Prospective exosome-focused translational research for afatinib (EXTRA) study of patients with nonsmall cell lung cancer harboring EGFR mutation: an observational clinical study.

Background: The exosome-focused translational research for afatinib (EXTRA) study is the first trial to identify novel predictive biomarkers for longer treatment efficacy of afatinib in patients with epidermal growth factor receptor (EGFR) mutation-positive nonsmall cell lung cancer (NSCLC) via a comprehensive association study using genomic, proteomic, epigenomic, and metabolomic analyses. Objectives: We report details of the clinical portion prior to omics analyses. Design: A prospective, single-arm, observational study was conducted using afatinib 40 mg/day as an initial dose in untreated patients with EGFR mutation-positive NSCLC. Dose reduction to 20 mg every other day was allowed. Methods: Progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated. Results: A total of 103 patients (median age 70 years, range 42-88 years) were enrolled from 21 institutions in Japan between February 2017 and March 2018. After a median follow-up of 35.0 months, 21% remained on afatinib treatment, whereas 9% had discontinued treatment because of AEs. The median PFS was 18.4 months, with a 3-year PFS rate of 23.3%. The median afatinib treatment duration in patients with final doses of 40 (n = 27), 30 (n = 23), and 20 mg/day (n = 35), and 20 mg every other day (n = 18) were 13.4, 15.4, 18.8, and 18.3 months, respectively. The median OS was not reached, with a 3-year OS rate of 58.5%. The median OS in patients who did (n = 25) and did not (n = 78) receive osimertinib during the entire course of treatment were 42.4 months and not reached, respectively (p = 0.654). Conclusions: As the largest prospective study in Japan, this study confirmed favorable OS following first-line afatinib in patients with EGFR mutation-positive NSCLC in a real-world setting. Further analysis of the EXTRA study is expected to identify novel predictive biomarkers for afatinib. Trial registration: UMIN-CTR identifier (UMIN000024935, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_his_list.cgi?recptno=R000028688.

Risk-adjusted hazard analysis of survival after pulmonary metastasectomy for uterine malignancies in 319 cases.

Objective: There is little evidence of the outcome of pulmonary metastasectomy for uterine tumors when comparing different histologies. This study aimed to delineate the primary histology that leads to more favorable outcomes after pulmonary metastasectomy. Methods: The database of the Metastatic Lung Tumor Study Group of Japan for 1984 to 2016 was used to analyze the outcomes of patients with gynecologic malignancies who underwent pulmonary metastasectomy. Prognostic factors and long-term outcomes were compared according to the histology of the primary uterine tumors, specifically adenocarcinoma, squamous cell carcinoma, and sarcoma. The adjusted hazard risks according to disease-free intervals (DFIs) and the number and maximum size of resected tumors were also analyzed to delineate the pattern of risk trends. Results: A total of 319 patients were included in the analysis (122 with adenocarcinomas, 113 with squamous cell carcinomas, 46 with sarcomas, and 38 with other types). The 5-year survival rate was 66.5% for the entire cohort, 71.6% for the patients with adenocarcinoma, 61.3% for those with squamous cell carcinoma, and 55.4% for those with sarcoma. Multivariate analyses identified the positive prognostic factors as DFI ≥12 months in adenocarcinoma and sarcoma and the primary site (corpus) of uterine tumors in adenocarcinoma. The nonlinear adjusted hazard risks indicated that a shorter DFI was associated with an elevated risk of death in patients with adenocarcinoma and sarcoma. Conclusions: The survival outcome after pulmonary metastasectomy varies according to primary tumor histology, and the prognostic factors differ among histologic subtypes. Surgical indications should be determined based on the prognostic factors for each histology.

[Growing Mixed Squamous Cell and Glandular Papilloma Difficult to Differentiate from Primary Lung Cancer:Report of a Case].

