Comparison of SP263 and 22C3 pharmDx assays to test programmed death ligand-1 (PD-L1) expression in surgically resected non-small cell lung cancer.

BACKGROUND: Atezolizumab, one of the immune checkpoint inhibitors, has been approved as an adjuvant treatment following resection and platinum-based chemotherapy in patients with stage II-IIIA non-small cell lung cancer with 1% or more programmed death ligand-1 (PD-L1) expression. The Food and Drug Administration (FDA) has approved SP263 as a companion diagnostic assay for adjuvant treatment with atezolizumab; however, in clinical practice, the 22C3 assay is most commonly used for advanced non-small cell lung cancer. Therefore, our study aimed to compare two PD-L1 assays, SP263 and 22C3, to evaluate whether 22C3 could replace SP263 when deciding whether to administer adjuvant atezolizumab. METHODS: We retrospectively and prospectively analyzed 98 patients who underwent surgical resection at Kanagawa Cancer Center (Japan). An immunohistochemistry assay was performed for all the cases with both SP263 and 22C3. We statistically analyzed the concordance of PD-L1 expression between SP263 and 22C3 assays. RESULTS: The concordance between the two assays using Cohen's kappa was κ = 0.670 (95% CI: 0.522-0.818) at the 1% cutoff and κ = 0.796 (95% CI: 0.639-0.954) at the 50% cutoff. The Spearman correlation coefficient of 0.874 (p < 0.01) indicated high concordance. PD-L1 expression with 22C3 resulted slightly higher than that with SP263. CONCLUSIONS: This study showed a high concordance of PD-L1 expression with the SP263 and 22C3 assays. Further studies examining the therapeutic effects of adjuvant atezolizumab are required.

Right S3 segmentectomy for lung cancer with partial anomalous pulmonary venous return in the right upper pulmonary vein: A case report.

Partial anomalous pulmonary venous return (PAPVR) is a rare congenital malformation where the pulmonary vein partially refluxes into the venous system. Here, we present the first robotic-assisted right S3 segmentectomy in a 70-year-old male with early-stage lung cancer and PAPVR in the right upper pulmonary vein. The patient, with suspected primary lung cancer (11 mm diameter, pure solid appearance in right S3 segment), exhibited clinical stage T1bN0M0 stage IA2. Preoperative computed tomography revealed severe lung emphysema, and right V1-3 returned directly to the superior vena cava. However, no signs of right-sided heart failure were observed, and echocardiogram was normal with a pulmonary-to-systemic blood flow ratio of 1.4. Successful robot-assisted right S3 segmentectomy with hilar nodal dissection was performed, and the patient was discharged on the sixth postoperative day without complications. One year postoperatively, there has been no recurrence of lung cancer or respiratory/right-sided heart failure symptoms.

Preoperative predictors for recurrence sites associated with poor post-recurrence survival after surgery of non-small cell lung cancer: a multicenter study.

BACKGROUND: The recurrence site that influences post-recurrence survival (PRS) in patients with non-small cell lung cancer (NSCLC) undergoing surgery and the preoperative predictors of recurrence remain unclear. METHODS: Cohorts 1 and 2 had 4520 (who underwent complete resection for p-stage 0-IIIA NSCLC) and 727 (who experienced recurrence after surgery) patients, respectively. The initial sites of recurrence were the lungs (309 cases), thoracic lymph nodes (225 cases), pleura (112 cases), bone (110 cases), central nervous system (86 cases), adrenal gland (25 cases), abdomen (60 cases), cervical and axillary lymph nodes (38 cases), chest wall (13 cases), skin (5 cases), and eye and tongue (3 cases). For cohort 2 analysis, the initial recurrence site that resulted in poor PRS was analyzed by multivariable analysis using a Cox proportional hazard model. For cohort 1 analysis, the preoperative predictors of recurrence patterns with poor PRS were analyzed by multivariable analysis using a logistic regression model. RESULTS: In cohort 2 analysis, recurrence in the central nervous system (hazard ratio [HR], 1.70; p < 0.001), bone (HR, 1.75; p < 0.001), abdomen (HR, 2.39; p < 0.001), and pleura (HR, 1.69; p < 0.001) were independent poor prognostic recurrent sites for PRS and they were high-risk sites (HRS). Intrathoracic lymph nodes, cervical and axillary lymph nodes, lungs, chest wall, adrenal gland, eye and tongue, and skin were low-risk sites (LRS) that did not affect PRS. Patients with multiple LRS without HRS recurrence had a worse prognosis than those with a single LRS without HRS recurrence (5-year PRS 20.2% vs. 37.7%, p < 0.001) and were comparable to those with HRS recurrence (p = 1.000). In cohort 1 analysis, preoperative predictors for HRS and multiple LRS recurrences were positron emission tomography (PET) maximum standardized uptake value (maxSUV) ≥ 3.2 (HR, 5.09; p < 0.001), clinical nodal metastasis (HR, 2.00; p < 0.001), tumor size ≥ 2.4 cm (HR, 1.96; p < 0.001) and carcinoembryonic antigen (CEA) ≥ 5 ng/ml (HR, 1.41; p = 0.004). The cumulative incidence rates of HRS and multiple LRS recurrences within 5 years were 55.9%, 40.9%, 26.3%, 11.1%, and 3.5% (p < 0.001) in patients with 4, 3, 2, 1 and 0 of the above risks, respectively. CONCLUSIONS: HRS and multiple LRS were vital recurrences associated with poor PRS. Preoperative PET maxSUV, clinical nodal metastasis, tumor size, and CEA level predicted the incidence of vital recurrence.

