RNF128 expression in lung adenocarcinoma is a favorable prognostic factor associated with decreased tumor-associated macrophages.

OBJECTIVES: Molecular-level research has linked RING finger (RNF) protein family members to carcinogenesis and tumor progression. Among them, RNF128 is related to tumor progression, but reports on its association with lung cancer are few. This study aimed to clarify the unknown association between RNF128 expression and clinical outcomes in patients with lung adenocarcinoma. METHODS: Clinical data of 545 patients with therapy-naïve lung adenocarcinoma who underwent lobectomy with systematic lymph node dissection between 1999 and 2016 were retrospectively reviewed. Histological and immunohistochemical analyses were conducted to evaluate the relationship between RNF128 expression and prognosis. RESULTS: Among adenocarcinoma histologic types, acinar, micropapillary, and solid tumors did not express RNF128 compared with other histologic types (p < 0.001). Patients with high RNF128 expression exhibited fewer clusters of differentiated (CD) 68+ tumor-associated macrophages (TAMs) and CD163+ TAMs. Multivariate analysis of relapse-free survival (RFS) and overall survival (OS) revealed that the lack of RNF128 expression was an independent prognostic factor for poor RFS (hazard ratio [HR] 1.60, p = 0.029) and OS (HR 1.83, p = 0.041), suggesting that RNF128 expression is a favorable prognostic factor. CONCLUSION: RNF128 expression may be an independent predictor of favorable outcomes in Japanese patients with untreated lung adenocarcinoma who undergo surgical resection. Further elucidation of the role of TAM-related E3 ubiquitin ligase in immune function may facilitate the development of effective immunomodulatory therapies for lung adenocarcinoma.

[Mixed Squamous Cell and Glandular Papilloma in the Peripheral Lung:Report of a Case].

Pulmonary papillary tumors are usually occur in the upper respiratory tract, and solitary papilloma in the peripheral lung are extremely rare. Lung papillomas sometimes show the elevation of tumor marker or F18-fluorodeoxyglucose (FDG) uptake, and are difficult to distinguish from lung carcinoma. Here we report a case of mixed squamous cell and glandular papilloma in the peripheral lung. An 85-years-old man without smoking history had been presented with an 8-mm nodule in right lower lobe in chest computed tomographic (CT) 2 years before. Since the diameter of the nodule increased to 12 mm, and positron emission tomography (PET) revealed an abnormally increased FDG uptake in the mass (SUVmax 4.61). StageIA2 lung cancer (cT1bN0M0) was suspected and wedge resection of the lung to make a definitive diagnosis and for treatment was performed. The definite pathological diagnosis was mixed squamous cell and glandular papilloma.

MMP-7 expression is associated with a higher rate of tumor spread through air spaces in resected lung adenocarcinomas.

OBJECTIVES: The spread through air spaces (STAS) of adenocarcinoma (ADC) is a unique pattern for local invasion, which comprises the spread of tumor cells within air spaces beyond the tumor edge without a direct connection with the primary tumor. Matrix metalloproteinase-7 (MMP-7), a secreted proteolytic enzyme that degrades various extracellular matrix components and other substrates, regulates several pathophysiological processes as well as the occurrence and development of cancers in humans. Here, we retrospectively analyzed a cohort of Japanese patients with treatment-naive, surgically-resected lung ADC to assess whether MMP-7 is associated with STAS development and if it could be used as a predictor of STAS. MATERIALS AND METHODS: We performed histological evaluation using hematoxylin and eosin staining and immunohistochemical analysis using microarrays. Thereafter, we scored the examined tissues for immune markers to identify significant tumor STAS predictors. RESULTS: We identified that high MMP-7 expression is an independent predictor of a high STAS incidence. Multivariate analysis revealed that MMP-7 expression was correlated with tumor behavior and poor prognosis. Furthermore, STAS remained significantly associated with a higher risk of ADC recurrence. CONCLUSION: The development of tumor STAS could be promoted by the functioning of MMP-7. This study could be a crucial basis for future investigations on the detection of tumor STAS.

Segmentectomy Provides Comparable Outcomes to Lobectomy for Stage IA Non-small Cell Lung Cancer with Spread through Air Spaces.

