Salivary metabolomic biomarkers for non-invasive lung cancer detection.

Identifying novel biomarkers for early detection of lung cancer is crucial. Non-invasively available saliva is an ideal biofluid for biomarker exploration; however, the rationale underlying biomarker detection from organs distal to the oral cavity in saliva requires clarification. Therefore, we analyzed metabolomic profiles of cancer tissues compared with those of adjacent non-cancerous tissues, as well as plasma and saliva samples collected from patients with lung cancer (n = 109 pairs). Additionally, we analyzed plasma and saliva samples collected from control participants (n = 83 and 71, respectively). Capillary electrophoresis-mass spectrometry and liquid chromatography-mass spectrometry were performed to comprehensively quantify hydrophilic metabolites. Paired tissues were compared, revealing 53 significantly different metabolites. Plasma and saliva showed 44 and 40 significantly different metabolites, respectively, between patients and controls. Of these, 12 metabolites exhibited significant differences in all three comparisons and primarily belonged to the polyamine and amino acid pathways; N1-acetylspermidine exhibited the highest discrimination ability. A combination of 12 salivary metabolites was evaluated using a machine learning method to differentiate patients with lung cancer from controls. Salivary data were randomly split into training and validation datasets. Areas under the receiver operating characteristic curve were 0.744 for cross-validation using training data and 0.792 for validation data. This model exhibited a higher discrimination ability for N1-acetylspermidine than that for other metabolites. The probability of lung cancer calculated using this model was independent of most patient characteristics. These results suggest that consistently different salivary biomarkers in both plasma and lung tissues might facilitate non-invasive lung cancer screening.

[S10 Segmentectomy by Thoracoscopic Surgery for a Bronchial Foreign Body Presenting More than One Year].

It is often difficult to remove long-standing bronchial foreign bodies by bronchoscopy. A 77-year-old male was referred to our department for removal of a foreign body. Chest computed tomography revealed a nail in the right S10b. A bronchoscopic examination could not detect the nail due to locating beyond the subsegmental tree, so thoracoscopic right S10 segmentectomy was performed. Intraoperative ultrasonography and X-ray fluoroscopy were useful in understanding the margin for resection.

[Lymphangiography by Inguinal Lymph Node Puncture was Effective for Chylothorax after Lobectomy].

A 74-year-old female with lung cancer underwent thoracoscopic right upper lobectomy. The patient was diagnosed chylothorax due to the milky drain effusion on postoperative day 1 (POD 1). Despite fasting management, chylothorax was not improved. Lymphangiography by inguinal lymph node puncture was performed on POD 4. The amount of drainage decreased on POD 6 and disappered by following pleurodesis. Early lymphangiography is recommended prior to surgical treatment for patients with chyle leakages who are unlikely to be cured by conservative treatment alone.

[Video-assisted Thoracic Surgery of an Hourglass Transmural Lipoma;Report of a Case].

Hourglass transmural lipomas are rare. A 79-year-old male was referred to our hospital due to an abnormal shadow incidentally found on a chest X-ray 6 years ago. Chest computed tomography and magnetic resonance imaging revealed a well-defined fatty mass like an hourglass, penetrating the right 4th intercostal muscle. The tumor tended to grow slightly and we considered the possibility of well-differentiated liposarcoma. We performed a complete resection of the tumor with partial resection of the 5th rib with the assist of thoracoscopy. The chest wall was reconstructed using an expanded polytetrafluoroethylene (ePTFE) sheet. The tumor was 55×52×47 mm in size and histologically diagnosed as an intermuscular lipoma. Thoracoscopy was useful to determine the excision line.

[Thoracoscopic Resection of a Mediastinal Enteric Cyst Assisted with Artificial Pneumothorax in the Prone Position].

