Differences in the Prognostic Impact between Single-zone and Multi-zone N2 Node Metastasis in Patients with Station-based Multiple N2 Non-Small Cell Lung Cancer.

Purpose: The International Association for the Study of Lung Cancer suggest further subdivision of pathologic N (pN) stage in non-small-cell lung cancer (NSCLC) by incorporating the location and number of involved lymph node (LN) stations. We reclassified patients with the station-based N2b disease into single-zone and multi-zone N2b groups and compared survival outcomes between the groups. Materials and Methods: This retrospective study included patients with pN2 NSCLC who underwent lobectomy from 2006 to 2019. The N2 disease was subdivided into four categories: single-station N2 without N1 (N2a1), single-station N2 with N1 (N2a2), multiple-station N2 with single zone involvement (single-zone N2b), and multiple-station N2 with multiple zone involvement (multi-zone N2b). LN zones included in the subdivision of N2 disease were upper mediastinal, lower mediastinal, aortopulmonary, and subcarinal. Results: Among 996 eligible patients, 211 (21.2%), 394 (39.6%) and 391 (39.4) were confirmed to have pN2a1, pN2a2, and pN2b disease, respectively. In multivariable analysis after adjustment for sex, age, pT stage, and adjuvant chemotherapy, overall survival was significantly better with single-zone N2b disease (n=125, 12.6%) than with multi-zone N2b disease (n=266, 26.7%) (hazard ratio 0.67, 95% confidence interval 0.49-0.90, p<0.009) and was comparable to that of N2a2 disease (1.12, 0.83-1.49, p=0.46). Conclusion: Prognosis of single-zone LN metastasis was better than that of multiple-zone LN metastasis in patients with N2b NSCLC. Along with the station-based N descriptors, zone-based descriptors might ensure optimal staging, enabling the most appropriate decision-making on adjuvant therapy for patients with pN2 NSCLC.

Irisin reduces amyloid-ß by inducing the release of neprilysin from astrocytes following downregulation of ERK-STAT3 signaling.

A pathological hallmark of Alzheimer's disease (AD) is the deposition of amyloid-ß (Aß) protein in the brain. Physical exercise has been shown to reduce Aß burden in various AD mouse models, but the underlying mechanisms have not been elucidated. Irisin, an exercise-induced hormone, is the secreted form of fibronectin type-III-domain-containing 5 (FNDC5). Here, using a three-dimensional (3D) cell culture model of AD, we show that irisin significantly reduces Aß pathology by increasing astrocytic release of the Aß-degrading enzyme neprilysin (NEP). This is mediated by downregulation of ERK-STAT3 signaling. Finally, we show that integrin αV/ß5 acts as the irisin receptor on astrocytes required for irisin-induced release of astrocytic NEP, leading to clearance of Aß. Our findings reveal for the first time a cellular and molecular mechanism by which exercise-induced irisin attenuates Aß pathology, suggesting a new target pathway for therapies aimed at the prevention and treatment of AD.

High-dose chemotherapy followed by autologous stem cell transplantation in pediatric patients with relapsed osteosarcoma.

BACKGROUND: Patients with relapsed osteosarcoma have poor treatment outcomes. High-dose chemotherapy with autologous stem cell transplantation (HDCT/ASCT) has been used in several high-risk malignant solid tumors; however, few studies have evaluated their role in treating osteosarcoma. We evaluated the effectiveness of HDCT/ASCT in relapsed pediatric osteosarcoma cases. PROCEDURE: We retrospectively reviewed the medical records of 40 patients diagnosed with and treated for relapsed osteosarcoma at Asan Medical Center and Samsung Medical Center from January 1996 to July 2019. RESULTS: The median age of this cohort was 13.4 years (range: 6.1-18.2). The cohort's 5-year overall survival (OS) was 51.0% ± 0.1% during a median follow-up period of 67.5 months. Twenty-five patients (62.5%) achieved complete remission (CR) with salvage treatment, and the 5-year OS was 82.4% ± 0.1%, whereas none of the remaining 15 patients who did not achieve CR survived (p < .0001). Of the 25 CR cases, 15 underwent subsequent HDCT/ASCT. We compared the effect of HDCT/ASCT among patients who achieved CR. There were no significant differences in the 5-year OS outcomes between patients who did and did not receive HDCT/ASCT (83.9% ± 0.1%, 13/15 vs. 80.0% ± 0.1%, 8/10, respectively; p = .923). CONCLUSION: To our knowledge, we report the first comparative cohort study that proved HDCT/ASCT does not significantly improve survival outcomes in relapsed osteosarcoma. Achievement of CR remains the most crucial factor for good survival outcomes.

