Stereotypic T cell receptor clonotypes in the thymus and peripheral blood of Myasthenia gravis patients.

Myasthenia Gravis (MG) patients with anti-acetylcholine receptor (AChR) antibodies frequently show hyperplastic thymi with ectopic germinal centers, where autoreactive B cells proliferate with the aid of T cells. In this study, thymus and peripheral blood (PB) samples were collected from ten AChR antibody-positive MG patients. T cell receptor (TCR) repertoires were analyzed using next-generation sequencing (NGS), and compared with that of an age and sex matched control group generated from a public database. Certain V genes and VJ gene recombination pairs were significantly upregulated in the TCR chains of αß-T cells in the PB of MG patients compared to the control group. Furthermore, the TCR chains found in the thymi of MG patients had a weighted distribution to longer CDR3 lengths when compared to the PB of MG patients, and the TCR beta chains (TRB) in the MG group's PB showed increased clonality encoded by one upregulated V gene. When TRB sequences were sub-divided into groups based on their CDR3 lengths, certain groups showed decreased clonality in the MG group's PB compared to the control group's PB. Finally, we demonstrated that stereotypic MG patient-specific TCR clonotypes co-exist in both the PB and thymi at a much higher frequency than that of the clonotypes confined to the PB. These results strongly suggest the existence of a biased T cell-mediated immune response in MG patients, as observed in other autoimmune diseases.

Germinal centers are associated with postthymectomy myasthenia gravis in patients with thymoma.

BACKGROUND AND PURPOSE: Germinal centers (GCs) can be observed in the thymic tissues of patients with thymoma-associated myasthenia gravis (MG). Although an association between thymic GCs and MG has been suggested, it is unknown whether the presence of GCs could predict the development of MG after the resection of thymoma, known as postthymectomy MG. METHODS: We conducted a retrospective analysis of previously nonmyasthenic patients who underwent surgical removal of the thymoma. All available thymic tissue slides were rereviewed by a pathologist to assess for GCs. Patients were classified into GC-positive and GC-negative groups based on the presence of GCs. The incidence of postthymectomy MG was compared between the two groups, and the risk factors for postthymectomy MG were assessed. RESULTS: Of the 196 previously nonmyasthenic patients who underwent thymoma resection, 21 were GC-positive, whereas 175 were GC-negative. Postthymectomy MG developed in 11 (5.6%) patients and showed a higher incidence in the GC-positive group than in the GC-negative group (33.3% vs. 2.3%, p < 0.001). No postoperative radiotherapy and the presence of GCs were risk factors for postthymectomy MG in the univariate analysis. In multivariate analysis, invasive thymoma (hazard ratio [HR] = 9.835, 95% confidence interval [CI] = 1.358-105.372), postoperative radiotherapy (HR = 0.160, 95% CI = 0.029-0.893), and presence of GCs (HR = 15.834, 95% CI = 3.742-67.000) were significantly associated with postthymectomy MG. CONCLUSIONS: Thymic GCs may be a significant risk factor for postthymectomy MG. Even in patients with thymoma who do not show clinical symptoms of MG, postthymectomy MG should be considered, especially if thymic GCs are observed.

Completely Resectable (cT1-2) Esophageal Squamous Cell Carcinoma with Minimal Lymph Node Involvement (cN1): Is Neoadjuvant Chemoradiation Therapy the Only Viable Treatment Option?

BACKGROUND: Neoadjuvant chemoradiation therapy (nCRT) is recommended when lymph node metastasis is evident or strongly suspected on preoperative imaging studies, even for a completely resectable (cT1-2) tumor with minimal lymph node involvement (cN1). We evaluated the validity of upfront surgical approach in this patient group. METHODS: We retrospectively reviewed data from 247 patients with cT1-2 esophageal squamous cell carcinoma (ESCC) who underwent upfront radical esophagectomy followed by the pathology-based adjuvant treatment. Oncologic outcomes of cN1 patients were compared with those of cN0 patients. RESULTS: There were 203 cN0 and 44 cN1 patients. The lymph node yield was 62.0 (interquartile range [IQR], 51.0-76.0) in cN0 and 65.5 (IQR, 57.5-85.0) in cN1 patients (p = 0.033). The size of metastatic node was 0.6 cm (IQR, 0.4-0.9 cm) in cN0 and 0.8 cm (IQR, 0.5-1.3 cm) in cN1 patients (p = 0.001). Nodal upstaging was identified in 29.1% of cN0 and 40.9% of cN1 patients, whereas 18.2% of the cN1 had no actual lymph node metastasis (pN0). The 5-year disease-free survival rate was not significantly different between the groups (cN0, 74.4%; cN1, 71.8%; p = 0.529). Survival rates were closely correlated with pN stage, and a multivariate analysis revealed that pN2-3 stage was a risk factor for poor disease-free survival. CONCLUSIONS: Upfront radical surgery provided accurate nodal staging information, potentially sparing some cN1 patients from unnecessary nCRT while demonstrating comparable survival rates. It might be a valid option for the treatment of cT1-2N1 ESCC.