Impact of RBM10 and PD-L1 expression on the prognosis of pathologic N1-N2 epidermal growth factor receptor mutant lung adenocarcinoma.

Background: Impact of RNA-binding motif protein 10 (RBM10) and programmed death-ligand 1 (PD-L1) on the postoperative prognosis of patients with epidermal growth factor receptor gene mutation (EGFR-Mt) lung adenocarcinoma with pathological lymph node metastasis is still unclear. Methods: Patients who underwent curative surgery for pN1-N2 EGFR-Mt lung adenocarcinoma (n=129) harboring the EGFR exon 19 deletion mutation (Ex19) (n=66) or EGFR exon 21 L858R mutation (Ex21) (n=63) between January 2010 and December 2020 were included in this retrospective study. The prognoses of patients with low/high cytoplasmic RBM10 expression and PD-L1 negativity/positivity based on immunohistochemistry (IHC) of resected specimens were compared using the log-rank test. The effects of RBM10 and PD-L1 expression on overall survival (OS) were examined via multivariable analysis using the Cox proportional hazards regression model. The effects of RBM10 and PD-L1 expression on progression-free survival (PFS) of EGFR-tyrosine kinase inhibitors (TKIs) therapy among patients with recurrent pN1-N2 EGFR-Mt lung adenocarcinoma (n=67) were examined using log-rank tests. Results: The RBM10 low expression group showed significantly better 5-year OS than the RBM10 high expression group (89.4% vs. 71.5%, P=0.020), and the PD-L1 negative group tended to have longer 5-year OS than the PD-L1 positive group (86.4% vs. 68.4%, P=0.050). Multivariable analysis showed that high RBM10 expression [hazard ratio (HR), 3.12; 95% confidence interval (CI): 1.19-8.17; P=0.021] and PD-L1 positivity (HR, 3.80; 95% CI: 1.64-8.84; P=0.002) were independent poor prognostic factors for OS. PFS of patients with relapse and first-line EGFR-TKI treatment was significantly better in the PD-L1-negative group than in the PD-L1-positive group (34.5 vs. 12.1 months, P=0.045). PFS of patients with Ex21 relapse and first-line EGFR-TKI treatment was significantly better in the RBM10 low expression group than in the RBM10 high expression group (25.5 vs. 13.0 months, P=0.025). Conclusions: High RBM10 expression and PD-L1 positivity are poor prognostic factors for OS in patients with pN1-N2 EGFR-Mt lung adenocarcinoma after curative surgery. In patients with recurrent pN1-N2 EGFR-Mt lung adenocarcinoma, PD-L1 and RBM10 expression may influence response to EGFR-TKIs.

Wedge resection vs. segmentectomy for lung cancer measuring ≤ 2 cm with consolidation tumor ratio > 0.25.

Objectives: We aimed to clarify the differences in prognosis between wedge resection and segmentectomy performed for cN0 non-small cell lung cancer (NSCLC) measuring ≤ 2 cm, with consolidation tumor ratio (CTR) > 0.25. Methods: This multicenter study included 570 patients with cN0 NSCLC (tumor size ≤ 2 cm, CTR > 0.25) who underwent wedge resection (n = 244) and segmentectomy (n = 326) between January 2010 and December 2018. After propensity score matching (PSM, 1:1 method), 182 patients were matched for clinical characteristics (age, sex, laterality, smoking index, tumor size, CTR, carcinoembryonic antigen value, positron-emission tomography-documented maximum standardized uptake value, clinical stage, and tumor disappearance rate) and intergroup comparison of disease-free survival (DFS) and overall survival (OS). Using Gray's test, an intergroup comparison of the cumulative incidence of lung cancer-specific mortality was performed. Results: After PSM, similar DFS (5-year DFS, 79.9% vs. 87.1%, p = 0.103) and OS (5-year OS, 88.7% vs. 88.9%, p = 0.719) rates were observed in the wedge resection and segmentectomy groups. We observed no significant intergroup differences in lung cancer-specific mortality (5-year cumulative incidence: 4.6% vs. 3.5%; p = 0.235). Subgroup analysis revealed no specific subgroup demonstrating improved DFS or OS after undergoing wedge resection or segmentectomy. Conclusion: DFS, OS, and lung cancer-specific mortality were comparable between wedge resection and segmentectomy of cN0 NSCLC-tumor size ≤ 2 cm and CTR > 0.25. Large-scale prospective clinical trials are warranted to compare the prognoses of wedge resection and segmentectomy for these tumors.