Mediastinal enteric cysts are very rare among in adults and usually asymptomatic. A 54-year-old male was referred to our hospital due to an abnormal shadow incidentally found on a chest X-ray at health check. Chest computed tomography scan revealed a cystic mass in the posterior and inferior mediastinum surrounded by diaphragm, inferior vena cava, and esophagus. Based on many reports of thoracoscopic esophagectomy in the prone position in recent years, we chose thoracoscopic resection of the mediastinal tumor in the prone position with artificial pneumothorax. The prone position with artificial pneumothorax provided much better exposure of the operating field and the surgery was performed successfully.

[Bronchial Typical Carcinoid Requiring Left Upper Sleeve Lobectomy after Rigid Bronchoscopic Intervention].

A 17-year-old girl was referred to our hospital with atelectasis of left lung due to tumor occlusion. Clearance of the tumor was performed by mechanical removal and application of Nd-YAG laser or electrocautery. The histopathological diagnosis was typical carcinoid. Chest computed tomography showed extraluminal residual lesions. Left upper lung sleeve lobectomy was performed 1 year after initial treatment. Interestingly, the histology of the resected specimen showed that the tumor cells exist only on the outer side of the bronchial cartilage and not in the bronchial luminal surface, suggesting the effectiveness of the initial bronchoscopic treatment.

Tumor volume determines the feasibility of cell-free DNA sequencing for mutation detection in non-small cell lung cancer.

Next-generation sequencing (NGS) and digital PCR technologies allow analysis of the mutational profile of circulating cell-free DNA (cfDNA) in individuals with advanced lung cancer. We have now evaluated the feasibility of cfDNA sequencing for mutation detection in patients with non-small cell lung cancer at earlier stages. A total of 150 matched tumor and serum samples were collected from non-small cell lung cancer patients at stages IA-IIIA. Amplicon sequencing with DNA extracted from tumor tissue detected frequent mutations in EGFR (37% of patients), TP53 (39%), and KRAS (10%), consistent with previous findings. In contrast, NGS of cfDNA identified only EGFR, TP53, and PIK3CA mutations in three, five, and one patient, respectively, even though adequate amounts of cfDNA were extracted (median of 4936 copies/mL serum). Next-generation sequencing showed a high accuracy (98.8%) compared with droplet digital PCR for cfDNA mutation detection, suggesting that the low frequency of mutations in cfDNA was not due to a low assay sensitivity. Whereas the yield of cfDNA did not differ among tumor stages, the cfDNA mutations were detected in seven patients at stages IIA-IIIA and at T2b or T3. Tumor volume was significantly higher in the cfDNA mutation-positive patients than in the negative patients at stages T2b-T4 (159.1 ± 58.0 vs. 52.5 ± 9.9 cm3 , P = 0.014). Our results thus suggest that tumor volume is a determinant of the feasibility of mutation detection with cfDNA as the analyte.

Influence of background cardiovascular risk factors on VEGF inhibitor-related adverse vascular events in patients with non-small cell lung cancer: a retrospective study.

PURPOSE: Vascular endothelial growth factor (VEGF) inhibitors are widely used in chemotherapy for non-small lung cancer (NSCLC). The purpose of the current study was to examine the impact of background cardiovascular risk factors on VEGF inhibitor-related adverse vascular events (VEGF-related AVEs) in patients with NSCLC who also had comorbidities. METHODS: We conducted a retrospective study of 118 NSCLC patients treated with bevacizumab or ramucirumab from April 2010 to December 2022. We compared baseline cardiovascular risk factors with VEGF-related AVEs. RESULTS: VEGF-related AVEs and discontinuation due to VEGF-related AVEs were reported in 54 patients and 21 patients, respectively. VEGF-related AVEs were significantly more common with male sex, smoking history, history of hypertension, dyslipidemia, diabetes mellitus, or cardiovascular disease. Discontinuation due to VEGF-related AVEs was significantly more common in patients with history of hypertension or chronic kidney disease. VEGF-related AVEs were significantly more common in patients with ≥ 3 cardiovascular risk factors than patients with < 3. Discontinuation due to VEGF-related AVEs was significantly more common in patients with ≥ 4 cardiovascular risk factors than patients with < 4. Multivariate analysis demonstrated that male sex, hypertension, and ≥ 6 cycles of VEGF inhibitors were each associated with VEGF-related AVEs and hypertension was associated with discontinuation due to VEGF-related AVEs. CONCLUSION: Our study demonstrated that history of hypertension was independently associated with increased risk of both VEGF-related AVEs and discontinuation due to VEGF-related AVEs. In conclusion, we need to be aware of VEGF-related AVEs when using VEGF inhibitors for patients with ≥ 3 cardiovascular risk factors.