A 76-year-old woman was referred to our hospital due to abnormal chest radiography findings. Chest computed tomography (CT) revealed a nodule in the right lower lobe. Fluorodeoxyglucose-positronemission tomography (FDG-PET) showed abnormal accumulation in the nodule. Bronchoscopy did not provide a definitive diagnosis. Since the nodule tended to increase in size, primary lung cancer was suspected and surgery was performed. During the surgery, pathological diagnosis of squamous cell carcinoma was made, and a right lower lobectomy was performed. Subsequently, a pathological diagnosis of mixed squamous cell and glandular papilloma (mixed papilloma) was made. She has had no sign of recurrence for approximately four years since the surgery.

Presence of a Ground-Glass Opacity Component Is the True Prognostic Determinant in Clinical Stage I NSCLC.

Introduction: Recent studies have suggested that including presence or absence of ground-glass opacity (GGO) may improve the tumor descriptor (T descriptor) classification in clinical stage I NSCLC. In this study, we analyzed prognostic implications of presence or absence of GGO, size of the solid component, and predominant histology to identify the true prognostic determinant for early-stage NSCLC. Methods: We retrospectively examined 384 patients with clinical stage I NSCLC (solid: 242, part solid: 142) who underwent complete resection between 2009 and 2013. Results: Survival curves of the whole cohort revealed good separation using the current TNM classification. Nevertheless, the part-solid group had a favorable prognosis irrespective of solid component size. Conversely, patients in the solid tumor group with tumors between 3 and 4 cm had a worse prognosis than patients whose tumors were less than or equal to 3 cm. Thus, we propose the following novel T descriptor classification: IA, part-solid tumors; IB, solid tumors less than or equal to 3 cm; and IC, solid tumors between 3 and 4 cm. This novel classification system stratified patient prognosis better than the current classification. On pathologic evaluation, the part-solid group always had better prognoses than the solid group in each subgroup divided by pathologic grade. Conclusions: These results suggest that presence of GGO is the true prognostic determinant of stage I NSCLC, irrespective of the size of the solid component. Our novel T descriptor classification system could more accurately predict prognoses of clinical stage I NSCLC cases.

[Carinal Resection and Reconstruction for Second Primary Lung Cancer Five Years After the Left Upper Lobectomy].

A tumor was detected at the tracheal carina to the orifice of the left main bronchus in a 66-year-old man who had undergone a left upper lobectomy for lung cancer five years before and was diagnosed as a squamous cell carcinoma. Carinal resection and reconstruction was performed because of the tumor relapse after the treatment by argon plasma coagulator. Carinal resection was performed under the median sternotomy with reconstruction by the montage method. The patient was discharged on the 8th postoperative day without any postoperative complications.

[Diffuse Pulmonary Meningotheliomatosis Needed to be Differentiate from Metastatic Lung Tumor:Report of a Case].

A 77-year-old woman was found to have multiple granular shadows in the bilateral lungs and a right mammary mass on chest computed tomography (CT) scan for preoperative check of colorectal cancer. The right mammary mass was diagnosed as breast cancer as a result of vacuum-assisted breast biopsy. Fluorodeoxyglucose-positron emission tomography( FDG-PET) showed no abnormal uptake in the lung fields. Since a transbronchial lung biopsy did not establish a diagnosis, an incisional biopsy was performed via a thoracoscopic approach. The histology of the pulmonary nodules revealed minute pulmonary meningothelial-like nodules (MPMNs) and the patient was diagnosed with diffuse pulmonary meningotheliomatosis (DPM). When multiple pulmonary nodules are found in patients with coexisting malignancy, DPM should be considered in addition to metastatic lung tumors.

[Mediastinal Dedifferentiated Liposarcoma Resected with Partial Resection of Pericardium].

An anterior mediastinal tumor was detected by computed tomography (CT) in a 66-year-old man who complained of left flank pain, and the surgical treatment was performed. At surgery, partial resection of the pericardium was also conducted because the pericardial inversion was suspected. The histopathological diagnosis was dedifferentiated liposarcoma. The patient is well without adjuvant chemotherapy 23 months after the surgery.