Immediate Postoperative High Syndecan-1 is Associated with Short-Term Morbidity and Mortality After Robot-Assisted Esophagectomy: A Prospective Observational Study.

BACKGROUND: Disruption of the endothelial glycocalyx (EG) is associated with a poor prognosis in various clinical settings. This study aimed to determine the association between immediate postoperative serum syndecan-1 levels, a representative marker for EG degradation, and major postoperative morbidity and mortality in patients undergoing robot-assisted esophagectomy. METHODS: Patients who underwent robot-assisted esophagectomy between 2018 and 2022 were prospectively enrolled. The primary outcome was the association between immediate postoperative syndecan-1 levels and the occurrence of major postoperative morbidity and mortality within 30 days of surgery. Patients were classified into low and high syndecan-1 groups based on the optimal cut-off value of syndecan-1 for predicting major morbidity and mortality. A multivariable logistic regression analysis was performed to investigate the risk factors for major morbidity and mortality. RESULTS: A total of 207 patients were analyzed. Patients with high syndecan-1 levels (≥48 ng/mL) showed a significantly greater incidence of unexpected returns to the operating room and anastomotic leaks and longer durations of hospital and intensive care unit stays than patients with low syndecan-1 levels (<48 ng/mL). Immediate postoperative syndecan-1 levels ≥48 ng/mL (odds ratio [OR] 2.32, 95% confidence interval [CI] 1.23-4.76), American Society of Anesthesiologists physical status ≥III (OR 3.36, 95% CI 1.56-7.22), and current smoker (OR 4.02, 95% CI 1.52-10.61) were independently associated with major morbidity and mortality within 30 days of esophagectomy. CONCLUSIONS: Immediate postoperative syndecan-1 levels ≥48 ng/mL could be used for the early detection of patients at high risk of complications after robot-assisted esophagectomy.

Clinical Outcomes of Thymic Carcinoma: The Role of Radiotherapy Combined with Multimodal Treatments.

INTRODUCTION: We aimed to identify the role of radiotherapy (RT) in the treatment of thymic carcinoma as well as the optimal RT target volume. MATERIALS AND METHODS: This single-institution retrospective study included 116 patients diagnosed with thymic carcinoma between November 2006 and December 2021 who received multimodal treatment including RT with or without surgery or chemotherapy. Seventy-nine patients (68.1%) were treated with postoperative RT, 17 patients (14.7%) with preoperative RT, 11 patients (9.5%) with definitive RT, and nine patients (7.8%) with palliative RT. The target volume was defined as the tumor bed or gross tumor with margin, and selective irradiation of the regional nodal area was performed when involved. RESULTS: With a median follow-up of 37.0 (range, 6.7-174.3) months, the 5-year overall survival (OS), progression-free survival, and local recurrence-free survival rates were 75.2%, 47.7% and 94.7%, respectively. The 5-year OS was 51.9% in patients with unresectable disease. Overall, 53 recurrences were observed, of which distant metastasis was the most common pattern of failure (n = 32, 60.4%) after RT. No isolated infield or marginal failures were observed. Thirty patients (25.8%) who had lymph node metastases at the initial diagnosis had regional nodal areas irradiated. There was no lymph node failure inside the RT field. A tumor dimension of ≥5.7 cm (hazard ratio [HR] 3.01; 95% confidence interval [CI] 1.25-7.26; p = 0.030) and postoperative RT (HR 0.20; 95% CI 0.08-0.52; p = 0.001) were independently associated with OS. Intensity-modulated-RT-treated patients developed less overall toxicity (p < 0.001) and esophagitis (p < 0.021) than three-dimensional-conformal-RT-treated patients. CONCLUSIONS: A high local control rate was achieved with RT in the primary tumor sites and involved lymph node area in the treatment of thymic carcinoma. A target volume confined to the tumor bed or gross tumor plus margin with the involved lymph node stations seems reasonable. The advanced RT techniques with intensity-modulated RT have led to reduced RT-related toxicity.