Utility of small-animal positron emission tomographic imaging of rats for preclinical development of drugs acting on the serotonin transporter.

Visualization of neurotransmission components in living small animals using positron emission tomography (PET) has the potential of contributing to the preclinical development of neuroactive drugs, although it is yet to be examined whether quantitative animal PET data on candidate compounds can be extrapolated to humans. Here, we investigated the comparability of the occupancies of serotonin transporter (5-HTT) by therapeutic agents in rat PET studies with our predetermined data from ex- vivo animal experiments and clinical PET scans. Rats were treated with varying doses of fluvoxamine and a newly developed compound, (2S)-1-[4-(3,4-dichlorophenyl) piperidin-1-yl]-3-[2-(5-methyl-1,3,4-oxadiazol-2-yl)benzo[b]furan-4-yloxy]propan-2-ol monohydrochloride (Wf-516), and underwent PET scans with [11C]3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile ([11C]DASB), a selective radioligand for in-vivo quantification of 5-HTT. PET images indicated a reduction of [11C]DASB binding to 5-HTT as a function of the doses and/or plasma concentrations of fluvoxamine and Wf-516. The doses of these drugs at half-maximal effect (15.2 mg/kg and 3.1 mg/kg, respectively), determined that using binding potentials for [11C]DASB, were comparable to those estimated by our previous ex-vivo measurements in rats (4.5 mg/kg and 1.1 mg/kg, respectively), as there was only a 3-fold difference between these results. Moreover, the plasma concentration of fluvoxamine needed for 50% occupancy of central 5-HTT (6.1 ng/ml) was almost equivalent to the value determined in human PET studies (4.6 ng/ml). These findings support the view that the conjunctive use of small-animal PET and [11C]DASB facilitates a quantitative comparison of in-development drugs targeting 5-HTT with established inhibitors and a predictive estimation of their plasma concentrations exerting therapeutic effects in humans.

Cytological differences between invasive and noninvasive or minimally invasive lung adenocarcinomas diagnosed in Japanese patients using needle biopsy specimens of pulmonary lesions ≤3 cm in diameter.

BACKGROUND: According to the WHO classification for lung cancer, adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) have a better prognosis than invasive adenocarcinoma (IAD). However, detecting the foci of invasion in lung adenocarcinomas radiologically remains difficult. The present study examined whether or not differences in the cytological characteristics between IAD and AIS or MIA (noninvasive or minimally invasive adenocarcinomas [NMIAD]) plays a role in the differential diagnosis. METHODS: Seventy surgical resection specimens of primary lung adenocarcinoma with preoperative cytology, in which several parameters were evaluated and assessed. RESULTS: The histopathological diagnoses of surgical resection specimens were AIS in 8, MIA in 31, IAD in 31 including lepidic adenocarcinoma in 9, and papillary adenocarcinoma in 22. NMIAD had a 100% 5-year recurrence-free survival (RFS), while IAD had an 82.8% 5-year RFS. The numbers of tumor cells (at ×10 magnification in 10 fields) were 60.3 ± 40.5 in IAD and 39.8 ± 28.7 in NMIAD (P = 0.0017). A univariate analysis of cytological parameters revealed significant differences in large tumor cell clusters, three-dimensional (3D) tumor cell clusters, and irregular nuclear contours between the two groups. The frequency of irregular nuclear contours continued to be significantly different according to a multivariate analysis. CONCLUSION: Large or 3D tumor cell clusters and irregular nuclear contours may be important cytological factors for distinguishing IAD from NMIAD, with the latter being potentially more important for distinguishing between the two groups.

