Impact of central nervous system metastasis after complete resection of lung adenocarcinomas harboring common EGFR mutation - A real-world database study in Japan: The CReGYT-01 EGFR study.

OBJECTIVES: To clarify the impact of central nervous system (CNS) metastasis on performance status (PS) at relapse, on subsequent treatment(s), and on survival of patients with lung adenocarcinoma harboring common epidermal growth factor receptor (EGFR) mutation. METHODS: We conducted the multicenter real-world database study for patients with radical resections for lung adenocarcinomas between 2015 and 2018 at 21 centers in Japan. EGFR mutational status was examined at each center. RESULTS: Of 4181 patients enrolled, 1431 underwent complete anatomical resection for lung adenocarcinoma harboring common EGFR mutations. Three-hundred-and-twenty patients experienced disease relapse, and 78 (24%) had CNS metastasis. CNS metastasis was significantly more frequent in patients with conventional adjuvant chemotherapy than those without (30% vs. 20%, P = 0.036). Adjuvant chemotherapy did not significantly improve relapse-free survival at any pathological stage (adjusted hazard ratio for stage IA2-3, IB, and II-III was 1.363, 1.287, and 1.004, respectively). CNS metastasis did not affect PS at relapse. Subsequent treatment, mainly consisting of EGFR-tyrosine kinase inhibitors (TKIs), could be equally given in patients with or without CNS metastasis (96% vs. 94%). Overall survival after relapse was equivalent between patients with and without CNS metastasis. CONCLUSION: The efficacy of conventional adjuvant chemotherapy may be limited in patients with lung adenocarcinoma harboring EGFR mutations. CNS metastasis is likely to be found in practice before deterioration in PS, and may have little negative impact on compliance with subsequent EGFR-TKIs and survival after relapse. In this era of adjuvant TKI therapy, further prospective observational studies are desirable to elucidate the optimal management of CNS metastasis.

Tumor volume doubling time as a potential predictor of prognosis in clinical stage I lung squamous cell carcinoma.

Background: Tumor volume doubling time (VDT) has been shown to predict prognosis in various non-small cell lung carcinoma with scant evidence for lung squamous cell carcinoma (SCC). The purpose of this study was to investigate the prognostic value of tumor VDT in resected lung SCCs. Methods: In this study, subjects were 51 patients who underwent lobectomy for clinical stage I SCC of the peripheral lung at our institution between January 2006 and April 2020. Univariable and multivariable analyses of overall survival (OS) and recurrence-free survival (RFS) were performed using the Cox proportional hazards model. The Kaplan-Meier method was used to create OS and RFS curves and to determine statistical significance. The cut-off value of VDT was defined by receiver operating characteristic (ROC) curve analysis on survival. Results: Multivariable analysis found only VDT (HR, 0.990; 95% CI: 0.979-0.997) to be an independent predictor of OS. Also, only VDT (HR, 0.989; 95% CI: 0.978-0.995) was an independent predictor of RFS. The 5-year OS rates were 88.4% and 30.4% in the long (≥150 days) and short (<150 days) VDT groups, respectively (P=0.002). The 5-year RFS rates were 88.8% and 26.5% in the long (≥150 days) and short (<150 days) VDT groups, respectively (P<0.001). Conclusions: Tumor VDT was found to be a useful prognostic predictor in clinical stage I lung SCC in this study.

[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.

Prognostic impact of the tumor volume doubling time in clinical T1 non-small cell lung cancer with solid radiological findings.

BACKGROUND: The purpose of this study was to investigate better radiological prognostic factors in clinical T1 pure-solid non-small cell lung cancer (NSCLC). METHODS: This study enrolled 284 patients with clinical T1 solid NSCLC who underwent anatomical lung resection. The Cox proportional hazard model was used to evaluate the prognostic impact of tumor volume doubling time (VDT) at disease-free survival (DFS) and cancer-specific survival (CSS). RESULTS: The median VDT was 347 days. Age (hazard ratio (HR) = 1.04; 95% confidence interval (CI), 1.01-1.07) and standardized uptake value max (SUVmax) (>6.0) (HR = 2.61; 95% CI, 1.52-4.66) were identified as significantly independent worse prognostic factors for DFS in a multivariable analysis without VDT. Furthermore, a multivariable analysis without SUVmax identified age (HR = 1.06; 95% CI, 1.03-1.09), CEA (>5.0 ng/ml) (HR = 2.34; 95% CI, 1.30-4.02), tumor diameter on CT (>2.0 cm) (HR = 1.91; 95% CI, 1.18-3.13), and VDT (HR = 4.03; 95% CI, 2.41-6.93) as significantly independent worse prognostic factors for DFS. CONCLUSIONS: The VDT value could be a useful prognostic factor in clinical T1 solid NSCLC.