Risk factors of pneumothorax and pneumomediastinum in COVID-19: a matched case-control study.

BACKGROUND: During the novel coronavirus disease-2019 pandemic, a considerable number of pneumothorax (PNX)/pneumomediastinum (PNM) associated with COVID-19 have been reported, and the incidence is higher in critically ill patients. Despite using a protective ventilation strategy, PNX/PNM still occurs in patients on invasive mechanical ventilation (IMV). This matched case-control study aims to identify the risk factors and clinical characteristics of PNX/PNM in COVID-19. METHODS: This retrospective study enrolled adult patients with COVID-19, admitted to a critical care unit from March 1, 2020, to January 31, 2022. COVID-19 patients with PNX/PNM were compared, in a 1-2 ratio, to COVID-19 patients without PNX/PNM, matched for age, gender, and worst National Institute of Allergy and Infectious Diseases ordinal scale. Conditional logistic regression analysis was performed to assess the risk factors for PNX/PNM in COVID-19. RESULTS: 427 patients with COVID-19 were admitted during the period, and 24 patients were diagnosed with PNX/PNM. Body mass index (BMI) was significantly lower in the case group (22.8 kg/m2 and 24.7 kg/m2; P = 0.048). BMI was statistically significant risk factor for PNX/PNM in univariate conditional logistic regression analysis [odds ratio (OR), 0.85; confidence interval (CI), 0.72-0.996; P = 0.044]. For patients on IMV support, univariate conditional logistic regression analysis showed the statistical significance of the duration from symptom onset to intubation (OR, 1.14; CI, 1.006-1.293; P = 0.041). CONCLUSIONS: Higher BMI tended to show a protective effect against PNX/PNM due to COVID-19 and delayed application of IMV might be a contributive factor for this complication.

Proposal of a revised International Association for the Study of Lung Cancer grading system in pulmonary non-mucinous adenocarcinoma: The importance of the lepidic proportion.

OBJECTIVES: We aimed to measure the validity of the International Association for the Study of Lung Cancer (IASLC) grading system in Korean patients and propose a modification for an increase of its predictability, especially in grade 2 patients. MATERIALS AND METHODS: From 2012 to 2017, histopathologic characteristics of 1358 patients with invasive pulmonary adenocarcinoma (stage I-III) from two institutions were retrospectively reviewed and re-classified according to the IASLC grading system. Considering the amount of the lepidic proportion, the validity of the revised model (Lepidic-10), derived from the training cohort (hospital A), was measured using the validation cohort (hospital B). Its predictability was compared to that of the IASLC system. RESULTS: Of the 1358 patients, 259 had a recurrence, and 189 died during follow-up. The Harrell's concordance index and area under the curve of the IASLC system were 0.685 and 0.699 for recurrence-free survival (RFS) and 0.669 and 0.679 for death, respectively. From the training cohort, the IASLC grade 2 patients were divided into grades 2a and 2b (Lepidic-10 model) with a 10 % lepidic pattern. This new model further distinguished patients in both institutions that had better performance than the IASLC grading (Hospital A, p < 0.001 for RFS and death; Hospital B, p = 0.0215 for RFS, p = 0.0429 for death). CONCLUSION: The IASLC grading system was easily applicable; its clinical use in predicting the prognosis of Korean patients with pulmonary adenocarcinoma was validated. Furthermore, the introduction of the lepidic proportion as an additional criterion to differentiate grade 2 patients improved its predictability.

Importance of Local Ablative Therapies for Lung Metastases in Patients With Colorectal Cancer.