Natural medicine HLXL targets multiple pathways of amyloid-mediated neuroinflammation and immune response in treating alzheimer's disease.

BACKGROUND: Based on the complex pathology of AD, a single chemical approach may not be sufficient to deal simultaneously with multiple pathways of amyloid-tau neuroinflammation. A polydrug approach which contains multiple bioactive components targeting multiple pathways in AD would be more appropriate. Here we focused on a Chinese medicine (HLXL), which contains 56 bioactive natural products identified in 11 medicinal plants and displays potent anti-inflammatory and immuno-modulatory activity. HYPOTHESIS/PURPOSE: We investigated the neuroimmune and neuroinflammation mechanisms by which HLXL may attenuate AD neuropathology. Specifically, we investigated the effects of HLXL on the neuropathology of AD using both transgenic mouse models as well as microglial cell-based models. STUDY DESIGN: The 5XFAD transgenic animals and microglial cell models were respectively treated with HLXL and Aß42, and/or lipopolysaccharide (LPS), and then analyzed focusing on microglia mediated Aß uptake and clearance, as well as pathway changes. METHODS: We showed that HLXL significantly reduced amyloid neuropathology by upregulation of microglia-mediated phagocytosis of Aß both in vivo and in vitro. HLXL displayed multi-modal mechanisms regulating pathways of phagocytosis and energy metabolism. RESULTS: Our results may not only open a new avenue to support pharmacologic modulation of neuroinflammation and the neuroimmune system for AD intervention, but also identify HLXL as a promising natural medicine for AD. CONCLUSION: It is conceivable that the traditional wisdom of natural medicine in combination with modern science and technology would be the best strategy in developing effective therapeutics for AD.

Exercise hormone irisin is a critical regulator of cognitive function.

Identifying secreted mediators that drive the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in ageing or Alzheimer's disease (AD). Here, we show that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the benefits of exercise on cognitive function. Genetic deletion of Fndc5/irisin (global Fndc5 knock-out (KO) mice; F5KO) impairs cognitive function in exercise, ageing and AD. Diminished pattern separation in F5KO mice can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moiety. In F5KO mice, adult-born neurons in the dentate gyrus are morphologically, transcriptionally and functionally abnormal. Importantly, elevation of circulating irisin levels by peripheral delivery of irisin via adeno-associated viral overexpression in the liver results in enrichment of central irisin and is sufficient to improve both the cognitive deficit and neuropathology in AD mouse models. Irisin is a crucial regulator of the cognitive benefits of exercise and is a potential therapeutic agent for treating cognitive disorders including AD.

Surgical Outcome of Pulmonary Metastasectomy for Hepatocellular Carcinoma Recurrence in Liver Transplant Patients.