The Frequency of DNA Mismatch Repair Deficiency Is Very Low in Surgically Resected Lung Carcinoma.

INTRODUCTION: DNA mismatch repair (MMR) deficiency leads to changes in the length of nucleotide repeat sequences of tumor DNA. In that situation, DNA replicational errors occur and accumulate during DNA replication. As a result, this mechanism frequently affects the coding regions of oncogenes and tumor suppressor genes and causes carcinogenesis. Recently, DNA MMR deficiency has been recognized as a predictive biomarker for immunotherapy. The aim of this study is to examine the frequency of DNA MMR deficiency and clinicopathological characteristics in surgically resected lung carcinoma (LC) and their correlation. METHODS: A total of 1153 LCs were examined. Tissue microarrays were constructed. The status of MMR deficiency was evaluated by immunohistochemical analysis of MMR protein expression (hMLH1, hMSH2, hMSH6, and hPMS2). Microsatellite instability analysis, BRAF mutation, and MLH1 methylation analysis were performed for cases that showed MMR deficiency. RESULTS: Only 2 of the 1153 cases (0.17%) showed a loss of hMLH1/hPMS2 protein expression. They also had high levels of microsatellite instability (MSI-H), had neither MLH1 promoter methylation nor BRAF mutation, and were male smokers. Histopathologically, one was a squamous cell carcinoma, and the other was combined small cell carcinoma with squamous cell carcinoma. Regarding PD-L1 protein expression, one had high expression, and the other had none. CONCLUSION: The frequency of MMR deficiency was very low in LC. However, our two cases were non-adenocarcinoma and differed from previous studies. Because of its very low frequency, MMR deficiency is not a practical biomarker to predict the effect of immune checkpoint inhibitors in LC.

[Lung Abscess by Drug-resistant Pseudomonas Aeruginosa Necessary to Differentiate from Lung Cancer:Report of a Case].

A 64-year-old man visited our hospital because of an abnormal shadow on an annual health check-up. Chest computed tomography demonstrated a nodule 22 mm in size in the right lung. 18-F fluorodeoxyglucose positron emission tomography showed abnormal accumulation in the nodule. Since lung cancer was suspected, a right wedge resection was performed. Pathological examination showed no malignant findings in the nodule. The diagnosis of lung abscess by drug resistance Pseudomonas aeruginosa was made by the pus culture and the postoperative course was uneventful.

Prognostic significance of propofol-based intravenous anesthesia in early-stage lung cancer surgery.

PURPOSE: The purpose of this study was to assess whether the anesthetic type is associated with the prognosis of pathological stage I non-small cell lung cancer (NSCLC). METHODS: Clinicopathological data from 431 consecutive patients who underwent lobectomy for NSCLC between 2010 and 2016 were collected. Patients were classified into groups according to the type of anesthesia: propofol-based total intravenous anesthesia (TIVA) or inhalation anesthesia (INHA). We investigated the prognostic differences between these two groups. RESULTS: A total of 72 patients in the TIVA group and 158 patients in the INHA group were eligible for the analysis. Recurrence was observed in 4 (5.6%) patients in the TIVA group and 19 (12.0%) patients in the INHA group (P = 0.159), and all-cause death occurred in 4 (5.6%) patients in the TIVA group and 24 (15.2%) patients in the INHA group (P = 0.049). The 5-year recurrence-free survival (RFS) and overall survival rates of the TIVA/INHA groups were 91.7%/77.4% and 94.4%/83.5%, respectively. TIVA was associated with a significantly better prognosis. A multivariable analysis of factors associated with RFS revealed that the type of anesthesia as a significant prognostic factor (P = 0.047). CONCLUSION: Propofol-based TIVA was associated with a better prognosis in comparison to INHA in patients with surgically resected pathological stage I NSCLC.

Pulmonary metastasectomy for pulmonary metastasis of breast cancer has a limited prognostic impact: a multi-institutional retrospective analysis.

