speed 3-dimensional (3D) image analysis system (SYNAPSE VINCENT, Fujifilm Corp, Tokyo, Japan) to determine the best positioning of robotic arms and instruments preoperatively. The da Vinci S (Intuitive Surgical Inc, Sunnyvale, CA) was easily set up accurately and rapidly for this operation. Preoperative simulation and intraoperative navigation using the SYNAPSE VINCENT for robot-assisted thoracic operations enabled efficient planning of the operation settings. The SYNAPSE VINCENT can detect the tumor location and depict surrounding tissues quickly, accurately, and safely. This system is also excellent for navigational and educational use., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

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 &lt; .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.

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 &lt; .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.

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.

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.

Introduction: Loss of E-cadherin confers a poor prognosis in lung cancer patients and is associated with in vitro resistance to endothelial growth factor receptor inhibitors. Zinc finger E box-binding homeobox (ZEB)-1, the predominant transcriptional suppressor of E-cadherin in lung tumor lines, recruits histone deacetylases (HDACs) as co-repressors., Methods: NSCLC cell lines were treated with HDAC inhibitors and analyzed for E-cadherin induction, growth inhibition and apoptosis. National Cancer Institute-H157 cells expressing ectopic E-cadherin were tested for tumorigenicity in murine xenografts., Results: We found that treatment with MS-275, compared to vorinostat (SAHA), valproic acid or trichostatin A, was most effective in E-cadherin up-regulation and persistence in non-small cell lung cancers. As with other tumor types and HDAC inhibitors, MS-275 inhibited growth and induced apoptosis. Importantly, blocking E-cadherin induction by short hairpin RNA resulted in less inhibition by MS-275, implicating the epithelial to mesenchymal phenotype process as a contributing factor. In contrast to H460 and H661, H157 cells were resistant to E-cadherin up-regulation by HDAC inhibitors. However, E-cadherin was restored, in a synergistic manner, by combined knockdown of ZEB-1 and ZEB-2. In addition, H157 cells stably transfected with E-cadherin were markedly attenuated in their tumor forming ability. Lastly, combining MS-275 with the microtubule stabilizing agent, paclitaxel, or 17-(allylamino)-17-demethoxygeldanamycin, a heat shock protein 90 inhibitor, resulted in synergistic growth inhibition. Since MS-275 has no reported activity against HDAC6, which regulates both microtubule and heat shock protein 90 functions, other mechanisms of synergy are anticipated., Conclusions: These results support the role of ZEB proteins and HDAC inhibitors in the pathogenesis and treatment of lung cancer.

Archival biopsy materials from 20 randomly selected asymptomatic volunteers from the Czech uranium miners (CZ UM) risk group (n=98) were examined for p21 and ki-67 immunostatning. There were 16 areas with normal respiratory epithelium and 22 areas with bronchial intra-epithelial neoplasia (IEN). Normal and IEN areas were identified by autofluorescence (System Autofluorescence Endoscopy, SAFE-1000) and monitored during 1998-2002. The majority of specimens from areas with normal autofluorescence intensity with ciliated columnar bronchial epithelium showed strong predominantly cytoplasmic p21 positivity. The SAFE monitoring divided areas of decreased autofluorescence intensity with early stage IEN lesions into two groups. Persistent lesions (P)-showing a spectrum of p21 cytoplasmic staining ranging from negative or isolated negativity to weak or moderate positivity combined with higher proliferative capacity proved by ki-67 nuclear staining. Disappearing lesions (D)-showing strong cytoplasmic p21 positivity and negative ki-67 staining. The IEN lesions were classified into three groups based on p21/ki-67 immunostaining: proliferative lesions at risk (R) with low or without p21 plasma immunostaining combined with high ki-67 nuclear reactivity; ambiguous lesions (A) including cases combining strong p21 cytoplasmic positivity with high ki-67 nuclear reactivity or p21 cytoplasmic negativity with ki-67 negativity staining patterns; the quiescent lesion group (Q) was characterized by strong p21 cytoplasmic positivity and negative ki-67 immunostaining.