BACKGROUND Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) results in poor survival outcome. This study assessed the clinical outcomes of pulmonary metastasectomy in LT recipients with pulmonary metastasis of HCC in a high-volume transplant center and analyzed factors prognostic of survival following metastasectomy. MATERIAL AND METHODS This study analyzed outcomes in 52 patients who underwent pulmonary resection due to pulmonary metastasis as the first recurrence of HCC after LT from January 2004 to December 2017 in a single center. RESULTS The 52 enrolled patients included 46 men and 6 women, aged 56.0±6.6 years. Their 1-, 3-, and 5-year survival rates after pulmonary resection were 75.0%, 43.5%, and 33.9%, respectively. The 1-, 3-, and 5-year survival rates were 85.3%, 47.1%, and 34.2%, respectively, in patients with further metastases and 55.6%, 38.1%, and 38.1%, respectively, in patients without further metastases (P=0.45). The size and number of pulmonary metastatic nodules were unrelated to survival rates (all P>0.10). A shorter recurrence-free period after LT (hazard ratio [HR]=0.553, P=0.006), elevated alpha-fetoprotein concentration at metastasectomy (HR=2.142, P=0.03), and adjuvant chemotherapy after metastasectomy (HR=3.79, P=0.003) were independent risk factors for survival after metastasectomy. CONCLUSIONS Pulmonary metastasectomy for HCC recurrence in LT recipients showed favorable survival outcomes. Independent risk factors for survival after metastasectomy included recurrence-free survival after LT, alpha-fetoprotein level at metastasectomy, and adjuvant chemotherapy after metastasectomy.

Recent improvement in survival outcomes and reappraisal of prognostic factors in hepatoblastoma.

BACKGROUND: Prognostic factors in hepatoblastoma need to be reevaluated considering the advances in treatment modalities. The study aimed to evaluate current outcomes of hepatoblastoma and reappraise the association of prognostic factors, including pre-treatment extent of tumor (PRETEXT) stage with annotation factors and Children's Hepatic tumors International Collaboration-Hepatoblastoma Stratification (CHIC-HS) system, with survival outcomes. METHODS: We evaluated 103 consecutive patients with hepatoblastoma retrospectively according to the treatment period based on the introduction of a liver transplantation program. RESULTS: The 5-year overall survival (OS), event-free survival (EFS), and transplant-free survival rates were 80.2%, 74.2%, and 61.8%, respectively. EFS and OS were improved significantly from 58.6% to 81.6% (P = 0.024) and from 58.6% to 90.8% (P < 0.001), respectively, in the late period (N = 74) compared with the early period (N = 29). The PRETEXT stage was significant or marginally significant for EFS and OS in the early period but not in the late period. The P, F, R, and C factors were significant for OS and EFS in the early period. However, in the late period, only the P factor was significant for OS, and the F and M factors were significant for EFS. The CHIC-HS system was significant or marginally significant for EFS in both the early and late periods; however, it was significant for OS only in the early period. CONCLUSION: Survival rates were significantly improved in children with hepatoblastoma, especially in those with advanced PRETEXT stages with positive annotation factors and in a high-risk CHIC-HS group. Prognostic factors had different clinical implications with evolved treatment modalities.

Intensive pulmonary rehabilitation in a pediatric lung transplantation patient: A case report.

BACKGROUND: The pediatric lung transplant is a very important treatment for patients with end-stage lung diseae, and pulmonary rehabilitation (PR) is also an important factor in determining the prognosis. However, there is no much literature available on pulmonary rehabilitation in pediatric patients' post lung transplant. Through this case report, we would like to present our intensive PR program for pediatric patients' post-lung transplant. PATIENT CONCERNS: The 10-year-old boy's breathing before receiving a lung transplant continued to deteriorate and he eventually became dependent on a wheelchair. DIAGNOSIS: He was diagnosed with infantile acute lymphoblastic leukemia at 6 months of age. At the age of one year, he underwent allogeneic bone marrow transplantation, but was diagnosed with post-transplantation bronchiolitis obliterans (PTBO) two months later. He had a lung transplant at the age of 10. INTERVENTIONS: He was hospitalized and received an initial assessment. This assessment included functional, cognitive, and psychological evaluations. He additionally completed PR exercises twice daily for two weeks. After discharge, he continued to participate in an outpatient-based PR program for three months. During the outpatient phase, PR exercises were performed once weekly, in addition to home-based cognitive training. OUTCOMES: Our intensive post-lung PR program improved our patient's exercise capacity, lung function, and quality of life. As a comprehensive rehabilitation service, our program also included a cognitive training component. CONCLUSION: We describe an intensive PR program tailored to pediatric patients' post-lung transplant. The program was feasible and resulted in improvements in functional exercise capacity, lung function, and quality of life. Future research into our method is necessary for continued improvement of this novel program.