Epidermal growth factor receptor mutation subtype has differential effects on adjuvant chemotherapy for resected adenocarcinoma pathological stages II-III.

The aim of the present study was to investigate epidermal growth factor receptor (EGFR) mutations as a prognostic factor for postoperative patients with positive EGFR mutations treated with postoperative platinum-based adjuvant chemotherapy (PBAC), and whether two common EGFR mutations exhibit different responses to PBAC. A total of 110 patients who underwent complete surgical resection were enrolled, and overall survival (OS) and disease-free survival (DFS) were investigated based on EGFR mutation status and PBAC. The 3 year OS rate in patient groups were as follows: Patients with EGFR mutations (MT) undergoing PBAC, 89.3%; MT patients without PBAC, 83.3%; wild-type (WT) patients with PBAC, 82.3%; and WT patients without PBAC, 62.2%. Statistically significant differences were observed between WT patients based on PBAC (P=0.026). No statistically significant differences were observed between MT patients with PBAC and MT patients without PBAC. On the basis of mutation subtypes, the 3 year OS rate of patient groups were as follows: Patients with in-frame deletions in exon19 (19 del) with PBAC, 92.3%; patients with 19 del without PBAC, 85.7%; patients with the point mutation L858R inexon21 (21L858R) with PBAC, 86.7%; and patients with 21L858R without PBAC, 81.5%; the respective 3-year DFS rates were 53.8, 14.3, 40.2 and 26.9%. Statistically significant differences were observed in the DFS rates in 19 del patients, which was dependent on PBAC (P=0.040). EGFR mutation-positive patients exhibited a decreased benefit from PBAC for increasing in survival rate compared with WT patients. It may be necessary to consider postoperative strategies based on EGFR mutations and their subtype in the future.

Quantitative p16 and ESR1 methylation in the peripheral blood of patients with non-small cell lung cancer.

Inactivation of the p16 and ESR1 tumor suppressor genes by promoter lesion methylation has been reported in many tumor types, including lung cancer. We examined the blood of 95 non-small cell lung cancer patients (66 cases of adenocarcinoma, 23 of squamous cell carcinoma and 6 of large cell carcinoma) and 30 controls consisting of normal subjects and benign disease patients to determine the methylation ratios of p16 and ESR1 using real-time PCR. For both genes, there was a statistically significant difference in the methylation ratio between non-small cell lung cancer patients and controls (p16; p<0.01, ESR1; p<0.001). In addition, there was a strong correlation between the methylation ratio of each gene and old age (p16; p<0.01, ESR1; p<0.001 and p16 or ESR1; p<0.001), and between p16 or ESR1 methylation rate and smoking history (p<0.01). Moreover in Stage I cases, the methylation positive rate of each gene (p16, ESR1 and p16 or ESR1) was higher than the CEA positive rate (p<0.05, p<0.001, p<0.001). Evaluation of p16 and ESR1 promoter methylation in blood using real-time PCR appears to be very useful for lung cancer diagnosis and there is some possibility that these methylated genes might come to represent useful biomarkers for the early detection of lung cancer. Our study results also suggested that comparative evaluation of the methylation ratio before and after surgery might be a powerful tool to predict the prognosis of lung cancer patients.

Clinical applications of virtual navigation bronchial intervention.