This study aimed to compare the recurrence-free survival (RFS) and overall survival (OS) among wedge resection (non-anatomical resection), segmentectomy and lobectomy for pathological stage IA non-small cell lung cancer (NSCLC) with spread through air spaces (STAS). Patients underwent surgical treatment for pathological stage IA NSCLC between January 1, 2005, and March 31, 2016, at our hospital. Surgical procedures were classified as lobectomy, segmentectomy, and wedge resection. Among the 555 analyzed cases, STAS was observed in 148 patients (26.7%). STAS was correlated with worse RFS (P < 0.001) and OS (P < 0.001) and was an independent poor prognostic factor for RFS (hazard ratio: 2.37, P < 0.001) and OS (hazard ratio: 2.02, P < 0.001) in the multivariate analysis. In patients with STAS, the RFS and OS in the segmentectomy group were comparable to those in the lobectomy group. However, the RFS and OS in the wedge resection group were significantly lower than those in the lobectomy group (RFS, P < 0.001; OS, P = 0.001). Wedge resection was an independent prognostic factor for poor RFS (hazard ratio [HR] = 3.87; 95% confidence interval [CI] = 1.84 - 8.12, P < 0.001), and poor OS (hazard ratio [HR] = 3.39; 95% confidence interval [CI] = 1.33 - 8.76, P = 0.011) in the multivariate analysis. Segmentectomy is an adequate operation for patients with stage IA NSCLC with or without STAS. However, wedge resection is associated with a higher risk of recurrence in this patient population.

Dual Image Navigation to Secure Surgical Margins in Thoracoscopic Segmentectomy.

PURPOSE: Video-assisted thoracoscopic surgery (VATS) segmentectomy is being increasingly used for the management of non-small cell lung cancer. For non-palpable lesions, surgeons frequently find difficulty in ensuring a sufficient surgical resection margin. OBJECTIVE: The purpose of this study was to evaluate the role of intraoperative dual image navigation in combination with the infrared thoracoscopy with intravenous injection of indocyanine green (IRT-ICG) method and intraoperative computed tomography (CT) in detecting oncological margins. METHODS: This study involved 34 consecutive patients who underwent both IRT-ICG and intraoperative CT-assisted thoracoscopic segmentectomy between October 2017 and July 2021. The intersegmental line on the visceral pleura was visualized using the IRT-ICG method. The intersegmental line was marked by clipping, and an intraoperative CT scan was performed under bilateral lung ventilation. Intraoperative CT or three-dimensional CT reconstruction images were used by surgeons to confirm the correct anatomic segmental border and to secure a sufficient resection margin. RESULTS: A well-defined intersegmental line was observed in 91.2% of patients. In eight cases, the surgeon needed to make some modifications to the resection line to secure a sufficient surgical margin. The mean surgical margin assessed on gross examination by the pathologist was 23.4 ± 9.0 mm. Complete resection was achieved in all patients using this approach. CONCLUSIONS: Intraoperative dual image navigation combined with the IRT-ICG method and intraoperative CT scan enables surgeons to perform definitive VATS segmentectomy for non-palpable lesions.

Tumor-associated CD163+ macrophage as a predictor of tumor spread through air spaces and with CD25+ lymphocyte as a prognostic factor in resected stage I lung adenocarcinoma.

