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Lung cancer remains the most common cause of cancer deaths worldwide, yet there is currently a lack of diagnostic noninvasive biomarkers that could guide treatment decisions. Small molecules (<1,500 Da) were measured in urine collected from 469 patients with lung cancer and 536 population controls using unbiased liquid chromatography/mass spectrometry. Clinical putative diagnostic and prognostic biomarkers were validated by quantitation and normalized to creatinine levels at two different time points and further confirmed in an independent sample set, which comprises 80 cases and 78 population controls, with similar demographic and clinical characteristics when compared with the training set. Creatine riboside (IUPAC name: 2-{2-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-oxolan-2-yl]-1-methylcarbamimidamido}acetic acid), a novel molecule identified in this study, and N-acetylneuraminic acid (NANA) were each significantly (P < 0.00001) elevated in non-small cell lung cancer and associated with worse prognosis [HR = 1.81 (P = 0.0002), and 1.54 (P = 0.025), respectively]. Creatine riboside was the strongest classifier of lung cancer status in all and stage I-II cases, important for early detection, and also associated with worse prognosis in stage I-II lung cancer (HR = 1.71, P = 0.048). All measurements were highly reproducible with intraclass correlation coefficients ranging from 0.82 to 0.99. Both metabolites were significantly (P < 0.03) enriched in tumor tissue compared with adjacent nontumor tissue (N = 48), thus revealing their direct association with tumor metabolism. Creatine riboside and NANA may be robust urinary clinical metabolomic markers that are elevated in tumor tissue and associated with early lung cancer diagnosis and worse prognosis., (©2014 American Association for Cancer Research.)

Objectives: Survival of patients with left-sided stage I non-small cell lung cancer (NSCLC) is unsatisfactory, probably because of the high incidence of contralateral mediastinal node involvement. In this study, occult micrometastases to the right upper mediastinal nodes were retrospectively investigated in patients with left-sided stage I NSCLC., Methods: Nineteen patients with clinical stage I NSCLC underwent video-assisted thoracoscopic lobectomy and bilateral mediastinal node dissection (BMD). Clinical data and survival of patients with BMD were compared with those of 25 left-unilateral mediastinal node dissection (UMD) patients. Occult micrometastases were detected using the cytokeratin 19 mRNA reverse transcription-polymerase chain reaction method., Results: Pathological N2 disease was found in 1 patient, and 18 had pN0 disease. The operative time, blood loss, duration of chest tube drainage and duration of postoperative hospital stay were not different between BMD and UMD patients. Nodal micrometastases were detected in 11/19 (57.8%) patients. Skip micrometastases to the level N3 nodes without N1 and N2 node involvement were observed in 8/11 (72.7%) patients. Patients with BMD are all alive and have had no recurrence during the median follow-up period of 21.4 months. Overall 3-year survival and disease-free 3-year survival were not significantly different between the two groups., Conclusion: In this preliminary study, occult micrometastases to the level N3 nodes occurred frequently in patients with left-sided clinical N0 stage I NSCLC. Postoperative survival of patients with occult micrometastases to the level N3 node does not appear to be poor. Further follow-up and work are needed.

Objectives: Segmentectomy is one of the treatment options for small-sized non-small cell lung cancer (NSCLC). Although growing results support the feasibility and efficacy, it still remains unclear in segmentectomy. The International Association for the Study of Lung Cancer recommended a revised classification of TNM staging in 2009 (the seventh edition) and multidisciplinary classification of adenocarcinoma. We report here the outcome of totally thoracoscopic segmentectomy and lobectomy for T factor and adenocarcinoma., Methods: Ninety patients with Stage IA NSCLC underwent thoracoscopic segmentectomy between September 2003 and June 2011. A total of 124 patients were referred as a control group to compare the peri-operative outcome, local recurrence rate and survival. These survivals were analysed using the Kaplan-Meier method with the log-rank test and propensity score analyses., Results: The peri-operative outcome, including operative time, blood loss, duration of chest tube drainage and length of hospital stay, was not significantly different between groups. The number of dissected lymph nodes with segmentectomy was less than that with lobectomy. Morbidity and mortality were not significantly different between groups. Seven patients relapsed in each group and propensity score analysis in disease-free and overall survivals showed no differences between two groups in Stage IA. Subclass analyses revealed that disease-free and overall survivals in T1a and T1b were not significantly different between the two groups., Conclusions: Our study demonstrated that thoracoscopic segmentectomy was feasible with regard to peri-operative and oncological outcomes for Stage IA NSCLC, especially T1a and carefully selected T1b descriptor.

