Improving intraoperative diagnosis of spread through air spaces: A cryo-embedding-medium inflation method for frozen section analysis.

Objective: Accurate intraoperative diagnosis of spread through air spaces (STAS), a known poor prognostic factor in lung cancer, is crucial for guiding surgical decision-making during sublobar resections. This study aimed to evaluate the diagnostic sensitivity of STAS using frozen section (FS) slides prepared with the cryo-embedding medium inflation technique. Methods: In this prospective study at Shinshu University Hospital, 99 patients undergoing lung resection for tumors <3 cm in size were included, a total of 114 lesions. FS slides were prepared with injecting diluted cryo-embedding medium into the lung parenchyma of resected specimens. The diagnostic performance of these FS slides for STAS detection was evaluated by comparing FS-STAS results with the gold-standard STAS status. Results: The incidence of STAS, determined by the gold standard, was 43 (38%) of 114 lesions, including 31 (37%) of 84 primary lung cancers and 12 (40%) of 30 metastatic lung tumors. The sensitivity, specificity, positive and negative predictive values, and accuracy of FS slides for STAS detection were 81%, 89%, 81%, 89%, and 86%, respectively. Specifically, in primary lung cancers, these values were 90%, 89%, 82%, 94%, and 89%, respectively. Regarding metastatic lung tumors, the corresponding values were 58%, 89%, 78%, 76%, and 77%, respectively. Conclusions: Our adapted cryo-embedding medium inflation method has demonstrated enhanced sensitivity in detecting STAS on FS slides, providing results similar to the gold-standard STAS detection. Compared with historical benchmarks, this technique could show excellent performance and be readily incorporated into clinical practice without requiring additional resources beyond those used for standard FS analysis.

Sublobar resection or lobectomy and postoperative respiratory complications in emphysematous lungs.

OBJECTIVES: Pulmonary resection in patients with severe emphysema may impact postoperative respiratory complications. Low-attenuation areas evaluated using three-dimensional computed tomography to assess emphysematous changes are strongly associated with postoperative respiratory complications. Herein, we investigated the relationship between low-attenuation area, the surgical procedure and resected lung volume, which has not been explored in previous studies. METHODS: We retrospectively evaluated patients with primary or metastatic lung cancer who underwent surgical resection. The low-attenuation area percentage (low-attenuation area/total lung area × 100) and resected lung volume were calculated using three-dimensional computed tomography software, and the relationship with postoperative respiratory complications was analysed. RESULTS: Postoperative respiratory complications occurred in 66 patients (17%) in the total cohort (n = 383). We set the median value of 1.1% as the cut-off value for low-attenuation area percentage to predict postoperative respiratory complications, which occurred in 24% and 10% of patients with low-attenuation area >1.1% and <1.1%, respectively (P < 0.001). Postoperative respiratory complications occurred in approximately one-third of the patients with low-attenuation area >1.1%, whose resected lung volume was ≥15.8% or ≥5 resected subsegments. Multivariable analysis revealed that sublobar resection was associated with a significantly lower risk of postoperative respiratory complications in patients with low-attenuation area >1.1% (odds ratio 0.4, 95% confidence interval 0.183-0.875). CONCLUSIONS: Emphysema is a risk factor for postoperative respiratory complications, and lobectomy is an independent predictive risk factor. Preserving more lung parenchyma may yield better short-term prognoses in patients with emphysematous lungs.

Segmentectomy-oriented anatomical model for enhanced precision surgery of the left upper lobe.

Objective: To optimize surgical outcomes and minimize complications in complex segmentectomy of the left upper lobe, we investigated the topographical anatomy of the left upper lobe and developed a segmentectomy-oriented anatomical model. Methods: A state-of-the-art 3-dimensional computed tomography workstation was used to visualize the intersegmental planes and associated veins to categorize the anatomical patterns influencing surgical procedures during left upper lobe segmentectomy. This included the central vein affecting S1+2 (apicoposterior segment) segmentectomy, the transverse S3 (anterior segment) affecting S3 segmentectomy, and other venous branching patterns in 395 patients who underwent thoracic surgery at our institution. Results: The central vein was observed in 32% of the patients, necessitating access from the interlobar area after segmental artery and bronchus division. Transverse S3 incidence was 27%, revealing that only one-third of the patients required complete left upper lobe transection between S4 and S3 during S3 segmentectomy. A significant negative correlation was observed between the presence of transverse S3 and the central vein (<10% of patients with the central vein had transverse S3 and vice versa). In 6% of patients, the lingular segmental veins partially or entirely drained into the inferior pulmonary vein, potentially causing excessive or insufficient resection during surgery. Conclusions: This study offers valuable insights into the topographic anatomy of the left upper lobe and presents a segmentectomy-oriented anatomical model for complex segmentectomies. Our approach enables a more precise and individualized surgical planning for patients undergoing segmentectomy based on their unique anatomy, which could thereby lead to improved patient outcomes.