Predictors of post-thymectomy long-term neurological remission in thymomatous myasthenia gravis: an analysis from a multi-institutional database.

OBJECTIVES: Thymectomy is the treatment of choice for thymomatous myasthenia gravis (MG) for both oncological and neurological aspects. However, only a few studies comprising small numbers of patients have investigated post-thymectomy neurological outcomes. We examined post-thymectomy long-term neurological outcomes and predictors of thymomatous MG using a multi-institutional database. METHODS: In total, 193 patients (47.3 ± 12.0 years; male:female = 90:103) with surgically resected thymomatous MG between 2000 and 2013 were included. Complete stable remission (CSR) and composite neurological remission (CNR), defined as the achievement of CSR and pharmacological remission after thymectomy, were evaluated. Predictors for CSR and CNR were examined by Cox regression analysis. RESULTS: The median duration between MG and thymectomy was 3.1 months. In addition, 161 patients (83.4%) had symptoms less than Myasthenia Gravis Foundation of America clinical classification III. All patients underwent an extended thymectomy; there were no perioperative deaths. The 10-year cumulative probability of CSR and CNR was 36.9% and 69.1%, respectively. Mild preoperative symptoms were a significant predictor for CSR (P = 0.040), and a large tumour was a predictor for CNR (P < 0.001). Patients with a large tumour were associated with early MG onset and no steroid treatment. Surgical methods, thymoma stage and histological subtypes were not associated with long-term neurological remission. CONCLUSIONS: Large tumour size and preoperative mild symptoms were predictors for long-term neurological outcome in thymomatous MG. Considering that patients with early onset of MG and no immunosuppressive treatment tend to have large tumours, early surgical intervention for patients with thymomatous MG having mild symptoms might be beneficial for controlling neurological outcomes.

TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer's Disease.

The microglial receptors CD33 and TREM2 have been associated with risk for Alzheimer's disease (AD). Here, we investigated crosstalk between CD33 and TREM2. We showed that knockout of CD33 attenuated amyloid beta (Aß) pathology and improved cognition in 5xFAD mice, both of which were abrogated by additional TREM2 knockout. Knocking out TREM2 in 5xFAD mice exacerbated Aß pathology and neurodegeneration but reduced Iba1+ cell numbers, all of which could not be rescued by additional CD33 knockout. RNA-seq profiling of microglia revealed that genes related to phagocytosis and signaling (IL-6, IL-8, acute phase response) are upregulated in 5xFAD;CD33-/- and downregulated in 5xFAD;TREM2-/- mice. Differential gene expression in 5xFAD;CD33-/- microglia depended on the presence of TREM2, suggesting TREM2 acts downstream of CD33. Crosstalk between CD33 and TREM2 includes regulation of the IL-1ß/IL-1RN axis and a gene set in the "receptor activity chemokine" cluster. Our results should facilitate AD therapeutics targeting these receptors.

Effect of inferior pulmonary ligament division on residual lung volume and function after a right upper lobectomy.