OBJECTIVE: Lung cancer can spread in numerous ways, including spread through air spaces (STAS). A high number of CD68+ tumor-associated macrophages (TAMs), which creates a favorable microenvironment for tumor progression, is an independent predictor of increased STAS rate and is used as a pan-macrophage marker, whereas CD163 is used as an M2 macrophage marker. A high number of CD25+ tumor-infiltrating lymphocytes (TILs) is associated with the frequency of STAS. This study investigated the influence of M2 macrophages and CD25+ TILs on STAS and postoperative recurrence in patients with stage I lung adenocarcinoma who underwent curative resection. METHODS: We analyzed data from 485 patients with stage 0-I lung adenocarcinoma who underwent resection between 1999 and 2016. Tissue microarrays were constructed, and immunohistochemical analysis was performed for CD3, CD4, CD8, CD45RO, CD25, CD20, CD68, and CD163. Three tumor areas with the highest density of immune cells were photographed, and the immune cells were quantified. Associations between variables were analyzed using chi-square tests and Mann-Whitney U tests. Recurrence-free probability (RFP) was analyzed using log-rank tests and Cox proportional hazards models. RESULTS: CD163+ TAMs were identified as an independent predictor of a higher rate of STAS (P < 0.001). Analysis of biologically relevant immune cell combinations revealed that patients with high CD25+ TILs and high CD163+ TAMs had a significantly lower RFP (5-year RFP, 74%) than those with other combinations of CD25 and CD163 (5-year RFP, 90%; P < 0.001). Multivariate analysis showed that high CD25+/high CD163+ immune cell infiltration was an independent predictor of RFP. CONCLUSION: We demonstrated that a higher density of M2 macrophages is an independent predictor of a higher STAS incidence. A high CD25+/high CD163+ immune cell infiltration ratio is a significant prognostic factor for stage 0-I lung adenocarcinoma.

IgG4-related lung disease with recurrent pulmonary lesions during steroid therapy and difficulty in differentiating from malignancy: a case report.

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is characterized by the formation of inflammatory lesions with fibrosis and infiltration of IgG4-positive plasma cells and lymphocytes in various organs of the body. Since the first report of IgG4-related autoimmune pancreatitis, IgG4-RD affecting various organs has been reported; however, only a few reports of IgG4-related lung disease (IgG4-RLD) exist. In this report, we describe a case of IgG4-RLD that was difficult to differentiate from malignancy, and the usefulness of the surgical approach in determining the appropriate diagnosis and treatment plan. CASE PRESENTATION: A 61-year-old man was referred to our hospital after a chest radiograph revealed an abnormal chest shadow. At the time of his first visit, he had a slight fever and dyspnea on exertion. Chest computed tomography (CT) revealed a middle lobe hilar mass with irregular margins and swelling of the right hilar and mediastinal lymph nodes. These findings were not present on CT 1.5 years ago. 18F-fluorodeoxyglucose-positron emission tomography revealed a mass lesion with a maximum diameter of 5.5 cm, maximum standardized uptake value (SUVmax) of 11.0, and areas with high SUV in the hilar and mediastinal lymph nodes. We suspected lung cancer or malignant lymphoma and performed a thoracoscopic lung biopsy to confirm the diagnosis. Histopathological examination revealed no malignant findings, and IgG4-RLD was diagnosed. One month after treatment with prednisolone (PSL), the tumor had shrunk, but a CT scan during the third month of PSL treatment revealed multiple nodular shadows in both lungs. Considering the possibility of malignant complications and multiple lung metastases, we performed thoracoscopic partial lung resection of the new left lung nodules to determine the treatment strategy. Histopathological examination revealed no malignant findings in any of the lesions, and the patient was diagnosed with IgG4-RLD refractory to PSL monotherapy. CONCLUSIONS: IgG4-RLD refractory to PSL monotherapy showed changes from a solitary large mass (pseudotumor) to multiple nodules on chest CT. It was difficult to distinguish malignancy from IgG4-RLD based on imaging tests and blood samples alone, and the surgical approach was useful in determining the appropriate diagnosis and treatment plan.

A New Method to Identify Air Leaks After Pulmonary Resection Using Indocyanine Green Aerosol.

BACKGROUND: This study investigated whether air leak sites resulting from pulmonary resection could be identified by the administration of aerosolized indocyanine green into the airway. METHODS: Sixty-one patients who underwent lung resection surgery (54 video-assisted thoracoscopic surgeries and 7 thoracotomies) during 2019 to 2021 were enrolled. An additional sealing test including indocyanine green administration and observation with a near-infrared camera was performed after the conventional sealing test. The results of the indocyanine sealing test were compared with those of the conventional sealing test and evaluated. The observation period set for evaluating adverse events was 1 month. RESULTS: The conventional sealing test detected 38 air leak points, of which 20 were caused by stapler-related pleural defects. The indocyanine green sealing test identified 55 indocyanine green fluorescent sites. Among these, 37 sites were matched with air leak points identified in the conventional sealing test, and 18 new sites were identified in the indocyanine green test. Reexamination of newly identified indocyanine green fluorescent sites with the conventional sealing test showed 13 air leak sites additionally. The detection rate of the conventional sealing test was 75% and that of the indocyanine green sealing test was 98% (P = .001). No complications attributable to the aerosolized indocyanine green were encountered. CONCLUSIONS: The indocyanine green sealing test could identify air leak points overlooked by the conventional method. This procedure may be suitable in video-assisted surgery to improve surgical field visibility, and it allows prolonged observation of the lung in a collapsed state.