Long-term changes in psoas muscle mass after lobectomy and segmentectomy for early-stage lung cancer.

BACKGROUND: Segmentectomy is considered a less invasive procedure than lobectomy for patients with non-small cell lung cancer (NSCLC); however, little is known about the physiological mechanism underlying the lower invasiveness of segmentectomy. This study is aimed to compare the differences in the long-term changes in the psoas muscle mass after segmentectomy and lobectomy in patients with NSCLC. METHODS: Overall 315 recurrence-free patients who underwent segmentectomy (n = 93) or lobectomy (n = 222) for clinical stage 0-I NSCLC between January 2016 and December 2018 and underwent computed tomography during the entire period of 6 months ≤ postoperative year (POY) 0.5 < 12 months, 12 months ≤ POY 1 < 24 months, 24 months ≤ POY 2 < 36 months, and 36 months ≤ POY 3 < 48 months were included. Bilateral psoas muscle area (PMA) at the L3 level was measured using each cross-sectional computed tomography scan. Differences between the segmentectomy and lobectomy groups in the mean change of postoperative PMA from the preoperative period were analysed using Student's t-test and mixed analysis of variance. Multivariable analysis was performed to identify the risk factors for PMA loss on POY 3 using logistic regression analysis. RESULTS: The lobectomy group had a significantly larger PMA change than the segmentectomy group during each postoperative period (P < 0.001). Mixed analysis of variance revealed that the mean PMA change was significantly smaller in the segmentectomy group than in the lobectomy group during the observation period (P < 0.001). The mean change in the PMA was significantly larger from POY1 (-2.5%) to POY2 (-3.9%) and POY3 (-4.7%) in the lobectomy group (P = 0.003 and P < 0.001). However, PMA remained unchanged during the postoperative observation period in the segmentectomy group. In the multivariable analysis, the risk factors for PMA change ≤-3.3% (cut-off: mean change of PMA) at POY3 included lobectomy [odds ratio (OR), 3.32; 95% confidence interval (CI), 1.90-5.82; P < 0.001], male sex (OR, 1.92; 95% CI, 1.02-3.62; P = 0.044) and open thoracotomy (OR, 1.84; 95% CI, 1.11-3.05; P = 0.017). After propensity score matching, the mean change in PMA was smaller in the segmentectomy group (n = 75) than in the lobectomy group (n = 75) during the postoperative observation period (P < 0.001). CONCLUSIONS: Psoas muscle mass was better maintained during the postoperative period by segmentectomy than by lobectomy. Psoas muscle mass reduction progressed over a long postoperative period after lobectomy. Segmentectomy via complete video-assisted thoracic surgery is associated with a lower likelihood of sarcopenia progression.

Effect of Surgical Treatment for N2-Positive c-stage III Non-Small Cell Lung Carcinoma in the "PACIFIC" Era.

BACKGROUND: The PACIFIC trial findings drastically changed the c-stage III non-small cell lung cancer (NSCLC) treatment strategy. However, it remains uncertain whether surgery is no longer needed for treatment. We aimed to evaluate the efficacy of surgery and explore the prognostic factors of better outcomes in surgery-treated patients than in PACIFIC regimen-treated patients. PATIENTS AND METHODS: From 2010 to 2020, 107 patients with clinical N2-stage III NSCLC underwent lung resection in our institute. We analyzed and compared the yearly postoperative overall survival (OS) benchmarks of these patients to those of patients treated in the PACIFIC trial. RESULTS: The 1-, 2-, 3-, 4-, and 5-year OS rates of patients were 87.7%, 73.9%, 64.9%, 58.2%, and 55.4%, respectively, all of which were superior to those of PACIFIC regimen-treated patients. However, patients with cT3/T4 tumors and skip, multistation, distant, and bulky N2 metastases, as well as those who underwent bronchoplasty, showed inferior results in several yearly benchmarks than in PACIFIC regimen-treated patients. Multivariate analyses conducted among factors mentioned above showed that cT3/T4 tumor was a worse prognostic factor for surgery-treated patients than for PACIFIC regimen-treated patients (hazard ratio [HR] 1.89, P = .036). Distant N2 metastasis was also a worse prognostic factor, although its effect was not statistically significant (HR 1.81, P = .082). CONCLUSION: Surgery remains the mainstay of N2-positive c-stage III NSCLC treatment, and the PACIFIC regimen may be suitable only for patients with unresectable disease. However, surgery should be cautiously considered for patients with cT3/4 disease.