Re-evaluating the need for mediastinal lymph node dissection and exploring lncRNAs as biomarkers of N2 metastasis in T1 lung adenocarcinoma.

Background: Although a well-acknowledged component of curative surgery for lung cancer, investigators have recently questioned the need for mediastinal lymph node dissection (MLND) in early-stage lung cancer cases. As such, the accurate prediction of N2 stage prior to surgery has become increasingly critical. But diagnostic biomarkers predicting N2 metastases are deficient, which are urgently needed. Methods: We extracted the data of non-small cell lung cancer (NSCLC) patients whose clinical information and follow-up data are complete and without preoperative induction therapy from the Surveillance, Epidemiology, and End Results (SEER) database. The SEER program registries routinely collect demographic and clinic data on patients. And the prognostic differences were analyzed according to the presence or absence of MLND in their lung resection using the R package. Subsequently, the correlations between pN2 metastasis and clinical characteristics were analyzed. In parallel, the long non-coding RNAs (lncRNAs) associated with pN2 status were screened in The Cancer Genome Atlas (TCGA) database by expression difference analysis between pN0-N1 and pN2 patients using limma. Their diagnostic efficiency for detecting N2 metastases was evaluated using receiver operating characteristic (ROC) curves, and a combined diagnostic model was constructed using logistic regression and ROC curve analyses in lung adenocarcinoma (LUAD). Results: There were 16,772 patients in MLND group, and 2,699 cases in no-MLND group. The clinical data from SEER showed that the incidence of N2 metastasis was low in pT1 NSCLC (1,023/16,772, 6.10%), but the prognosis of no-MLND patients was poorer than those who underwent MLND (P<0.001, HR =1.605). Pathological N2 metastasis was correlated with age, histologic type, and tumor size. On the other hand, five lncRNAs (LINC00892, AC099522.2, LINC01481, SCAMP1-AS1, and AC004812.2) were screened and confirmed as potential diagnostic biomarkers for detecting N2 metastasis in pT1 LUAD. The AUC of the combined indicators was 0.857. Conclusions: MLND may be oncologically necessary for selected T1 NSCLC patients based on the metastasis incidence and prognosis. A diagnostic model combining LINC00892, AC099522.2, LINC01481, SCAMP1-AS1, and AC004812.2 expression levels may have the potential to be a diagnostic biomarker for detecting N2 metastasis in pT1 LUAD. This study suggests that MLND might be omitted in patients with lower expression level of this diagnostic model.

Preoperative Master's double two-step test may predict survival after lobectomy in patients with lung cancer.

BACKGROUND: The Master's double two-step test (MDT), which is used to screen for coronary heart disease, is difficult for physically impaired patients to complete. The purpose of this study was to clarify the relationship between the results of the MDT and prognosis after lung cancer surgery. METHODS: Between May 2004 and September 2019, 1,434 patients underwent complete resection for lung cancer at our hospital. Among them, 418 with pathological stage I disease who underwent lobectomy were evaluated. We defined patients who could accomplish the MDT as the complete MDT group and those who could not as the incomplete MDT group. Patients who could not perform the MDT due to physical problems were included in the incomplete MDT group. We explored the prognostic impact of the MDT results in these patients. RESULTS: Fifty-three patients (12.7%) were in the incomplete MDT group; compared with the complete MDT group, they were older and had poorer performance status and respiratory function. However, the incidence of postoperative complications and 90-day mortality did not differ significantly between groups. Multivariate analyses revealed that age (p < 0.001), Charlson comorbidity index (p = 0.013), incomplete MDT (p = 0.049) and carcinoembryonic antigen (CEA) level (p = 0.003) were prognostic factors for worse overall survival; age (p < 0.001) and incomplete MDT (p = 0.022) were prognostic factors for worse non-cancer-specific survival. CONCLUSIONS: Although incomplete MDT was not associated with postoperative complications, 90-day mortality or cancer-specific survival, MDT results may be significantly associated with non-cancer-specific survival.