BACKGROUND: In patients with bronchial tumors, we frequently consider endoscopic treatment as the first treatment of choice. All computed tomography (CT) must satisfy several conditions necessary to analyze images by Synapse Vincent. To select safer and more precise approaches for patients with bronchial tumors, we determined the indications and efficacy of virtual navigation intervention for the treatment of bronchial tumors. METHODS: We examined the efficacy of virtual navigation bronchial intervention for the treatment of bronchial tumors located at a variety of sites in the tracheobronchial tree using a high-speed 3-dimensional (3D) image analysis system, Synapse Vincent. Constructed images can be utilized to decide on the simulation and interventional strategy as well as for navigation during interventional manipulation in two cases. RESULTS: Synapse Vincent was used to determine the optimal planning of virtual navigation bronchial intervention. Moreover, this system can detect tumor location and alsodepict surrounding tissues, quickly, accurately, and safely. The feasibility and safety of Synapse Vincent in performing useful preoperative simulation and navigation of surgical procedures can lead to safer, more precise, and less invasion for the patient, and makes it easy to construct an image, depending on the purpose, in 5-10 minutes using Synapse Vincent. Moreover, if the lesion is in the parenchyma or sub-bronchial lumen, it helps to perform simulation with virtual skeletal subtraction to estimate potential lesion movement. By using virtual navigation system for simulation, bronchial intervention was performed with no complications safely and precisely. CONCLUSIONS: Preoperative simulation using virtual navigation bronchial intervention reduces the surgeon's stress levels, particularly when highly skilled techniques are needed to operate on lesions. This task, including both preoperative simulation and intraoperative navigation, leads to greater safety and precision. These technological instruments are helpful for bronchial intervention procedures, and are also excellent devices for educational training.

Prognostic impact of the integration of volumetric quantification of the solid part of the tumor on 3DCT and FDG-PET imaging in clinical stage IA adenocarcinoma of the lung.

OBJECTIVES: The aim of this study was to conduct comparative analyses of the biological malignant potential of clinical stage IA adenocarcinoma using positron emission tomography/computed tomography (PET/CT), high-resolution CT (HRCT), and three-dimensional CT (3DCT). The predictive performance of these parameters was evaluated in terms of clinical outcomes and pathological invasiveness (positive lymphatic permeation, blood-vessel invasion, pleural invasion, and lymph-node metastasis). MATERIALS AND METHODS: We enrolled 170 patients with c-IA adenocarcinoma who underwent PET/CT, HRCT, and 3D reconstruction of lung structures using the Synapse Vincent system (Fujifilm Corporation, Tokyo, Japan) followed by complete resection. Maximum standardized uptake values (SUVmax) of F18-fluorodeoxyglucose and the size and volume of the solid part of the tumor were quantified and analyzed in relation to surgical outcomes. RESULTS: Univariate analysis demonstrated that all the three parameters and whole-tumor volume were associated with unfavorable disease-free survival (DFS), while the volume of the solid part was the independent predictor on multivariate analysis (p < .001). The receiver operating characteristic curves for pathological invasiveness, determined using the variables dichotomized at each cut-off level (SUVmax 2.4; solid-part size 1.23 cm; solid-part volume 779 mm3), showed that all were significantly correlated with pathological invasiveness and prognosis, whereas the combination of SUVmax and the solid-part volume was the most powerful predictor of survival and pathological invasiveness compared to any other parameters: the 4-year DFS and proportion of pathological invasiveness in patients with SUVmax > 2.4 and solid-part volume > 779 mm3 versus those with SUVmax ≤ 2.4 or solid-part volume ≤779 mm3 were 81.2% versus 98.3% (p < .001) and 84.3% versus 15.1% (p < .001), respectively. CONCLUSION: In c-IA adenocarcinoma, the volume of the solid part of the tumor was the independent predictor for unfavorable DFS, and the integration of the volume of the solid part and SUVmax was highly beneficial for the prediction of survival and pathological invasiveness.

Napsin A (TA02) is a useful alternative to thyroid transcription factor-1 (TTF-1) for the identification of pulmonary adenocarcinoma cells in pleural effusions.