Purpose: The application of sentinel node navigation surgery in non-small cell lung cancer (NSCLC) is not popular because of the difficulty of sentinel node identification and the low incidence of complications after systemic lymph node dissection. We report the intraoperative assessment of sentinel node metastasis by thoracoscopic ICG fluorescence imaging system and real-time reverse transcription-polymerase chain reaction (RT-PCR)., Methods: Sixty-one patients who underwent surgery between January 2009 and December 2010 were investigated for sentinel node biopsy. ICG fluorescence imaging was applied by an infrared light CCD system, and sentinel nodes were identified and dissected. Intraoperative real-time quantitative RT-PCR to determine the expression of cytokeratin 19 (CK-19) was performed for evaluation of metastasis and finally histologic examination of hematoxylin and eosin-stained, paraffin-embedded sections., Results: Sixteen (80%) of 20 patients with segmentectomy and 33 (80.5%) of 41 with lobectomy were identified for sentinel lymph nodes. The total identification rate was 80.3% (49 of 61). The false-negative rate was 2.1% (1 of 49). The overall accuracy rate was 78.7% (48 of 61 patients). Disease of four of these patients was upstaged to stage IIA by RT-PCR for CK-19 expression, which was positive for sentinel nodes and micrometastases., Conclusions: These results demonstrated that thoracoscopic ICG fluorescence imaging-guided surgery and real-time quantitative RT-PCR were useful for sentinel node biopsy and might be a powerful tool for more focused pathologic or molecular evaluation for staging.

Objectives: Segmentectomy is the treatment of choice for small-sized non-small cell lung cancer (NSCLC); however, it is difficult to decide the surgical procedure because accurate evaluation of hilar lymph node metastasis remains unclear. We here report the outcome of video-assisted thoracic surgery (VATS) segmentectomy with and without the assessment of sentinel nodes., Materials and Methods: Eighty-three patients with stage IA NSCLC underwent VATS segmentectomy between January 2003 and December 2010. Twenty patients underwent indocyanine green fluorescence imaging for sentinel node biopsy (SNB) and 63 did not. Intraoperative real-time quantitative RT-PCR to determine the expression of CK-19 was used for evaluation of metastasis. Perioperative outcome, local recurrence rates and survival were compared in both groups., Results: Sentinel lymph nodes were identified in 16 of 20 patients (80%) with segmentectomy in the SNB group. The false negative rate was 0%. By RT-PCR for CK-19 expression, only one of these patients showed positive sentinel nodes, which indicated isolated tumor cells; however, segmentectomy was not converted to lobectomy. Seven of 63 patients with VATS segementectomy without SNB and none of the SNB group relapsed. In the relapsed patients without SNB, 4 (6.3%) were local recurrences and 3 (4.7%) were distant metastases. Recurrence-free survival rates in both groups were not significantly different because of the short follow-up period of the SNB group., Conclusions: Our study demonstrated that VATS segmentectomy with SNB was useful for deciding intraoperatively to perform segmentectomy with an accurate lymph node status.