[Standard Approach and Education of Video-assisted Thoracoscopic Surgery for Anterior Mediastinal Tumors].

There are various approaches to surgery for anterior mediastinal tumors, including median sternotomy, multi-port and single-port video-assisted thoracic surgery, and robot-assisted thoracic surgery. According to the 2017 Annual Report of The Japanese Association for Thoracic Surgery, mediastinal tumor resection is about one-tenth of lung resection. Therefore, we consider that it is necessary to standardize the technique at each institution to acquire stable minimally invasive surgical techniques. We reported on our center's techniques and innovations in minimally invasive surgery for anterior mediastinal tumors, and used a learning curve to reveal that sharing knowledge within the team can reduce operative time.

Prognostic factors for relapse-free survival in stage IB-IIIA primary lung adenocarcinoma by epidermal growth factor receptor mutation status.

BACKGROUND: Pathological stage IB-IIIA lung adenocarcinoma with an epidermal growth factor receptor (EGFR) mutation (Mt) has a high recurrence rate even after complete resection. However, there have been few reports on the risk factors for Mt recurrence. This study aimed to analyze the clinicopathological factors related to the relapse-free survival (RFS) of patients with pathological stage IB-IIIA primary lung adenocarcinoma with and without an EGFR mutation. METHODS: Patients who underwent curative surgery for Mt (n = 208) harboring the EGFR exon 21 L858R point mutation or EGFR exon 19 deletion mutation and EGFR mutation wild-type lung adenocarcinoma (Wt, n = 358) between January 2010 and December 2020 were included. Patients who received adjuvant EGFR-tyrosine kinase inhibitors were excluded. The prognostic factors for RFS were analyzed using a multivariable Cox regression analysis. RESULTS: The 5-year RFS rates in the Mt and Wt groups were 43.5 and 52.3%, respectively (p = 0.907). Prognostic factors for RFS in the Mt group included smoking history (hazard ratio [HR], 1.49; p = 0.049), blood vessel invasion (HR, 1.84; p = 0.023), and lymph node metastasis (HR, 1.96; p = 0.005). However, adjuvant chemotherapy was not a prognostic factor (HR, 1.02; p = 0.906). In contrast, positron emission tomography (PET) max standardized uptake value (SUV) ≥ 6.0 (HR, 1.53; p = 0.042), lymphatic vessel invasion (HR, 1.54; p = 0.036), lymph node metastasis (HR, 1.79; p = 0.002), and adjuvant chemotherapy (HR, 0.60; p = 0.008) were prognostic factors for RFS in the Wt group. CONCLUSIONS: Prognostic factors for RFS in stage IB-IIIA primary lung adenocarcinoma differ by epidermal growth factor receptor mutation status. The impact of adjuvant chemotherapy on RFS also differed by EGFR mutation status.

Radiological unilateral pleuroparenchymal fibroelastosis as a notable late complication after lung cancer surgery: incidence and perioperative associated factors.

OBJECTIVES: Pleuroparenchymal fibroelastosis (PPFE) is a rare idiopathic interstitial pneumonia characterized by pleural-parenchymal involvement, predominantly in the upper lobes. Unilateral upper lung field pulmonary fibrosis (upper-PF) that is radiologically consistent with PPFE reportedly develops after lung cancer surgery in the operated side and presents many clinical characteristics in common with PPFE. However, the incidence and perioperative associated factors remain unclear. METHODS: All consecutive patients with lung cancer resected completely from 2008 to 2016 were investigated retrospectively. Pre-/postoperative characteristics were compared between patients with and without unilateral upper-PF. Cumulative incidence curves were estimated using competing risk analysis. RESULTS: Among the 587 included patients, 25 patients (4.3%) were diagnosed as unilateral upper-PF. The 3-, 5- and 10-year cumulative incidence of unilateral upper-PF was 2.3%, 3.3% and 5.3%, respectively. In multivariable analysis, male sex, presence of a pulmonary apical cap, lobar resection and low % vital capacity (%VC < 80%) were independent perioperative associated factors. The 10-year cumulative incidence was 6.3% in patients treated with lobar resection, 8.0% in male patients, 10.3% in patients with pulmonary apical cap and 14.5% in patients with low %VC. Postoperative pleural effusion at 6 months after surgery was much more common in the patients who later developed unilateral upper-PF (96.0% vs 24.2%). This pleural effusion persisted and was accompanied thereafter by pleural thickening and subpleural pulmonary fibrosis. During the clinical courses of 25 patients with unilateral upper-PF, 18 patients presented symptoms related to upper-PF and 6 patients died. CONCLUSIONS: Unilateral upper-PF is an occasional but under-recognized late complication after lung cancer surgery.