OBJECTIVES: The requirement to divide an inferior pulmonary ligament (IPL) during an upper lobectomy has not been standardized. We evaluated the influence of the division of an IPL after a lobectomy of the right upper lobe. METHODS: We evaluated 52 patients with lung cancer who underwent a video-assisted thoracoscopic lobectomy of the right upper lobe at Asan Medical Center between January 2011 and April 2014. These cases were stratified by division of the IPL or not, i.e. a preservation group (group P, n = 21) and a division group (group D, n = 31). The angle between the bronchus intermedius and the right middle lobe bronchus and the lung volume were measured using computed tomography. The results of the pulmonary function tests and the prevalence of complications were also reviewed. RESULTS: The prevalences of atelectasis (P = 0.538), dead space (P = 0.084) and pleural effusion (P = 0.538) were not statistically different. The postoperative volumetric change of the right middle lobe (group P, -27 ± 97 ml; group D, -29 ± 111 ml; P = 0.950) and of the right lower lobe (group P, 397 ± 293 ml; group D, 335 ± 294 ml; P = 0.459) did not show statistical differences. The change in the bronchial angle was not statistically different between the groups (group P, -26.3 ± 13.7°; group D, -26.7 ± 13.6°; P = 0.930). The patients in group D experienced a greater loss in forced vital capacity than those in group P (group P, -0.16 ± 0.26 l; group D, -0.42 ± 0.33 l; P = 0.007), but the loss in the forced expiratory volume in 1 s was not significant (P = 0.328). CONCLUSIONS: An IPL division does not produce significant differences in lung volume, bronchial angle change or prevalence of complications other than loss of forced vital capacity.

Surgical Outcomes of Radiographically Noninvasive Lung Adenocarcinoma according to Surgical Strategy: Wedge Resection, Segmentectomy, and Lobectomy.

BACKGROUND: The aim of this study was to evaluate the outcomes of surgical resection in patients with radiographically noninvasive lung adenocarcinoma according to the surgical strategy. METHODS: A retrospective study was conducted of 128 patients who underwent pulmonary resection for ground-glass opacity (GGO)-dominant nodules measuring ≤2 cm with a consolidation/tumor ratio ≤0.25 based on computed tomography between 2008 and 2015. The 5-year disease-free survival (DFS) rate and 5-year overall survival (OS) rate were analyzed. RESULTS: Among the 128 patients, wedge resection, segmentectomy, and lobectomy were performed in 40 (31.2%), 22 (17.2%), and 66 patients (51.6%), respectively. No significant differences were found among the groups in the mean size of tumors (p=0.119), the rate of pure-GGO nodules (p=0.814), the consolidation/tumor ratio (p=0.695), or the rate of invasive adenocarcinoma (p=0.378). Centrally located tumors were more common in the lobectomy group (21.2%) than in the wedge resection (0%) or segmentectomy (0%) groups (p=0.001). There were no significant differences in the 5-year DFS rate (100%, 100%, 92.7%, respectively; p=0.76) or 5-year OS rate (100%, 100%, 100%; p=0.223) among the wedge resection, segmentectomy, and lobectomy groups. CONCLUSION: For radiographically noninvasive lung adenocarcinoma measuring ≤2 cm with a consolidation/tumor ratio ≤0.25, wedge resection and segmentectomy could be comparable surgical options to lobectomy.

Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer's mouse model.

Adult hippocampal neurogenesis (AHN) is impaired before the onset of Alzheimer's disease (AD) pathology. We found that exercise provided cognitive benefit to 5×FAD mice, a mouse model of AD, by inducing AHN and elevating levels of brain-derived neurotrophic factor (BDNF). Neither stimulation of AHN alone, nor exercise, in the absence of increased AHN, ameliorated cognition. We successfully mimicked the beneficial effects of exercise on AD mice by genetically and pharmacologically inducing AHN in combination with elevating BDNF levels. Suppressing AHN later led to worsened cognitive performance and loss of preexisting dentate neurons. Thus, pharmacological mimetics of exercise, enhancing AHN and elevating BDNF levels, may improve cognition in AD. Furthermore, applied at early stages of AD, these mimetics may protect against subsequent neuronal cell death.

Impact of Lymph Node Dissection on Thymic Malignancies: Multi-Institutional Propensity Score Matched Analysis.