BACKGROUND: Pulmonary metastasectomy (PM) for breast cancer-derived pulmonary metastasis is controversial. This study aimed to assess the prognostic factors and implication of PM for metastatic breast cancer using a multi-institutional database. METHODS: Clinical data of 253 females with pulmonary metastasis of breast cancer who underwent PM between 1982 and 2017 were analyzed retrospectively. RESULTS: The median patient age was 56 years. The median follow-up period was 5.4 years, and the median disease-free interval (DFI) was 4.8 years. The 5- and 10-year survival rates after PM were 64.9% and 50.4%, respectively, and the median overall survival was 10.1 years. Univariate analysis revealed that the period of PM before 2000, a DFI <36 months, lobectomy/pneumonectomy, large tumor size, and lymph node metastasis were predictive of a worse overall survival. In the multivariate analysis, a DFI <36 months, large tumor size, and lymph node metastasis remained significantly related to overall survival. The 5- and 10-year cancer-specific survival rates after PM were 66.9% and 54.7%, respectively, and the median cancer-specific survival was 13.1 years. Univariate analyses revealed that the period of PM before 2000, DFI <36 months, lobectomy/pneumonectomy, large tumor size, lymph node metastasis, and incomplete resection were predictive of a worse cancer-specific survival. Multivariate analysis confirmed that a DFI <36 months, large tumor size and incomplete resection were significantly related to cancer-specific survival. CONCLUSIONS: As PM has limited efficacy in breast cancer, it should be considered an optional treatment for pulmonary metastasis of breast cancer.

[Aspergillus Empyema with Bronchopleural Fistula due to Destroyed Lung after Postoperative Radiotherapy for Thymoma].

A 35-year-old man underwent adjuvant chemoradiation therapy to the surgical margin of the thymoma. Five years after the therapy, an area of the right upper lung lobe, which was included in the irradiation field, developed destroyed lung, resulting in Aspergillus empyema with bronchopleural fistula. To control the infection, an open window thoracostomy was performed. As the bronchopleural fistula resulted in pneumonia, bronchial embolization was performed with an Endobronchial Watanabe Spigot. After the empyema cavity was cleaned, the empyema space was closed with omental and muscular flap, thoracoplasty. Negative pressure wound therapy was carried out because of poor wound healing. The patient is doing well without relapse 15 months after the thoracoplasty.

Postoperative prognostic nutritional index as a prognostic factor after non-small cell lung cancer surgery.

OBJECTIVE: The prognostic nutritional index (PNI) is an immunonutrition index. Although preoperative PNI (pre-PNI) has been reported as a prognostic factor for patients with surgically resected non-small cell lung cancer (NSCLC), it is unclear whether postoperative PNI (post-PNI) and perioperative PNI change is a prognostic factor. METHODS: Clinicopathological data from 262 consecutive patients who underwent lobectomy for NSCLC were collected. Pre-PNI and post-PNI were calculated within 1 month before surgery and at 1 month after surgery, respectively. We investigated which clinicopathological factors contributed to the post-PNI, the differences in prognosis according to the post-PNI status, and the impact of perioperative PNI change on prognosis. RESULTS: We set 50 and 45 as an optimal cutoff value of pre-PNI and post-PNI for OS using a receiver operating characteristic curve. Patients who were older and male and who had lower pre-PNI, larger thoracotomy size, longer operative duration, larger blood loss during surgery, and postoperative pulmonary complications showed significantly lower post-PNI. The 5-year overall survival (OS), lung cancer-specific survival, and recurrence-free survival rates for the high/low post-PNI groups were 87.4%/58.4% (P < 0.001), 92.0%/74.8% (P = 0.001), and 80.5%/55.3% (P < 0.001). respectively. Multivariate analysis showed that the post-PNI was a significant prognostic factor (P < 0.001). We further revealed the equivalent OS with "low pre-PNI and high post-PNI" patients or "high pre-PNI and high post-PNI" patients. CONCLUSIONS: Post-PNI status was a significant prognostic factor and perioperative PNI changes could play a significant role in the survival of patients with NSCLC after surgery.