OBJECTIVE: To assess the effect of local ablative therapy (LAT) on overall survival in patients with lung metastases from colorectal cancer (CRC) compared with patients treated with systemic therapy. SUMMARY BACKGROUND DATA: CRC affects approximately 1.4 million individuals worldwide every year. The lungs are commonly affected by CRC, and there is no treatment standard for a secondary lung metastasis from CRC. METHODS: This longitudinal, retrospective cohort study (2010-2018) quantified the pulmonary and extrapulmonary tumor burden of 1143 patients by retrospectively reviewing computed tomography images captured at diagnosis. A comprehensive multidisciplinary approach informed how and when surgery and/or stereotactic body radiotherapy was administered. RESULTS: Among 1143 patients, 473 patients (41%) received LAT, with surgery first (n = 421) or stereotactic ablative radiation therapy first (n = 52) either at the time of diagnosis (n = 288), within 1 year (n = 132), or after 1 year (n = 53). LAT was repeated in 158 patients (33.4%, 384 total sessions) when new lung metastases were detected. The 5- and 10-year survival rates for patients treated with LAT (71.2% and 64.0%, respectively) were significantly higher than those of patients treated with systemic therapy alone (14.2% and 10.0%, respectively; P <0.001). The overall survival of patients who received LAT intervention increased as the total tumor burden decreased. CONCLUSIONS: A high long-term survival rate was achievable in a significant portion of patients with lung metastasis from CRC by the timely administrations of LAT to standard systemic therapy. The tumor burden and LAT feasibility should be included in a discussion during the follow-up period.

The Role of Adjuvant Therapy Following Surgical Resection of Small Cell Lung Cancer: A Multi-Center Study.

PURPOSE: This multi-center, retrospective study was conducted to evaluate the long-term survival in patients who underwent surgical resection for small cell lung cancer (SCLC) and to identify the benefit of adjuvant therapy following surgery. MATERIALS AND METHODS: The data of 213 patients who underwent surgical resection for SCLC at four institutions were retrospectively reviewed. Patients who received neoadjuvant therapy or an incomplete resection were excluded. RESULTS: The mean patient age was 65.29±8.93 years, and 184 patients (86.4%) were male. Lobectomies and pneumonectomies were performed in 173 patients (81.2%), and 198 (93%) underwent systematic mediastinal lymph node dissections. Overall, 170 patients (79.8%) underwent adjuvant chemotherapy, 42 (19.7%) underwent radiotherapy to the mediastinum, and 23 (10.8%) underwent prophylactic cranial irradiation. The median follow-up period was 31.08 months (interquartile range, 13.79 to 64.52 months). The 5-year overall survival (OS) and disease-free survival were 53.4% and 46.9%, respectively. The 5-year OS significantly improved after adjuvant chemotherapy in all patients (57.4% vs. 40.3%, p=0.007), and the survival benefit of adjuvant chemotherapy was significant in patients with negative node pathology (70.8% vs. 39.7%, p=0.004). Adjuvant radiotherapy did not affect the 5-year OS (54.6% vs. 48.5%, p=0.458). Age (hazard ratio [HR], 1.032; p=0.017), node metastasis (HR, 2.190; p < 0.001), and adjuvant chemotherapy (HR, 0.558; p=0.019) were associated with OS. CONCLUSION: Adjuvant chemotherapy after surgical resection in patients with SCLC improved the OS, though adjuvant radiotherapy to the mediastinum did not improve the survival or decrease the locoregional recurrence rate.

Prognosis of resected invasive mucinous adenocarcinoma compared with the IASLC histologic grading system for invasive nonmucinous adenocarcinoma: Surgical database study in the TKIs era in Korea.

BACKGROUND: The prognosis of invasive mucinous adenocarcinoma (IMA) remains controversial and should be clarified by comparison with the International Association for the Study of Lung Cancer (IASLC) histologic grading system for invasive nonmucinous adenocarcinoma (INMA). METHODS: This study included patients with IMA who underwent curative resection. Their clinicopathological outcomes were compared with those of patients with INMA. Propensity score matching was performed to compare the prognosis of IMA with IASLC grade 2 or 3. Kaplan-Meier survival curves and log-rank tests were used to analyze recurrence-free survival (RFS) and overall survival (OS). RESULTS: The prognoses of IMA and IASLC grade 2 were similar in terms of RFS and OS. Although patients with IMA had better RFS than patients with IASLC grade 3, the OS was not significantly different. After propensity score matching, IMA demonstrated similar RFS to IASLC grade 2 but superior to IASLC grade 3; there was no difference in the OS compared with grades 2/3. Multivariate analysis revealed that tumor size (hazard ratio [HR] = 1.20, p = 0.028), lymphovascular invasion (HR = 127.5, p = 0.003), and maximum standardized uptake value (HR = 1.24, p = 0.005) were poor prognostic predictors for RFS. Patients with IMA demonstrated RFS similar to and significantly better than that of patients with IASLC grades 2 and 3, respectively. For OS, IMA prognosis was between that of IASLC grades 2 and 3. CONCLUSIONS: Since the prognosis of IMA among lung adenocarcinomas appears to be relatively worse, further clinical studies investigating IMA-specific treatment and follow-up plans are necessary to draw more inferences.