Saving Lives in Thoracic Surgery: Balancing Oncological Radicality and Functional Preservation, Transitioning from Standard Pneumonectomy to Targeted Sublobar Resection.

This review chronicles the evolution of thoracic surgical interventions, from the standardized pneumonectomy to the precise approach of sublobar resections. It discusses the emergence and acceptance of minimally invasive and robot-assisted surgical techniques, highlighting their impact on improving outcomes beyond cancer and their influence on the surgical management of early-stage lung cancer. Evaluating historical developments alongside present methodologies, this review underscores the critical need for meticulous surgical planning and execution to optimize both oncological radicality and functional preservation. This evolution portrayed not only technical advancements but also a shift in the clinical approach towards tailored, organ-preserving methodologies, culminating in a contemporary framework promoting sublobar resections as the standard for specific patient profiles, signifying a new era of precision in thoracic surgery.

Five-Year Survival Outcomes After Carbon-Ion Radiotherapy for Operable Stage I NSCLC: A Japanese National Registry Study (J-CROS-LUNG).

INTRODUCTION: The standard therapy for stage I NSCLC is surgery, but some operable patients refuse this option and instead undergo radiotherapy. Carbon-ion radiotherapy (CIRT) is a type of radiotherapy. The Japanese prospective nationwide registry study on CIRT began in 2016. Here, we analyzed real-world clinical outcomes of CIRT for operable patients with stage I NSCLC. METHODS: All patients with operable stage I NSCLC treated with CIRT in Japan between 2016 and 2018 were enrolled. The dose fractionations for CIRT were selected from several options approved by the Japanese Society for Radiation Oncology. CIRT was delivered to the primary tumor, not to lymph nodes. RESULTS: The median follow-up period was 56 months. Among 136 patients, 117 (86%) had clinical stage IA NSCLC and 19 (14%) had clinical stage IB NSCLC. There were 50 patients (37%) diagnosed clinically without having been diagnosed histologically. Most tumors (97%) were located in the periphery. The 5-year overall survival, cause-specific survival, progression-free survival, and local control rate were 81.8% (95% confidence interval [CI]: 75.1-89.2), 91.2% (95% CI: 86.0-96.8), 65.9% (95% CI: 58.2-74.6), and 95.8% (95% CI: 92.3-99.5), respectively. Multivariate analysis identified age as a significant factor for overall survival (p = 0.018), whereas age and consolidation/tumor ratio (p = 0.010 and p = 0.004) were significant factors for progression-free survival. There was no grade 4 or higher toxicity. Grade 3 radiation pneumonitis occurred in one patient. CONCLUSIONS: This study reports the long-term outcomes of CIRT for operable NSCLC in the real world. CIRT for operable patients has been found to have favorable outcomes, with tolerable toxicity.

The oncogenic role of LGR6 overexpression induced by aberrant Wnt/ß-catenin signaling in lung cancer.

BACKGROUND: Molecular abnormalities in the Wnt/ß-catenin pathway confer malignant phenotypes in lung cancer. Previously, we identified the association of leucine-rich repeat-containing G protein-coupled receptor 6 (LGR6) with oncogenic Wnt signaling, and its downregulation upon ß-catenin knockdown in non-small cell lung cancer (NSCLC) cells carrying CTNNB1 mutations. The aim of this study was to explore the mechanisms underlying this association and the accompanying phenotypes. METHODS: LGR6 expression in lung cancer cell lines and surgical specimens was analyzed using quantitative RT-PCR and immunohistochemistry. Cell growth was assessed using colony formation assay. Additionally, mRNA sequencing was performed to compare the expression profiles of cells subjected to different treatments. RESULTS: LGR6 was overexpressed in small cell lung cancer (SCLC) and NSCLC cell lines, including the CTNNB1-mutated NSCLC cell lines HCC15 and A427. In both cell lines, LGR6 knockdown inhibited cell growth. LGR6 expression was upregulated in spheroids compared to adherent cultures of A427 cells, suggesting that LGR6 participates in the acquisition of cancer stem cell properties. Immunohistochemical analysis of lung cancer specimens revealed that the LGR6 protein was predominantly overexpressed in SCLCs, large cell neuroendocrine carcinomas, and lung adenocarcinomas, wherein LGR6 overexpression was associated with vascular invasion, the wild-type EGFR genotype, and an unfavorable prognosis. Integrated mRNA sequencing analysis of HCC15 and A427 cells with or without LGR6 knockdown revealed LGR6-related pathways and genes associated with cancer development and stemness properties. CONCLUSIONS: Our findings highlight the oncogenic roles of LGR6 overexpression induced by aberrant Wnt/ß-catenin signaling in lung cancer.