A surgical case of mediastinal hematoma caused by a minor traffic injury.

BACKGROUND: Mediastinal hematoma rarely occurs after a minor traffic injury. CASE PRESENTATION: A woman in her forties was transferred to the emergency room by ambulance due to a traffic accident. Computed tomography (CT) revealed no abnormal findings, and she went home. Two days after the accident, the contrast-enhanced CT was repeated, which revealed cervical and mediastinal hematomas. Because it was possible that there was active bleeding from the right inferior thyroid artery, embolization of the right inferior thyroid artery was performed; however, her condition further deteriorated, so we performed emergency surgery to achieve hemostasis and remove the hematoma. Because of oozing from the right thyroid lobe, we performed right hemithyroidectomy and drainage of mediastinal space and right thoracic cavity. Since there was no bleeding site in the mediastinum, we thought that the mediastinal hematoma was due to bleeding from the thyroid gland. Her postoperative course was uneventful, and she is doing well at 9 months of follow-up after surgery. CONCLUSIONS: It is possible that mediastinal hematoma might be caused by a minor traffic injury.

Thymic Small Cell Carcinoma Associated With Lambert-Eaton Myasthenic Syndrome.

Thymic small cell cancer is a very rare type of thymic epithelial tumor. Lambert-Eaton myasthenic syndrome is a rare paraneoplastic syndrome associated with thymic epithelial tumors. We report an extremely rare case of Lambert-Eaton myasthenic syndrome associated with thymic small cell carcinoma. A 71-year-old man was referred to our institution for a mediastinal tumor and a 2-month history of ptosis, fatigue, and gait disorder. Based on radiologic findings thymoma associated with Lambert-Eaton myasthenic syndrome was diagnosed, and extended thymectomy was performed. After surgery the patient's symptoms had not improved. Anticholinesterase treatment alleviated his symptoms.

[Long-term Results of Sublobar Resection for Lung Cancer;a 10-year Follow-up Study].

As a treatment for lung cancer, sublobar resection has been performed not only for high-risk patients but also for patients with radiographic early stage lung cancer. Although many studies revealed the short-term results of sublobar resection, long-term outcomes are still unclear. Here, we examined the 10-year follow-up results of sublobar resection for lung cancer, especially in overall survival(OS), cause-specific survival(CSS)and recurrence or death dynamics. Data from 48 consecutive patients who underwent sublobar resection for lung cancer between 2004 to 2008 were collected(21 patients:segmentectomy, 27:wedge resection). The median length of follow-up was 10 years. During follow-up, recurrences developed in 12 patients(25%)and 19 patients(40%)died, including 9(19%)patient deaths due to lung cancer. The 3-/5-/10-year OS and CSS rates for all patients were 81/77/61% and 87/85/80%, respectively. In terms of recurrence or death, 11 out of 12 patients with recurrences were diagnosed within the 3rd year. The peak of death due to lung cancer was shown to be years after surgery to which wedge resection contributed. On contrast, small peaks of non-cancer death were shown to be 8-10 years after surgery without relation to surgical procedure.

Determination of the intersegmental plane using the slip-knot method.

BACKGROUND: Visualization of intersegmental planes in the lung is desirable for precise anatomical lung segmentectomy. We developed the slip-knot method for creating inflation-deflation lines. This study aimed to assess relevant data for thoracoscopic segmentectomy performed using this method. METHODS: In the slip-knot method, the objective segmental bronchus is looped with a monofilament thread. One end of the thread is then pulled during temporary bilateral ventilation, causing the knot to slip toward the bronchus. Thereafter, bronchial ligation is tightened to block the outflow of segmental air, ensuring that the segment remains expanded while the other reserved segments collapse on resumption of unilateral ventilation. Data from 221 patients who underwent thoracoscopic pulmonary segmentectomy between 2010 and 2016 were analyzed. RESULTS: A total of 147 patients (67%) were indicated for the slip-knot method, and 74 cases (33%) were non-adaptive cases. Ninety six percent of 147 cases were well adapted to the slip-knot method, which allowed us to obtain good inflation-deflation line images to determine the intersegmental plane. The mean operative time was 171±51 min (range, 71-367 min). The mean duration of chest tube insertion was 1.5±1.2 days (range, 1-7 days). Three cases (2.0%) had prolonged air-leakage and one (0.7%) case had readmission for late air-leakage. CONCLUSIONS: Our method enables determination of anatomical intersegmental planes using only one monofilament thread, thus facilitating thoracoscopic pulmonary anatomical segmentectomy.