Postoperative bronchopleural fistula repair: Surgical outcomes and adverse factors for its success.

BACKGROUND: The purpose of this study was to investigate the results of postoperative bronchopleural fistula repair and to identify adverse factors for its success. METHODS: We retrospectively reviewed the surgical results of 39 patients who underwent surgical repair for postoperative bronchopleural fistula between January 2010 and June 2020. Success of bronchopleural fistula repair was defined as the visual closure of the bronchopleural fistula with the absence of an air leak, a recurrence of bronchopleural fistula and infection in the thoracic cavity. RESULTS: Twenty-five (64.1%) bronchopleural fistulas occurred after pulmonary resection and 14 (35.9%) after lung transplantation. Bronchopleural fistula was diagnosed 19 days (median) and repaired 28 days (median) after the initial operation by primary closure in 27 (69.2%) patients, and by additional resection in 12 (30.8%) patients. The overall success rate was 59% (23/39) and the overall mortality was 56.4% (22/39). Multivariable analysis revealed that the patients who were supported by mechanical ventilation at the time of repair had significantly lower success rates than those without (15.4%, 2/13 vs. 80.8%, 21/26, respectively, p < 0.001). The omental flap group tended to have a better success rate than the muscle flap group (p = 0.07). CONCLUSIONS: There was a high overall mortality rate after bronchopleural fistula repair and a low success rate. Mechanical ventilation at the time of bronchopleural fistula repair was significantly related to the failure of bronchopleural fistula repair.

Skeletonizing En Bloc Esophagectomy Revisited: Oncologic Outcome in Association with the Presence of Thoracic Duct Lymph Nodes.

BACKGROUND: Skeletonizing en bloc esophagectomy (SEBE) involves the removal of the esophagus en bloc with locoregional soft tissues and lymph nodes, including the thoracic duct (TD); however, its oncologic benefits remain unclear. We evaluated the impact of SEBE on oncologic outcomes in patients with esophageal squamous cell carcinoma. METHODS: Patients undergoing McKeown esophagectomy without neoadjuvant therapy between 2013 and 2019 were evaluated. Outcomes after SEBE were compared with those after conventional esophagectomy (CE) using propensity score-matched analysis. RESULTS: Overall, 232 patients were identified, including 133 patients with SEBE and 99 patients with CE. Lymph node metastasis along the TD was identified in 7.5% (10/133) of the SEBE group, and the incidence was closely related with the tumor invasion depth (2.2% in pT1 and 19.0% in pT2-3). Based on the propensity score, 180 patients (90 pairs) were analyzed. Tumor recurrence was identified in 24.4% and 12.2% of CE and SEBE cases, respectively (p = 0.036). The observed difference was due to the higher incidence of locoregional recurrence in CE (10.5% vs. 2.2%; p = 0.024), while the incidence of systemic recurrence was similar (18.6% vs. 12.2%; p = 0.240). The 5-year disease-free survival rate was 83.6% and 62.4% in the SEBE and CE groups, respectively (p = 0.022). Multivariate analysis revealed that SEBE could significantly reduce the risk of recurrence or death in patients with pT2-3 tumors (hazard ratio 0.173, 95% confidence interval 0.048-0.628; p = 0.008). CONCLUSIONS: SEBE could identify and eradicate lymphatic metastasis along the TD and positively impact disease-free survival, particularly in patients with pT2-3 tumors.

Positive nodal status is still a risk factor for long-term survivors of non-small cell lung cancer 5 years after complete resection.