Prognostic impact of tumor-infiltrating lymphocytes and neutrophils in resected non-small cell lung carcinoma.

The prognostic impact of tumor-infiltrating lymphocytes (TILs) has been determined in non-small cell lung carcinoma; however, there is no standardized method for counting TILs. In this report, we applied the method proposed by the International Immuno-Oncology Biomarkers Working Group for the assessment of TILs to count the number of tumor-infiltrating neutrophils (TINs). We then analyzed the association between TIL counts, TIN counts, and clinicopathological factors in lung cancer. We retrospectively analyzed a series of 1191 Japanese patients with resected lung adenocarcinoma and squamous cell carcinoma, which were restaged according to the eighth edition of the TNM staging system. Tumors were classified according to the 2015 WHO classification of lung carcinoma. Recurrence-free probability (RFP) and overall survival (OS) were analyzed using the log-rank test and Cox proportional hazard model. Using multivariate analysis for patient outcome in patients with adenocarcinoma, high TIN counts were an independent prognostic factor for worse RFP (hazard ratio [HR]: 1.94, p < 0.001) and worse OS (hazard ratio [HR]: 1.75, p = 0.006). On the other hand, TIL counts were not related to patient outcome. We have demonstrated that high TINs are unfavorable prognostic markers for resected lung adenocarcinoma. In resected lung squamous cell carcinoma, TIL and TIN counts were not related to patient prognosis. It has been suggested that the immune response to cancer cells may differ depending on the histological type. An understanding of how neutrophils are programmed to perform protumor activities is necessary for the future design of targeted immunotherapies.

Regeneration of emphysematous lungs using gelatin sheets that release basic fibroblast growth factor.

PURPOSE: Basic fibroblast growth factor (bFGF) induces regeneration and neovascularization of the lungs. We conducted this study to demonstrate the regeneration of emphysematous lungs achieved by gelatin sheets that slowly release bFGF into the visceral pleura in a canine model. METHODS: Porcine pancreatic elastase was used to induce bilateral lower lobe pulmonary emphysema in dogs. Slow-release bFGF gelatin sheets were attached to the visceral pleura of the left lower lobe via thoracotomy. The subjects were divided into two groups: one treated with gelatin sheets containing slow-release bFGF (bFGF+ group, n = 5), and the other, treated with only gelatin sheets (bFGF- group, n = 5). The subjects were euthanized after 28 days and histologic lung assessment was performed. The results were evaluated in terms of the mean linear intercept (MLI) and microvessel count. RESULTS: The MLI was significantly shorter in the bFGF+ group than in the bFGF- group; (110.0 ± 24.38 vs. 208.9 ± 33.08 µm; P = 0.0006). The microvessel count was not significantly different between the bFGF+ and bFGF- groups (12.20 ± 3.007 vs. 5.35 ± 2.3425; P = 0.075); however, it was significantly higher in the bFGF-attached lungs than in the emphysema group (12.20 ± 3.007 vs. 4.57 ± 0.8896; P = 0.012). CONCLUSIONS: Attaching gelatin sheets with slow-release bFGF to the visceral pleura induced lung regeneration and vascularization in a canine pulmonary emphysema model.

High-grade tumor classified by new system is a prognostic predictor in resected lung adenocarcinoma.