The purpose of this study was to test napsin A as a diagnostic marker of metastatic lung adenocarcinoma in pleural effusions, and to compare its performance with TTF-1. Napsin A and TTF-1 reactivities were determined immunohistochemically on formalin-fixed paraffin embedded cell blocks from 50 pleural effusion (5 mesotheliomas, 10 mesothelial proliferations, 12 pulmonary, and 23 nonpulmonary metastases). The results were evaluated separately, and correlated to the final diagnoses. Concordant results were obtained in 48/50 cases. TTF-1 and Napsin A were positive in 8/12 and 10/12 pulmonary adenocarcinomas, respectively. Both markers were negative in 42 cases, including two lung carcinomas. Napsin reactivity was found in more than 75% of the tumor cells in 9/10 positive cases, whereas TTF-1 reactivity was seen in more than 75% of the tumor cells in 2/8 positive cases only (P < 0.05). This makes napsin A an alternative to TTF-1 in cytological diagnosis of effusions in which tumor cells may be scanty.

Computed tomographic findings of large cell neuroendocrine carcinoma of the lung.

The purpose of our study was to describe the computed tomography (CT) findings of large cell neuroendocrine carcinoma (LCNEC) and to correlate radiological and pathological findings. We reviewed the CT findings of 36 patients [including the high-resolution computed tomography (HRCT) findings of 29 patients] with resected LCNEC specimens. There were 33 men (92%), and 30 patients had a smoking history (83%). Only one case was of the central type. Mediastinal or hilar lymphadenopathy was seen in 12 (33%), but only one showed bulky lymphadenopathy. The HRCT findings of LCNEC consisted of irregular margins (66%), surrounding emphysema (41%), notching (38%), calcifications (21%), and pleural indentation (24%). Our study indicates that the CT image of LCNEC generally shows a peripherally located, expansively growing, irregularly margined pulmonary mass, with or without calcification, and without bulky lymphadenopathy. While the CT image of LCNEC resembles that of squamous cell carcinoma, cavitation is infrequent. LCNEC cannot be differentiated from poorly differentiated adenocarcinoma or atypical carcinoid on the basis of CT findings.

Coil embolization for pulmonary artery injury caused by chest tube drainage.

Pulmonary artery injury caused by chest tube drainage is rare, but it requires prompt diagnosis to perform urgent surgical repair. We report that a 53-year-old man who suffered from pulmonary artery injury by chest tube drainage was successfully treated by coil embolization.

Skin fluorescence following photodynamic therapy with NPe6 photosensitizer.

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.

(R)-3'-(3-methylbenzo[b]thiophen-5-yl)spiro[1-azabicyclo[2,2,2]octane-3,5'-oxazolidin]-2'-one, a novel and potent alpha7 nicotinic acetylcholine receptor partial agonist displays cognitive enhancing properties.

Recent studies have suggested that the alpha7 nicotinic acetylcholine receptors play important roles in learning and memory. Herein, we describe our research of the structure-activity relationships (SAR) in a series of (S)-spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin]-2'-ones bearing various bicyclic moieties to discover novel alpha7 receptor agonists. Through a number of SAR studies on the series, we have found out that inhibition of CYP 2D6 isozyme, which was a primary obstacle for the previously identified compound, was avoidable by the introduction of bicyclic moieties. Chemical optimization of the series led to the identification of a novel and potent alpha7 nicotinic acetylcholine receptor partial agonist 23. This compound not only possessed high binding affinity (K(i) = 3 nmol/L) toward the alpha7 receptor but also showed agonistic activity even at a concentration of 0.1 micromol/L. In addition, compound 23 improved cognition in several rat models, which might suggest the potential of the alpha7 receptor partial agonist for the treatment of neurological disorders including cognitive dysfunction.

The Frequency and Prognostic Impact of Pathological Microscopic Vascular Invasion According to Tumor Size in Non-Small Cell Lung Cancer.

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.