Power-Dependent Characteristics of Spin Current Transfer in Metal Bilayer Devices under High-Power Pulse Excitation.

The power-dependent transfer characteristics of spin currents generated at the interface of the permalloy/Pt bilayer device have been investigated over a wide power range from a few tens of milliwatt to 396 W. We built a high-power pulse excitation system for spin pumping, which achieves large electromotive force (EMF) values of 10 mV at 396 W excitation through the inverse spin Hall effect (ISHE) and demonstrates that the EMF generation after pulse excitation is very fast. Under strong pulse microwave excitation more than 80 W, the EMF spectrum exhibits an asymmetrical lineshape, which is well reproduced by simulations that take into account the fold-over effect due to the nonlinear ferromagnetic resonance excitation. The maximum output power at an external load through spin pumping and the ISHE is shown to increase in proportion to the square of the input microwave power (Pin) in the power range below 80 W. This power generation proportional to Pin2 is unique to spin current-mediated power flow. In the strong excitation regime with the fold-over type EMF spectra, the EMF values of the peak magnetic field position are found to increase less linearly due to spectral broadening. This feature can be used for power generation that increases nonlinearly with respect to the input excitation power, where the nonlinearity is adjusted by varying the magnetic field position.

[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.

Prediction of lymph node metastasis of clinical stage IA non-small cell lung cancer based on the tumor volume doubling time.

PURPOSE: To investigate whether the volume doubling time is a preoperative predictor of lymph node metastasis of clinical stage IA non-small cell lung cancer (NSCLC). METHODS: The subjects of this retrospective study were 204 patients who underwent lobectomy and mediastinal lymph node dissection for clinical stage IA NSCLC. We analyzed the relationship between lymph node metastasis and clinicopathological factors, including the volume doubling time. RESULTS: Lymph node metastasis developed in 24 (11.8%) patients. Multivariable analysis identified consolidation diameter (Odds ratio = 1.407; 95% confidence interval, 1.007-1.966, p = 0.046) and the solid-part tumor volume doubling time (Odds ratio = 0.982; 95% confidence interval, 0.973-0.991, p < 0.001) as independent predictors of lymph node metastasis. The combination of a larger consolidation diameter (> 1.9 cm) and a shorter solid-part tumor volume doubling time (< 132 days) had sensitivity, specificity, and accuracy of 79.2%, 94.4%, and 92.6%, respectively. CONCLUSIONS: The consolidation diameter and solid-part tumor volume doubling time can be useful preoperative predictors of lymph node metastasis of clinical stage IA NSCLC.

Outcome of thoracoscopic anatomical sublobar resection under 3-dimensional computed tomography simulation.

BACKGROUND: Previous studies have reported the feasibility and efficacy of thoracoscopic anatomical sublobar resection under three-dimensional computed tomography (3DCT) simulation; however, its long-term outcomes have not been clearly established in primary lung cancer. This study aimed to evaluate the long-term outcomes of this technique. METHODS: We retrospectively reviewed data from 112 consecutive patients with selected clinical stage IA non-small cell lung cancer (NSCLC) who underwent thoracoscopic anatomical sublobar resection from 2004 to 2014. This procedure was planned using preoperative 3DCT simulation to ensure sufficient surgical margins and enabled tailor-made surgery for each patient. Patients who had predominantly ground glass opacity lung cancers underwent anatomical sublobar resection as a curative-intent resection. Other patients who were high-risk candidates for lobectomy underwent anatomical sublobar resection as a compromised limited resection. RESULTS: Of the 112 cases, 82 had a curative-intent resection, while 30 had a compromised limited resection. Recurrence occurred in only 2 cases (1.8%), both of which were in the compromised limited group. A second primary lung cancer was observed in 5 cases (4.5%). Of the 5 patients, 4 underwent surgery for a second cancer and had no recurrence. The 5-year overall survival, lung cancer-specific overall survival, and recurrence-free survival rates were 92.5%, 100%, and 98.2%, respectively, for all cases; 97.6%, 100%, and 100%, respectively, in the curative-intent group; and 75.8%, 100% and 92.6%, respectively, in the compromised limited group. CONCLUSIONS: Thoracoscopic anatomical sublobar resection under 3DCT simulation may be an acceptable alternative treatment in selected patients with NSCLC. TRIAL AND CLINICAL REGISTRY: Clinical registration number: IRB No. 2020-98 (Dated: 2020.6.30).