INTRODUCTION: Surgical resection is a standard treatment for thymic malignancies. However, prognostic significance of nodal metastases and lymph node dissection remains unclear. The aim of this study is to determine prognostic significance of nodal metastases and the role of lymph node dissection (LND) in thymic malignancies. METHODS: Between 2000 and 2013, 1597 patients who underwent thymectomy due to thymic malignancy were included. Predictive factors for nodal metastasis and prognostic significance of LND were evaluated. Patients were divided into two groups: (1) LND+ group, with intentional LND (446 patients, 27.9%); and (2) LND- group, without intentional LND (1151 patients, 72.1%). Propensity score matching was performed between the two groups. RESULTS: Lymph node metastasis was identified in 20 (6.7%) of 298 patients with thymoma and 47 (31.7%) of 148 patients with thymic carcinoma. In multivariable analysis, thymic carcinoma (hazard ratio: 19.2, p < 0.001) and tumor size (hazard ratio: 1.09, p = 0.02) were significant predictive factors for lymph node metastasis. The 10-year freedom from recurrence rate of pN1 and pN2 was significantly worse than that of pN0 (p < 0.001). LND did not increase operative mortality or complication. There was no significant difference in 10-year freedom from recurrence rate between LND+ and LND- groups (82.4% versus 80.9%, p = 0.46 in thymoma; 45.7% versus 44.0%, p = 0.42 in thymic carcinoma). CONCLUSIONS: Lymph node metastasis was a significant prognostic factor in thymic malignancies. Although LND did not improve long-term outcomes in thymic malignancies, LND played a role in accurate staging, and improved prediction of prognosis.

Surgical Options for Malignant Mesothelioma: A Single-Center Experience.

BACKGROUND: We investigated the surgical outcomes of patients who underwent therapeutic surgery for malignant pleural mesothelioma (MPM) at a single center. METHODS: A retrospective review of 21 patients who underwent therapeutic surgery for MPM from January 2001 to June 2015 was conducted to assess their outcomes. The patients' characteristics and postoperative course, including complications, mortality, overall survival, and recurrence-free survival, were analyzed. RESULTS: Of the 21 patients who underwent therapeutic surgery, 15 (71.4%) underwent extrapleural pneumonectomy, 2 pleurectomy (9.5%), and 4 excision (19.1 %). The median age was 57 years (range, 32-79 years) and 15 were men (71.4%). The mean hospital stay was 16 days (range, 1-63 days). Median survival was 14.3 months. The survival rate was 54.2%, 35.6%, and 21.3% at 1, 3, and 5 years, respectively. In patients' postoperative course, heart failure was a major complication, occurring in 3 patients (14.3%). The in-hospital mortality rate was 2 of 21 (9.5%) due to a case of severe pneumonia and a case of acute heart failure. CONCLUSION: A fair 5-year survival rate of 21.3% was observed after surgical treatment. Heart failure was a major complication in our cohort. Various surgical methods can be utilized with MPM, each with its own benefits, taking into consideration the severity of the disease and the comorbidities of the patient. Patients with local recurrence may be candidates for surgical intervention, with possible satisfying results.

Prognosis of multi-level N2-positive non-small cell lung cancer according to lymph node staging using endobronchial ultrasound-transbronchial biopsy.

BACKGROUND: The optimal treatment for stage IIIA-N2 non-small cell lung cancer (NSCLC) remains controversial, and multidisciplinary team approaches are needed. Downstaging after induction therapy is a good prognostic factor in surgical patients; however, re-evaluation of nodal status before surgery is challenging. The aim of this study was to evaluate the prognosis of patients with multi-level N2 NSCLC who received surgery or chemoradiation therapy (CRT) according to restaging using endobronchial ultrasound-transbronchial aspiration (EBUS-TBNA). METHODS: This was a single center, prospective study that included 16 patients with biopsy-proven multi-level N2 disease on initial EBUS-TBNA that was restaged using EBUS-TBNA after induction therapy. Cases downstaged after rebiopsy were treated surgically. Three-year progression-free survival (PFS) and locoregional PFS were determined using Kaplan-Meier analysis. RESULTS: Of the 16 patients (median age 58 years, male 63%), eight had persistent N2 disease and eight showed N2 clearance on restaging using EBUS-TBNA. Ten patients underwent surgery, including two patients without N2 clearance. Recurrence and locoregional recurrence occurred in eight and five patients, respectively. The three-year PFS was longer in patients with N2 clearance than in those with N2 persistent disease (57.1% vs. 37.5%). Patients with N2 clearance also had longer three-year locoregional PFS than those with N2 persistent disease (71.4% vs. 62.5%). CONCLUSIONS: EBUS-TBNA could be an effective diagnostic method for restaging in multi-level N2 NSCLC patients after induction CRT. As this was a pilot study, further large-scale randomized studies are needed.