OBJECTIVES: A grading system for pulmonary adenocarcinoma has not been established; hence, the International Association for the Study of Lung Cancer (IASLC) pathology panel developed a new grading system for invasive adenocarcinoma. We aimed to evaluate the prognostic significance of the IASLC grading system for invasive pulmonary adenocarcinoma. METHODS: We conducted a retrospective analysis of 471 Japanese patients with resected lung adenocarcinoma. Tumors were classified in accordance with the IASLC grading system and 2015 World Health Organization classification. We analyzed recurrence-free probability (RFP) and overall survival (OS) using the log-rank test and compared the two grading systems using the Cox proportional hazards model. RESULTS: Grade 3 tumors of the IASLC system and high-grade tumors of the 2015 World Health Organization classification were present in 38% and 17% of patients, respectively. The 5-year RFP was lower in patients with IASLC Grade 3 tumors (45%) than in patients with IASLC Grade 1 and 2 tumors (91% and 83%, respectively). The 5-year RFP of patients with IASLC Grade 2 tumors (83%) was higher than of those with 2015 World Health Organization intermediate tumors (69%). On multivariate analysis for recurrence, IASLC Grade 3 was an independent prognostic factor of worse RFP. We showed similar results on analysis for the OS. CONCLUSIONS: The prognostic significance of IASLC Grade 3 tumors on recurrence-free probability was confirmed through both univariate and multivariate analyses. Thus, the IASLC Grade 3 tumor is an independent factor of poor prognosis in patients with resected lung adenocarcinoma.

Preoperative monocyte count is a predictor of recurrence after Stage I lung adenocarcinoma resection.

OBJECTIVES: High-grade tumours are observed even in Stage I lung adenocarcinomas. Tumour spread through air spaces (STAS) is a risk factor for recurrence after resection. However, there is no ideal predictive biomarker for STAS in high-grade Stage I lung adenocarcinoma. This study assessed the prognostic impact of the preoperative peripheral monocyte count in lung adenocarcinoma. METHODS: We retrospectively analysed the data of 444 patients with resected Stage I lung adenocarcinoma during 2006-2016. Univariable and multivariable Cox proportional analyses of recurrence-free probability (RFP) and overall survival (OS) were used to analyze preoperative complete peripheral blood cell count data. Since monocyte count was associated with poor prognosis, the relationship between preoperative peripheral monocyte count and clinicopathological factors, including STAS, was assessed. In addition, immunohistochemical CD68 staining was performed to evaluate tumour-associated macrophages (TAMs). RESULTS: A higher preoperative peripheral monocyte count was a predictor of lower RFP (P = 0.004) and lower OS (P < 0.001). In multivariable analysis, a higher peripheral monocyte count was an independent prognostic factor for RFP and OS (hazard ratio: 1.88, 95% confidence interval: 1.07-3.31, P = 0.029; hazard ratio: 2.13, 95% confidence interval: 1.22-3.75, P = 0.008, respectively). A higher peripheral monocyte count was associated with a higher frequency of STAS (P = 0.017) and higher number of CD68+ TAMs (P = 0.013). CONCLUSIONS: A higher preoperative peripheral monocyte count was an independent marker for a poor prognosis in Stage I lung adenocarcinoma and was associated with a higher frequency of STAS.

Safe pneumonectomy for locally advanced lung cancer after induction therapy.

PURPOSE: To assess the safety and long-term outcomes of pneumonectomy after IT (IT-Pn) versus upfront pneumonectomy without IT (U-Pn) for locally advanced non-small-cell lung cancer (NSCLC). METHODS: We reviewed the clinical records of 69 patients who underwent pneumonectomy as U-Pn (n = 30) or IT-Pn (n = 39) between 2000 and 2019 at our institution, RESULTS: U-Pn included patients with pathological N0 (n = 13), N1 (n = 11) and N2 (n = 6). Among the patients treated with IT-Pn, 18 had pathological N0 (including 7 with complete responses), 5 had N1, 14 had N2, and 2 had N3. It was suggested that 22 cases could be down-staged after IT. The 5-year overall survival (OS) was 28.1% in the U-Pn group and 43.1% in the IT-Pn group (p = 0.275), being 40.2% for IT-Pn with p-N2,3, but not reached for U-Pn with N2 (p = 0.307). The 90-day mortality was 6.7% for the U-Pn group and 5.1% for the IT-Pn group (p = 0.646). Major complications occurred in 25 patients (64.1%) treated with IT-Pn and 18 patients treated with U-Pn (60.0%; p = 0.602). CONCLUSIONS: Pneumonectomy for NSCLC can be performed safely after IT with favorable results. For patients with N2 disease, induction therapy followed by surgery may warrant further study.