[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.

[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.

[Pneumothorax during Pazopanib Therapy in a Patient with Soft Tissue Sarcoma].

Pazopanib is an anti-angiogenic multi-targeted tyrosine kinase inhibitor used for treating soft tissue sarcomas and renal cell carcinoma. Although the occurrence of pneumothorax during pazopanib treatment has been recognized as an adverse event, there have been no reports of pneumothorax in patients treated with pazopanib. Here, we present the case of a 71- year-old male patient who developed pneumothorax during adjuvant pazopanib therapy after surgery for metastasized renal cell carcinoma. Left hilar and mediastinal lymph node swelling was detected in the postoperative surveillance after surgery, and radiological findings showed lymph node metastasis from renal cell carcinoma. Consequently, left upper lobectomy and mediastinal lymph node dissection were performed, and subsequent pathological examination confirmed the aforementioned diagnosis. Pazopanib was administered as an adjuvant therapy. However, the patient developed left pneumothorax on day 101. Although chest tube drainage was performed, massive air leak continued. A surgery was performed to repair the persistent air leak. This case demonstrates that pneumothorax should be recognized as an adverse event of pazopanib.

[Congenital Defect of the Pericardium Incidentally Found during Surgery for Lung Cancer:Report of a Case].

A 78-year-old man was admitted to our hospital for further examination of a mass shadow in the left lower lobe noted on chest computed tomography. Because lung cancer was suspected, a left lower lobectomy was performed. During surgery, the left lower lobe and heart were so tightly adherent that the pericardial defect was not initially perceivable. As we proceeded with adhesion detachment, we discovered that the left lower lobe and the myocardium were directly adherent to one another through a complete defect of the pericardium, which required very careful surgical technique. Because of the complete defect of the pericardium, we considered the risk of heart failure to be low and accordingly did not perform a repair. The postoperative course was uneventful.

[Outcomes of Sublobar Resection for the Patients with a Metachronous Multiple Lung Cancer].

OBJECTIVES: In order to perform appropriate treatment for metachronous multiple lung cancer, it is important to verify the surgical treatment outcome. We evaluated the surgical outcome of metachronous multiple lung cancer focused on the sublobar resection of metachronous second lung cancer. METHODS: The subjects of this study were 1,513 cases that underwent radical resection for primary lung cancer in our institution from January 2004 to April 2020. We selected 23 (1.5%) patients who underwent lobectomy for initial primary lung cancer and underwent sublobar resection for metachronous second lung cancer. RESULTS: The median follow-up period from resection for initial primary lung cancer to resection for metachronous second lung cancer was 49 months. Regarding the analyses for survival, the median follow-up period after resection for initial primary lung cancer was 79 months with a five-year overall survival rate of 80.4% and a five-year relapse-free survival rate of 75.6%. Whereas the median follow-up period after resection for metachronous second lung cancer was 27 months with a five-year overall survival rate of 55.8% and a five-year relapse-free survival rate was 48.4%. CONCLUSIONS: The long-term outcome for sublobar resection for metachronous second lung cancer was similar to previous reports and the rate of complications tended to be low.

Preoperative predictors of lymph node metastasis in clinical T1 adenocarcinoma.