Surgical Outcomes after Pulmonary Resection for Non-Small Cell Lung Cancer with Localized Pleural Seeding First Detected during Surgery.

OBJECTIVES: Curative resection is not indicated for non-small cell lung cancer (NSCLC) with pleural seeding, which is classified as stage IV (M1a) disease. However, some patients with a presumably resectable main tumor are diagnosed with localized pleural seeding during surgery. METHODS: A retrospective analysis was performed of 3,975 patients who underwent surgery for NSCLC from 2000 to 2011. Among these cases, 78 (2.0%) patients had unexpected pleural seeding detected during surgery. Exploration with pleural biopsy was performed in 42 of these patients (exploration-only group) and pulmonary resection, including for the main tumor, was performed in 36 cases (resection group; sublobar resection in 12, lobectomy in 21, and pneumonectomy in 3 patients). Survival and cancer progression rates were estimated using the Kaplan-Meier method. Cox proportional hazard regression was used to evaluate prognostic factors associated with survival. RESULTS: Adenocarcinoma was the predominant histological type in both the exploration and resection groups (88.1 and 86.1%, respectively). Epidermal growth factor receptor expression was detected in 22 (52.4%) patients of the exploration group and 21 (58.3%) patients of the resection group. Baseline characteristics including age, sex, comorbidity, pulmonary function, and clinical T/N status were not significantly different between the two groups. There were no postoperative deaths in either group but postoperative complications occurred in two (4.8%) patients of the exploration group and three (8.3%) patients of the resection group. The overall 3- and 5-year survival rates in the exploration group were 41.1 and 15.2%, respectively, with a median survival time (MST) of 33 months, whereas they were 66.7 and 42.7%, respectively, in the resection group, with a 52-month MST (p = 0.012). Local and regional progression-free rates were significantly different (p < 0.001 and p = 0.029, respectively) between groups, whereas no difference was seen in the distant metastasis rates (p = 0.957). In multivariate survival analysis, surgical resection was the only significant prognostic factor (p = 0.01). CONCLUSIONS: Pulmonary resection including the main tumor, regardless of resection extent, may increase long-term survival for NSCLC patients with localized pleural seeding first detected during surgery, without a significant increase in hospital mortality or morbidity.

Surgical Outcome of Colon Interposition in Esophageal Cancer Surgery: Analysis of Risk Factors for Conduit-Related Morbidity.

BACKGROUND: We aimed to assess the feasibility, surgical outcomes, and conduit-related complications of colon interposition in patients with esophageal cancer. METHODS: Patients with esophageal cancer who underwent colon interposition for esophageal reconstruction between June 2000 and June 2013 were retrospectively reviewed. RESULTS: A total of 67 consecutive patients (mean age, 62.2 ± 7.9 years) were enrolled. During this time period, 944 patients underwent esophageal reconstruction using gastric conduit. Twelve patients (17.9%) also received neoadjuvant chemoradiotherapy (nCRT). The median follow-up duration was 44 months (range, 1-168 months); median survival duration was 63 months (range, 1-168 months); and 3- and 5-year overall survival rates were 61.6 and 49.4%, respectively. A total of 43 patients (64.2%) experienced at least 1 postoperative morbidity. According to the Clavien-Dindo grading system, 36 patients (54%) experienced postoperative morbidity of higher than Grade III. Pulmonary complications were most commonly observed complications among the patients (18 patients, 26.9%). Anastomosis site leakage developed in 11 patients (16.4%), and 3 of these patients (6.0%) eventually experienced graft failure. On multivariate analysis, nCRT was determined as a significant risk factor for conduit-related complications (leakage, graft failure, fistula, and stricture). CONCLUSION: Colon interposition is associated with relatively high complication rates, whereas nCRT is associated with conduit morbidity.