A 67-year-old man with exertional angina presented with a large pseudoaneurysm of the right coronary artery at eight months after balloon angioplasty. Intravascular ultrasound revealed a large saccular pseudoaneurysm of 10.9 x 5.7 mm diameter at the proximal segment of the right coronary artery. Complete closure of the coronary pseudoaneurysm was successfully obtained using a coronary stent graft consisting of a thin flexible polytetrafluoroethylene (PTFE) membrane placed between two stents using a unique sandwich technique. Follow-up angiography and intravascular ultrasound revealed no significant restenosis in the PTFE stent graft segment. PTFE coronary stent graft implantation is a feasible, safe and useful method to treat a large coronary pseudoaneurysm after coronary intervention.

Background/aims: Recently, it has been shown that the c-kit receptor tyrosine kinase (KIT) is expressed in the liver of young rats, and its expression is up-regulated in bile epithelial cells (BEC) after ligation of the common bile duct (BDL). To clarify a role of KIT in BEC, we examined whether BEC of Ws/Ws rats, whose KIT kinase activity was severely impaired, could proliferate in response to bile stasis after BDL., Methods/results: When 2-week-old control normal (+/+) and Ws/Ws mutant rats underwent BDL, only a few BEC were found in the portal field of livers of Ws/Ws rats, whereas many BEC were found in that of +/+ rats. Furthermore, Ki-67 immunostaining showed that the proliferative activity of BEC in 2-week-old Ws/Ws rats was much lower than that in +/+ rats of the same age. In contrast, when 6-week-old +/+ and Ws/Ws rats underwent BDL, BEC similarly proliferated in the livers of +/+ and Ws/Ws rats, and the proliferative activity of BEC was comparable., Conclusions: The mechanism whereby BEC proliferate in response to bile stasis after BDL may be different between 2- and 6-week-old rats, and KIT mediated-signal transduction plays a crucial role in the proliferation of immature BEC in young rats.

The attenuation of intracellular production of cyclic guanosine monophosphate (cGMP) has been known as a mechanism of nitrate tolerance. A recent in vitro study have shown an increase in superoxide levels and a reduced activation of guanylate cyclase in tolerant vessels. We investigated the preventive effect of an antioxidant, vitamin E, on the development of nitrate tolerance. In this double-blind, placebo-controlled study, 24 normal volunteers and 24 patients with ischemic heart disease (IHD patients) were randomized to receive either vitamin E (200 mg t. i. d.; vitamin E group) or placebo (placebo group). Vasodilator response to nitroglycerin was assessed with forearm plethysmography by measuring the change in the forearm blood flow before and 5 min after sublingual administration of 0.3 mg nitroglycerin, and at the same time, blood samples were taken from veins to measure the platelet cGMP level. Measurements of the forearm blood flow and blood sampling were obtained serially at baseline (day 0), 3 days after taking vitamin E or placebo alone (day 3), and 3 days after application of a 10 mg/24 hr nitroglycerin tape concomitantly with oral vitamin E or placebo (day 6). The response of forearm blood flow (%FBF) and cGMP (%cGMP) after sublingual nitroglycerin on day 0(%FBF: normal volunteers 32 +/- 12% vs 31 +/- 11%, IHD patients 35 +/- 15% vs 34 +/- 15%; %cGMP: normal volunteers 38 +/- 10% vs 35 +/- 11%, IHD patients 37 +/- 11% vs 38 +/- 12%; vitamin E group as placebo group) and day 3(%FBF: normal volunteers 33 +/- 9% vs 32 +/- 12%, IHD patients 35 +/- 12% vs 33 +/- 13%, %cGMP: normal volunteers 38 +/- 10% vs 37 +/- 11%, IHD patients 36 +/- 14% vs 37 +/- 10%, vitamin E group vs placebo group) were not different between the two groups. On day 6 %FBF and %cGMP in the placebo group were significantly lower compared with day 0, and there were significant differences in them between the two groups (%FBF: normal volunteers 30 +/- 12% vs 17 +/- 9%, p < 0.01; IHD patients 28 +/- 14% vs 17 +/- 8%, p < 0.01; %cGMP: normal volunteers 35 +/- 11% vs 8 +/- 5%, p < 0.01; IHD patients 38 +/- 10% vs 12 +/- 4%, p < 0.01, vitamin E group vs placebo group). In conclusion, the combination therapy with vitamin E is potentially a useful method to prevent the development of nitrate tolerance.