Perpendicular implantation of porcine trachea extracellular matrix for enhanced xenogeneic scaffold surface epithelialization in a canine model.

Objective: The availability of clinically applied medical materials in thoracic surgery remains insufficient, especially materials for treating tracheal defects. Herein, the potential of porcine extracellular matrix (P-ECM) as a new airway reconstruction material was explored by xenotransplanting it into a canine trachea. Methods: P-ECM was first transplanted into the buttocks of Narc Beagle dogs (n = 3) and its overall immuno-induced effects were evaluated. Subsequently, nine dogs underwent surgery to create a tracheal defect that was 1 × 2 cm. In group A, the P-ECM was implanted parallel to the tracheal axis (n = 3), whereas in group B the P-ECM was implanted perpendicular to the tracheal axis (n = 6). The grafts were periodically observed by bronchoscopy and evaluated postoperatively at 1 and 3 months through macroscopic and microscopic examinations. Immunosuppressants were not administered. Statistical evaluation was performed for Bronchoscopic stenosis rate, graft epithelialization rate, shrinkage rate and ECM live-implantation rate. Results: No sign of P-ECM rejection was observed after its implantation in the buttocks. Bronchoscopic findings showed no improvement concerning stenosis in group A until 3 months after surgery; epithelialization of the graft site was not evident, and the ECM site appeared scarred and faded. In contrast, stenosis gradually improved in group B, with continuous epithelium within the host tissues and P-ECM. Histologically, the graft site contracted longitudinally and no epithelialization was observed in group A, whereas full epithelialization was observed on the P-ECM in group B. No sign of cartilage regeneration was confirmed in both groups. No statistically significant differences were found in bronchoscopic stenosis rate, shrinkage rate and ECM live-implantation rate, but graft epithelialization rate showed a statistically significant difference (G-A; sporadic (25%) 3, vs. G-B; full covered (100%) 3; p = 0.047). Conclusions: P-ECM can support full re-epithelialization without chondrocyte regeneration, with perpendicular implantation facilitating epithelialization of the ECM. Our results showed that our decellularized tracheal matrix holds clinical potential as a biological xenogeneic material for airway defect repair.

[Anomalous V2 Preoperatively Identified by Three-dimensional Computed Tomography in a Patient with Primary Lung Cancer of Right Upper Lobe].

A 61-year-old woman was found to have multiple ground-glass nodules( GGNs) in both lungs by chest computed tomography (CT) scan. The lesion of the right S2 contained a partial solid component and was suspected to be minimally invasive adenocarcinoma. Three-dimensional CT showed two anomalous V2s descending dorsally to the intermediate bronchus and draining into the inferior pulmonary vein. Thoracoscopic segmentectomy of the right S2 was performed safely. The pathological diagnosis was adenocarcinoma in situ. Since aberrant pulmonary vessels increases the surgical risk during video-assisted thoracoscopic anatomical lung resection, preoperative three-dimensional CT is useful in performing safe surgical procedure.

[Surgical Approach for Treatment of Postoperative Bronchopleural Fistula and Pyothorax].

A bronchopleural fistula is a serious condition that can develop into pyothorax. The incidence of bronchopleural fistula depends on the surgical procedure. Bronchopleural fistulas are classified into early and late types based on the time of development following surgical intervention. Early-stage fistulas show poor prognosis and require prompt treatment. It is important to confirm the status of infection in the thoracic cavity to devise an optimal treatment plan. Bronchopleural fistula closure is challenging and may be unsuccessful in patients with uncontrolled infection. Immediate open window thoracostomy should be performed in patients with empyema. The window is closed after effective clearance of thoracic cavity infection. Prompt and systematic treatment improves prognosis.

Tumor-associated macrophage infiltration is associated with a higher rate of tumor spread through air spaces in resected lung adenocarcinomas.