Post-recurrence survival analysis of stage I non-small-cell lung cancer.

Background The aim of this retrospective study was to review recurrence patterns of stage I non-small-cell lung cancer and identify prognostic factors for post-recurrence survival. Methods Among 940 patients with pathological stage I non-small-cell lung cancer who underwent curative resection, 261 experienced a recurrence; of these, 188 had adenocarcinoma and 62 had squamous cell carcinoma. Oligo-recurrence was defined as 1-3 recurrent lesions restricted to a single organ. Potentially curative local treatment included surgery, stereotactic radiotherapy, and photodynamic therapy. Results The median follow-up duration was 65 months (range 4-186 months). The most common site of recurrence was the lung in 145 patients, followed by mediastinal lymph nodes in 49, pleura in 30, and brain in 27. Local treatment for recurrent tumors included surgery in 59 patients, stereotactic radiotherapy in 46, photodynamic therapy in 2, and other radiotherapy in 41. Seventy-eight patients received chemotherapy only, and 35 received conservative treatment. Among 125 patients who were evaluated for an epidermal growth factor receptor gene mutation, 31 were treated with epidermal growth factor receptor-tyrosine kinase inhibitor. The 3- and 5-year post-recurrence survival rates were 49.1% and 33.8%, respectively. Age at recurrence, adenocarcinoma cell type, disease-free interval, epidermal growth factor receptor-tyrosine kinase inhibitor treatment, and potentially curative local treatment were independent prognostic factors for survival in multivariate analysis. Conclusions Local treatment for recurrence should be considered in selected candidates, and use of epidermal growth factor receptor-tyrosine kinase inhibitor I is reasonable if an epidermal growth factor receptor mutation is detected.

Multiple receptor tyrosine kinase activation related to ALK inhibitor resistance in lung cancer cells with ALK rearrangement.

The activation of alternative receptor tyrosine kinases (RTKs) is known to mediate resistance to ALK inhibitors. However, the role of multiple RTK activation in resistance has yet to be determined. Two crizotinib-resistant (H3122/CR-1 and H3122/CR-2) and one TAE684-resistant (H2228/TR) cell lines were established. Multi-RTK arrays and Western blots were performed to detect the activation of bypass signals. There were no secondary mutations in the sequencing. EGFR and MET were activated in H3122/CR-1 cells whereas EGFR and IGF1R were activated in H3122/CR-2 cells. Concomitant activation of MET did not contribute to resistance as crizotinib completely suppressed both p-MET and p-ALK in H3122/CR-1 cells, whose survival was not affected by crizotinib. However, combined inhibition of EGFR and ALK was effective in controlling this resistant cell line. In H3122/CR-2 cells, the inhibition of both ALK and IGF1R could effectively suppress cell growth, whereas simultaneous inhibition of ALK and EGFR brought about a less-effective suppression, indicating that IGF1R activation is the main resistance mechanism. H2228/TR cells showed activation of the HER family (EGFR, ErbB2, and ErbB3). Afatinib, a pan-HER inhibitor, was more potent in suppressing resistant cells than gefitinib when combined with crizotinib, which suggests that coactivation of ErbB2 and ErbB3 also contributes to resistance. Interestingly, all three resistant cell lines responded well to AUY922, which can inhibit ALK, EGFR, and IGF1R activity. Activation of multiple RTKs can occur during acquired resistance to ALK inhibitors, in which case the dominant or significant bypass signal should be identified to provide a more appropriate combination therapy.