BACKGROUND: The subcategory "solid component of tumor" is a new criterion of tumor categories in the updated eighth edition of the TNM classification. Nevertheless, the predictors of lymph node metastasis among patients with clinical T1 adenocarcinoma, based on the TNM classification 8th edition, remain unclear. This study aimed to identify the preoperative predictors of lymph node metastasis in clinical T1 adenocarcinoma by comparing clinicopathological characteristics between the groups with and without lymph node metastasis. METHODS: We performed a retrospective observational single-center study at the Sendai Kousei Hospital. From January 2012 to September 2019, we included 515 patients who underwent curative lobectomy or segmentectomy and mediastinal lymph node dissection among those with clinical T1 adenocarcinoma according to the UICC-TNM staging 8th edition. They were divided into two groups: those with lymph node metastasis (positive group) and those without (negative group). The clinicopathological factors were retrospectively analyzed and compared between the groups. RESULTS: In univariate analysis, carcinoembryonic antigen (>5.0 ng/mL) (P=0.0007), maximum standardized uptake (>3.5) (P<0.0001), clinical T factor (T1c) (P<0.0001), and consolidation tumor ratio (>0.85) (P<0.0001) were significant predictors of lymph node metastasis. Multivariate analysis revealed that maximum standardized uptake SUVmax (>3.5) (odds ratio =10.4, P<0.0001) was independently associated with lymph node metastasis. In univariate analysis, carcinoembryonic antigen (>5.0) (P=0.048) was the only predictor of lymph node metastasis among patients of cT1b, while no parameters were identified as significant predictors among patients of cT1c. CONCLUSIONS: SUVmax and CEA are useful preoperative predictors of lymph node metastases in patients with clinical T1 adenocarcinoma, stratified to T1b and T1c, based on the 8th TNM classification.

[The Novel Procedure for Thoracoscopic Anatomical Segmentectomy].

Since 2004, over 300 patients have undergone thoracoscopic segmentectomy without mini-thoracotomy. Thoracoscopic segmentectomy is one of the most complicated surgeries. To perform the complex segmentectomies, pre-operative simulation and 3-dimensional multi-detector computed tomography( 3DCT) are both essential for safely performing operations and for securing adequate surgical margins. Comprehension of the intersegmental and intrasegmental veins to visualize the segmental border facilitates an easier parenchymal dissection. We describe our method and knack for creating an inflation-deflation line for lung segmentectomy that could especially be useful in thoracoscopic procedures for seg-mentectomy. The 5-year over overall survival, cancer specific survival and recurrence free survival rates were 91.8%( curative intent 98.1% versus compromised 74.6%), 100% and 98.1%( curative intent 100% versus compromised 93.3%). According to these technical aspects, our method of thoracoscopic segmentectomy is acceptable for selective patient.

Influx of air into the left atrium during lung resection.

OBJECTIVES: In this study, we aimed to determine conditions associated with the development of air bubbles in the pulmonary veins during lung resection. METHODS: A total of 28 patients who underwent lung resection at our institution between October 2016 and March 2018 were included in the study. An intraoperative transesophageal echocardiography was conducted, and the influx of air bubbles in the orifice of the pulmonary vein leading to the left atrium was observed during lung resection. RESULTS: The median age of all patients was 75 years. The study included 13 men and 15 women. Moreover, seven, 14, and seven patients underwent wedge resection, segmentectomy, and lobectomy, respectively. The presence of air bubbles was observed in 15 patients and was detected when the lung parenchyma was cut (13 patients) or compressed (3 patients) using staplers and when an energy device was used (1 patient). No postoperative organ infarction occurred in any patients. CONCLUSIONS: Although the presence of air bubbles was noted in the pulmonary vein during lung resection via transesophageal echocardiography, the clinical condition of the patients in our study did not deteriorate. The clinical significance of air bubbles is not clear. Therefore, more data about such events must be collected in future.

The preoperative assessment of subpleural lung cancer movement to distinguish thoracic wall adhesion or invasion using four-dimensional computed-tomography.

Four-dimensional computed tomography (4DCT) is a relatively new technology. A review of the relevant medical literature reveals only very limited previous investigations of the utility of this technique. We report two cases of lung cancer located adjacent to the pleura in which 4DCT was used to assess parietal pleural invasion or adhesion based on the differential movements of tumors. We performed 4DCT to determine the surgical approach after obtaining appropriate informed consent from the patient. Based on 4DCT, Patient 1 showed there was no adhesion and we could perform thoracoscopic right lower lobectomy and the final pathological diagnosis was pT1bN0M0. Patient 2 Based on 4DCT, showed suspicious of invasion or adhesion. we performed chest wall resection because of tumor invasion in the eighth and ninth costal bones; a final pathological diagnosis of pT3N0M0 was made.