BACKGROUND: Lung cancer has a poor prognosis; the number of long-term survivors (LTSs) is small compared with that of other cancers. Few studies have focused on late recurrence in LTSs with lung cancer. The purpose of this study was to analyze the risk factors for survival and late recurrence in LTSs after disease-free period of 5 years. METHODS: A retrospective analysis of patients with a disease-free survival of at least 5 years after surgical resection for non-small cell lung cancer (NSCLC) between January 1998 and December 2012 was conducted. Patients who underwent neo-adjuvant therapy, had an incomplete resection, or had advanced stage (stages IIIb and IV) cancer were excluded. RESULTS: A total of 1,254 (53.2%) of 2,357 patients were enrolled. Of these, 759 (60.5%) were men, and the mean patient age was 61.9±10.1 (range, 10-87 years) years. Pathologic N0 (997 patients, 79.5%) and stage I (860 patients, 68.6%) were the dominant stages. Late recurrence occurred in 22 patients (1.8%) 5 years postoperatively. On multivariate analysis, male sex, older age, node-positive status, and late recurrence were found to be independent risk factors for overall survival (OS), while a node-positive status was the only independent risk factor for disease-free survival [hazard ratio (HR) =3.824; P=0.002; 95% confidence interval (CI): 1.658-8.821]. CONCLUSIONS: The nodal stage at the time of surgical resection was found to be an independent risk factor for both OS and disease-free survival 5 years after initial treatment in patients with completely resected NSCLC.

Effects of mediastinal lymph node dissection in colorectal cancer-related pulmonary metastasectomy.

BACKGROUND: The benefits of mediastinal lymph node dissection (MLND) in colorectal cancer-related pulmonary metastasectomy (PM) have been poorly reported. This study aimed to determine whether MLND affects survival in patients undergoing PM and to identify the prognostic factors for survival. METHODS: We retrospectively reviewed 275 patients who had undergone colorectal cancer-related PM from January 2010 to December 2016. MLND was defined as the resection of at least six mediastinal lymph node stations according to the International Association for the Study of Lung Cancer criteria (N1, ≥3 stations; N2, ≥3 stations). The propensity score matching method was used to reduce bias. RESULTS: Thirty-three (12%) patients underwent MLND, and 13 (4.7%) patients had mediastinal lymph node involvement. This study showed no difference in 5-year overall survival (no MLND, 52.7% vs. MLND, 53.5%; p = 0.81). On multivariable analysis, negative prognostic factors for overall survival were preoperative carcinoembryonic antigen (CEA) level (p < 0.001), a higher number of metastatic nodules (p < 0.001), metastatic nodule size ≥2 cm (p < 0.001), and lymph node involvement (p = 0.006). CONCLUSIONS: Mediastinal lymph node involvement, preoperative CEA level, higher metastatic nodule number, and nodule size negatively affected survival whereas MLND in PM was not associated with survival.

Robot-Assisted Thoracoscopic Esophagectomy with Total Mediastinal Lymphadenectomy: A Guide to a Systematic Approach Using the Concept of Fascial Plane Dissection.

Recent case series and meta-analyses have suggested that robot-assisted minimally invasive esophagectomy (RAMIE) could be a useful alternative to video-assisted thoracic surgery esophagectomy. The advantages of RAMIE are a 3-dimensional view, 7 degrees of freedom, and tremor filtering, which enable more meticulous lymph node dissection with a lower incidence of complications. However, in radical esophagectomy, understanding the concepts of the fascia and compartment is crucial for successful and reliable dissection. The first RAMIE in Korea was performed by our team in July 2006, and since then, we have developed related techniques to achieve better short- and long-term outcomes. The key step in RAMIE for esophageal squamous cell carcinoma is dissection of the upper mediastinum due to the difficulty of lymph node dissection and the high incidence of nodal metastasis in the area. Herein, we describe the technique of fascial plane dissection with esophageal suspension during RAMIE.

Genetic Analysis and Operative Outcomes in Patients with Oncogene-Driven Advanced NSCLC Treated with Cytoreductive Surgery as a Component of Local Consolidative Therapy.