Fungus ball removal with video-cavernoscopy for complex aspergilloma.

OBJECTIVE: Complete resection with a clear margin is the only curative treatment for pulmonary aspergilloma. This requires a high-level technique, especially for complex aspergilloma (CA), because of patient conditions and wide dense adhesions. Fungus ball removal is used palliatively to control hemoptysis, rather than as a radical procedure, and may be performed using video-cavernoscopy as a simple and repeatable method. In this study, we examined this approach as an alternative treatment for CA. METHODS: Eight cases of fungus ball removal with video-cavernoscopy (video-cavernoscopic removal) treated at our center were retrospectively reviewed. The patient characteristics and surgical outcomes were compared with those of patients treated with one-stage radical surgery. RESULTS: There were 8 subjects (7 males, 1 female; median age 65 years) in the video-cavernoscopic removal group and 25 subjects (19 males, 6 females; median age 56 years) in the one-stage radical surgery group. The video-cavernoscopic removal group had a higher rate of emphysematous lung (p = 0.001), a lower body mass index (p = 0.039), and a lower percent vital capacity (p = 0.027). All cases in this group had preoperative hemoptysis that ceased after the procedure. Video-cavernoscopic removal was less invasive based on a shorter operative time (p = 0.000), less blood loss (p = 0.002), and a lower Common Terminology Criteria for Adverse Events grade (p = 0.023). However, four cases in this group (50%) relapsed with a median disease-free survival period of 471.5 days. CONCLUSIONS: Fungus ball removal with video-cavernoscopy is a simple technique for the prevention and control of massive hemoptysis that may be an alternative treatment for CA.

A spectrum of Thymic mucosa-associated lymphoid tissue lymphoma and Thymic amyloidosis in the patient with Auto immune disease: a case series.

BACKGROUND: The thymus is associated with an immunodeficient status, autoimmune disease (AD), and the common thymic tumor, thymoma. We encountered two rare thymic tumors, thymic mucosa-associated lymphoid tissue (MALT) lymphoma and localized thymic amyloidosis, both in the presence of Sjögren's syndrome (SjS). This suggests a possible link between rare thymic tumors and SjS. Therefore, we reviewed cases of thymic tumors to examine the spectrum of these tumors in patients with AD. METHODS: The clinical information of thymic amyloidosis and MALT lymphoma surgically treated at Kanagawa Cardiovascular and Respiratory Center, and Yokohama City University Hospital from January 2010 to December 2019 were reviewed. The correlation between resected thymic tumors at same period and ADs were also investigated. RESULTS: There were 5 cases of thymic amyloidosis and MALT lymphoma. ALL cases had coexistent ADs (4 SjS, 1 SSc). The median age was 66 (38-76) year-old, and 4 of the patients were female. Three cases had already diagnosed as ADs before detection of tumors. Only SSc case was received preceding steroid medication. Two cases diagnosed as SjS at the same time of the operation. The median maximum tumor diameter was 70 mm. On chest computed tomography (CT), tumors contained solid part and some cystic part at various rated. Calcification was recognized with appearance of amyloid deposition. All patients were surgically treated with total thymectomy and they are alive without recurrence. At the same period, there were 163 resected thymic tumors, including amyloidosis, MALT lymphoma, thymoma, thymic cancer, neuroendocrine tumor and so on. Among them, nine patients (5.5%) had ADs. There was a correlation between ADs and thymic MALT lymphoma/amyloidosis (P<0.001). CONCLUSIONS: We propose a process for tumorigenesis of thymic MALT lymphoma and amyloidosis. Underlying AD causes persistent and chronic inflammatory reactions. In this theory, ADs, especially SjS, might be important underlying conditions in formation of rare tumors. When the clinician encounters a patient with AD, routine chest CT is recommended and may provide thymic tumors. Conversely, in case of mediastinum tumor, screening test for AD is also recommended.