OBJECTIVE: Lung cancer can spread in numerous ways, one of which has been suggested to be spread through air spaces (STAS). The tumor immune microenvironment appears to play a significant role in this spread. Particularly, tumor-associated macrophages (TAMs) can create a favorable microenvironment for tumor progression. In this study, we analyzed data from 709 patients with stage 0-IIIA lung adenocarcinoma, resected between 1999 and 2016, and investigated whether immune cell infiltration was associated with the occurrence of STAS and clinical outcome of the disease. MATERIALS AND METHODS: Tissue microarrays were constructed, and immunohistochemical analysis was performed for CD3, CD4, CD8, CD45RO, CD25, CD20, and CD68. The three tumor areas with the highest density of immune cells were photographed, and the immune cells were quantified. Associations between variables were analyzed using chi-square tests and Mann-Whitney U tests. Recurrence-free probability and overall survival were analyzed using log-rank tests and Cox proportional hazards models. RESULTS: After analyzing the associations between STAS and each type of immune cell infiltration, high density of CD68 + TAMs was identified as an independent predictor of a high STAS rate (p =  0.014) and was found to be associated with a high risk of recurrence, using univariate analysis (p =  0.008). After adjusting for CD68+ TAMs, pathological stage, and lymphovascular invasion, STAS remained significantly associated with a high risk of recurrence (HR = 3.50, p < 0.001). CONCLUSION: We demonstrated that a high density of CD68 + TAMs is an independent predictor of an increased STAS rate. Additionally, STAS is correlated with aggressive tumor behavior characteristics.

Current status and perspectives of spread through air spaces in lung cancer.

According to the World Health Organization classification of 2015, spread through air spaces (STAS) is a newly recognized pattern of invasion in lung adenocarcinoma. Many researchers have reported that STAS is recognized in all histological subtypes, and there is a strong association between STAS and prognosis in lung cancer. However, there are several technical issues associated with STAS, such as distinction between the actual in vivo phenomenon and an artifact, difficulty in assessing STAS in frozen specimens, and establishing the relationship between morphological and molecular properties of STAS. This review focuses on the current state of knowledge and the outlook of the STAS phenomenon from the perspective of surgeons, pathologists, and radiologists.

Phase II Study of Neoadjuvant Concurrent Chemo-immuno-radiation Therapy Followed by Surgery and Adjuvant Immunotherapy for Resectable Stage IIIA-B (Discrete N2) Non-small-cell Lung Cancer: SQUAT trial (WJOG 12119L).

INTRODUCTION: We describe our ongoing multicenter, prospective, single-arm, phase II trial of neoadjuvant concurrent chemo-immuno-radiation therapy followed by surgical resection and adjuvant immunotherapy for resectable stage IIIA-B (discrete N2) non-small-cell lung cancer (NSCLC) (registered at the Japan Pharmaceutical Information Center, Clinical Trials Information-195069). PATIENTS AND METHODS: Key inclusion criteria include (1) clinical T1-3/T4 (tumor size) N2 stage IIIA-B NSCLC, and (2) pathologically confirmed N2 without extranodal invasion (based on diagnostic imaging). Patients will receive concurrent chemoradiotherapy (carboplatin [area under the curve = 2] and paclitaxel [40 mg/m2] on days 1, 8, 15, 22, and 29, with involved-field radiation therapy [RT] [dose 50 Gy] on days 1-25) and neoadjuvant immunotherapy (durvalumab [1500 mg] on days 1 and 29). Surgical resection with mediastinal lymph node dissection is performed within 2 to 6 weeks after RT. Consolidation therapy with durvalumab is administered for up to 1 year after surgery. The primary endpoint is major pathologic response (MPR) (≤10% residual viable tumor) according to the central pathological assessment. Secondary endpoints are progression-free survival, overall survival, and safety. The sample size is planned to be 31 patients based on the exact binomial distribution with a 1-sided significance level of 5% and a power of 80%, and assuming a threshold MPR rate of 40% and an expected MPR rate of 65%. CONCLUSION: This trial will help establish a novel treatment strategy for resectable N2-positive NSCLC.