Most patients with oncogene-driven advanced non-small cell lung cancer (NSCLC) demonstrate recurrence because of the developing targeted therapy resistance. In this retrospective study, we assessed the efficacy of surgical local consolidative treatment by analyzing the operative outcomes and genetic data in 44 patients who underwent pulmonary resection for stage IIIB/C-IV NSCLC after targeted therapy. The initial mutations were in the EGFR (n = 32), ALK (n = 11), and ROS1 (n = 1) genes. The median interval from the initiation of tyrosine kinase inhibitor (TKI) therapy immediately before the surgery to the actual operation was 9.8 months. Operative mortality was absent. Four patients showed complete remission. The median follow-up period after TKI therapy initiation was 23.1 months. The Kaplan-Meier survival analysis showed that the 2-year failure-free survival and overall survival rates from the initiation of TKI were 70.8% and 95.0%, respectively. During the follow-up period, two patients died and 15 suffered from disease progression. Among the 32 patients with EGFR mutations, 12 showed additional mutations, and targeted agents were replaced in nine patients after the operation. We conclude that pulmonary resection for advanced NSCLC after targeted therapy is feasible, and the surgical specimens could be used for planning further targeted therapy.

FCN3 functions as a tumor suppressor of lung adenocarcinoma through induction of endoplasmic reticulum stress.

In this study, we report a novel function of FCN3 (Ficolin 3), a secreted lectin capable of activating the complement pathway, as a tumor suppressor of lung adenocarcinoma (LUAD). First, the expression of FCN3 was strongly down-regulated in cancer tissues compared to matched normal lung tissues, and down-regulation of FCN3 was shown to be significantly correlated with increased mortality among LUAD patients. Interestingly, while ectopic expression of FCN3 led to cell cycle arrest and apoptosis in A549 and H23 cells derived from LUAD, the secreted form of the protein had no effect on the cells. Rather, we found evidence indicating that activation of the unfolded protein response from endoplasmic reticulum (ER) stress is induced by ectopic expression of FCN3. Consistently, inhibition of ER stress response led to enhanced survival of the LUAD cells. Of note, the fibrinogen domain, which is not secreted, turned out to be both necessary and sufficient for induction of apoptosis when localized to ER, consistent with our proposed mechanism. Collectively, our data indicate that FCN3 is a tumor suppressor gene functioning through induction of ER stress.

Earlier-Phased Cancer Immunity Cycle Strongly Influences Cancer Immunity in Operable Never-Smoker Lung Adenocarcinoma.

Exome and transcriptome analyses of clinically homogeneous early-stage never-smoker female patients with lung adenocarcinoma were performed to understand tumor-T cell interactions and immune escape points. Using our novel gene panels of eight functional categories in the cancer-immunity cycle, three distinct subgroups were identified in this immune checkpoint blockade-refractory cohort by defective gene expression in two major domains, i.e., type I interferon production/signaling pathway and antigen-presenting machinery. Our approach could play a critical role in understanding immune evasion mechanisms, developing a method for effective selection of rare immune checkpoint blockade responders, and finding new treatment strategies.

Characterization of TNNC1 as a Novel Tumor Suppressor of Lung Adenocarcinoma.

In this study, we describe a novel function of TNNC1 (Troponin C1, Slow Skeletal and Cardiac Type), a component of actin-bound troponin, as a tumor suppressor of lung adenocarcinoma (LUAD). First, the expression of TNNC1 was strongly down-regulated in cancer tissues compared to matched normal lung tissues, and down-regulation of TNNC1 was shown to be strongly correlated with increased mortality among LUAD patients. Interestingly, TNNC1 expression was enhanced by suppression of KRAS, and ectopic expression of TNNC1 in turn inhibited KRASG12D-mediated anchorage independent growth of NIH3T3 cells. Consistently, activation of KRAS pathway in LUAD patients was shown to be strongly correlated with down-regulation of TNNC1. In addition, ectopic expression of TNNC1 inhibited colony formation of multiple LUAD cell lines and induced DNA damage, cell cycle arrest and ultimately apoptosis. We further examined potential correlations between expression levels of TNNC1 and various clinical parameters and found that low-level expression is significantly associated with invasiveness of the tumor. Indeed, RNA interference-mediated down-regulation of TNNC1 led to significant enhancement of invasiveness in vitro. Collectively, our data indicate that TNNC1 has a novel function as a tumor suppressor and is targeted for down-regulation by KRAS pathway during the carcinogenesis of LUAD.