Background: Segmentectomy for small or early stage non-small cell lung cancer (NSCLC) has been controversial. Further, video-assisted thoracic surgery (VATS) for lung cancer was accepted during the past decade. We here compared the outcome between VATS segmentectomy and VATS lobectomy for stage I NSCLC., Methods: In the retrospective study, 109 consecutive patients in stage I underwent surgery at Oita University Hospital (Oita, Japan) between September 2003 and October 2008. VATS segmentectomy was performed in 38 patients and VATS lobectomy with systemic lymphadenectomy was performed in 71 patients. After clinicopathologic factors were compared in both groups, local recurrence rates and survivals were compared., Results: Five of 38 VATS segmentectomy and eight of 71 VATS lobectomy patients relapsed during the follow-up period (median 27.5 mo). In the relapsed patients after VATS segmentectomy, three (7.9%) were local recurrences and two (5.3%) were distant metastases. On the other hand, four (5.6%) were local recurrence and four (5.6%) were distant metastases in the VATS lobectomy group. There was no significant difference between the two groups. Furthermore, there was no difference in recurrence-free and overall survival between segmentectomy and lobectomy., Conclusions: Although the sample size is small, VATS segmentectomy is one of the appropriate procedures for stage I NSCLC., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: The primary objective was to assess the feasibility and accuracy of intraoperative sentinel lymph node mapping by using a video-assisted thoracoscopic indocyanine green fluorescence imaging system in patients with clinical stage I non-small-cell lung cancer., Methods: Thirty-one patients who underwent operation between January 2009 and September 2009 were investigated for sentinel node biopsy. Indocyanine green fluorescence imaging was applied by an infrared light charge-coupled device, and sentinel nodes were identified intraoperatively and dissected. Histologic examination by hematoxylin-eosin staining was used to evaluate metastases., Results: Sentinel lymph nodes were identified by segmentectomy in 11 of 14 patients (78.5%) and by lobectomy in 14 of 17 patients (82.4%). The total identification rate was 80.7% (25/31 patients), the false-negative rate was 0% (0/24 patients), and the overall accuracy rate was 80.7% (25/31 patients)., Conclusion: Video-assisted thoracoscopic indocyanine green fluorescence image-guided surgery is feasible for sentinel node biopsy and may be a powerful tool to eliminate unnecessary lymph node dissection in patients with lung cancer., (Copyright © 2011 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background: The possibility of a dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase gene, DYRK2, predicting benefit from chemotherapy for patients with recurrent non-small cell lung cancer (NSCLC) was investigated., Materials and Methods: Forty patients with recurrent disease after surgery received several combinations of platinum-based chemotherapy. The chemotherapy effectiveness was evaluated according to RECIST (response evaluation criteria in solid tumors). Immunohistochemical (IHC) analysis was used to determine the expression of DYRK2., Results: Although the response rates between the two groups did not show statistical differences, the disease control rate of the DYRK2-positive group (15 out of 17, 88%) was significantly different from the DYRK2-negative group (8 out of 23, 35%, p=0.001). The median time to the progression (TTP) of disease was significantly different between the two groups (310 days in the positive group, 120 days in the negative, HR=2.12, 95% CI=[1.1-4.09], p=0.024). Multivariate analysis showed that negative DYRK2 expression was a strong predictor of disease progression (HR=3.01, 95% CI=[1.45-6.26], p=0.003)., Conclusion: Patients with high DYRK2 expression could be good candidates for chemotherapy.

Background: p53AIP1 is a potential mediator of apoptosis depending on p53, which is mutated in many kinds of carcinoma. High survivin expression in non-small cell lung cancer is related with poor prognosis. To investigate the role of these genes in non-small cell lung cancer, we compared the relationship between p53AIP1 or survivin gene expression and the clinicopathological status of lung cancer., Materials and Methods: Forty-seven samples from non-small cell lung cancer patients were obtained between 1997 and 2003. For quantitative evaluation of RNA expression by PCR, we used Taqman PCR methods., Results: Although no correlation between p53AIP1 or survivin gene expression and clinicopathological factors was found, the relationship between survivin gene expression and nodal status was significant (p = 0.03). Overall survival in the p53AIP1-negative group was significantly worse than in the positive group (p = 0.04); however, although survivin expression was not a prognostic factor, the combination of p53AIP1 and survivin was a significant prognostic predictor (p = 0.04). In the multivariate cox proportional hazard model, the combination was an independent predictor of overall survival (p53AIP1 (+) survivin (+), HR 0.21, 95%CI = [0.01-1.66]; p53AIP1 (+) survivin (-), HR 0.01, 95%CI = [0.002-0.28]; p53AIP1 (-) survivin (-), HR 0.01, 95%CI = [0.002-3.1], against p53AIP1 (-) survivin (+), p = 0.03)., Conclusion: These data suggest that the combination of p53AIP1 and survivin gene expression may be a powerful tool to stratify subgroups with better or worse prognosis from the variable non-small cell lung cancer population.