Epidermal Growth Factor Receptor Mutation as a Risk Factor for Recurrence in Lung Adenocarcinoma.

BACKGROUND: The presence of epidermal growth factor receptor (EGFR) mutations is an established prognostic factor for patients with advanced lung adenocarcinoma. Here, we examined whether EGFR mutation status is a prognostic factor for patients who had undergone surgery. METHODS: Clinicopathologic data from 1,463 patients who underwent complete surgical resection for lung adenocarcinoma between 2005 and 2012 were collected. Differences in postoperative recurrence-free survival and overall survival according to EGFR mutation status were evaluated. RESULTS: Of 835 eligible patients, the numbers of patients with wild-type EGFR (WT), exon 19 deletion (Ex19), and exon 21 L858R (Ex21) were 426, 175, and 234, respectively. Patients with Ex19 had a significantly higher incidence of extrathoracic recurrence than patients with Ex21 (p = 0.004). The 5-year recurrence-free survival rates for patients with WT, Ex19, and Ex21 were 63.0%, 67.5%, and 78.2%, respectively. The Ex21 group had a significantly longer recurrence-free survival than the WT group (p < 0.001) and the Ex19 group (p = 0.016). The 5-year overall survival for patients with WT, Ex19, and Ex21 were 76.9%, 86.5%, and 87.5%, respectively. Patients with Ex19 and Ex21 had a significantly longer overall survival than patients with WT (Ex19, p = 0.009; Ex21, p < 0.001). Multivariate analysis for recurrence-free survival showed that Ex19 was significantly associated with a worse prognosis than Ex21 (p = 0.019). CONCLUSIONS: Patients with Ex19 had significantly shorter recurrence-free survival and had extrathoracic recurrence more frequently than patients with Ex21 among patients with resected lung adenocarcinoma, implying that Ex19 could be a worse prognostic factor.

Hyperbaric oxygen therapy for postoperative ischemic bronchitis after resection of lung cancer.

BACKGROUND: Hyperbaric oxygen therapy (HBOT) has been used successfully in the treatment of specific ischemic injuries, but has been a little evaluated specifically in postoperative ischemic bronchitis (POIB). The purpose of this study was to evaluate the effect of HBOT when used for POIB after resection of lung cancer. METHODS: From January 1999 to December 2016, 1,100 patients underwent lymph node dissection (LND) and either anatomic pulmonary resection or lung resection with bronchoplasty for lung cancer. POIB was diagnosed by bronchoscopy. HBOT was administered after POIB was diagnosed. HBOT comprised one 60-minute session daily in the hyperbaric chamber at 2.0 absolute atmospheres with 100% oxygen. We retrospectively analyzed the clinical course, timing of onset of POIB, outcomes, and any adverse events. RESULTS: Seven patients were identified to have had POIB treated with HBOT, all of whom were men with a smoking history and a median age of 65 years (range, 57-72 years). The operative procedures included three lung resections with bronchoplasty, three right lower lobectomies, and one right middle lobectomy performed owing to torsion of the middle lobe after right upper sleeve lobectomy. All 7 patients underwent subcarinal LND. POIB was diagnosed at a median of 11 days (range, 4-41 days) postoperatively. The median duration of an HBOT session was 7 days (range, 3-11 days). POIB resolved in 5 patients but worsened in 2, both of whom required further surgery. CONCLUSIONS: Prospective clinical trials are now needed to confirm the potential benefits of HBOT in POIB.