Predicting 1-year non-cancer-related adverse events after lung resection.

OBJECTIVES: Assessing the risk for non-cancer-related outcomes following lung cancer surgery is crucial for high-risk patients. This study examined non-cancer-related adverse events within 1 year after lung resection, emphasizing the role of resected lung volume and postoperative atrial fibrillation (POAF). METHODS: We conducted a retrospective analysis of 460 patients who underwent anatomical lung resection for malignant lung tumours. We assessed perioperative factors, such as the number of resected subsegments and POAF, as potential predictors of 1-year non-cancer-related adverse events. Additionally, we validated a previously published nomogram for predicting POAF. RESULTS: One-year non-cancer-related adverse events occurred in 20% of patients. Multivariable analysis identified higher age, lower percentage-predicted forced expiratory volume in 1 second, greater number of resected subsegments and POAF as independent predictors of these adverse events. The incidence of POAF was 8.5%, with higher age, history of atrial fibrillation, and open thoracotomy as independent predictors. A temporal link between POAF and other severe postoperative complications was observed, as 71% of POAF cases preceded other complications. The nomogram's predicted risk for POAF was associated well with the actual incidence. CONCLUSIONS: Resected lung volume and POAF are statistically significant factors associated with non-cancer-related outcomes after lung resection. Minimizing resected lung volume when oncologically and technically feasible, along with identifying patients at risk for POAF, may contribute to improved postoperative outcomes. Our results have implications for risk stratification and preoperative decision-making in lung cancer surgery.

Harnessing 3D-CT Simulation and Planning for Enhanced Precision Surgery: A Review of Applications and Advancements in Lung Cancer Treatment.

The clinical application of three-dimensional computed tomography (3D-CT) technology has rapidly expanded in the last decade and has been applied to lung cancer surgery. Two consecutive reports of large-scale prospective clinical trials from Japan and the United States have brought a paradigm shift in lung cancer surgery and may have led to a rapid increase in sublobar lung resections. Sublobar resection, especially segmentectomy, requires a more precise understanding of the anatomy than lobectomy, and preoperative 3D simulation and intraoperative navigation support it. The latest 3D simulation software packages are user-friendly. Therefore, in this narrative review, we focus on recent attempts to apply 3D imaging technologies, particularly in the sublobar resection of the lung, and review respective research and outcomes. Improvements in CT accuracy and the use of 3D technology have advanced lung segmental anatomy. Clinical applications have enabled the safe execution of complex sublobar resection through a minimally invasive approach, such as video-assisted thoracoscopic surgery and robotic surgery. However, currently, many facilities still render 3D images on two-dimensional monitors for usage. In the future, it will be challenging to further spread and advance intraoperative navigation through the application of 3D output technologies such as extended reality.

Erratum: Ligand-based, piggyBac-engineered CAR-T cells targeting EGFR are safe and effective against non-small cell lung cancers.

[This corrects the article DOI: 10.1016/j.omto.2023.100728.].

Ligand-based, piggyBac-engineered CAR-T cells targeting EGFR are safe and effective against non-small cell lung cancers.

Epidermal growth factor receptor (EGFR) is overexpressed in various cancers, including non-small cell lung cancer (NSCLC), and in some somatic cells at a limited level, rendering it an attractive antitumor target. In this study, we engineered chimeric antigen receptor (CAR)-T cells using the piggyBac transposon system, autologous artificial antigen-presenting cells, and natural ligands of EGFR. We showed that this approach yielded CAR-T cells with favorable phenotypes and CAR positivity. They exhibited potent antitumor activity against NSCLC both in vitro and in vivo. When administered to tumor-bearing mice and non-tumor-bearing cynomolgus macaques, they did not elicit toxicity despite their cross-reactivity to both murine and simian EGFRs. In total we tested three ligands and found that the CAR candidate with the highest affinity consistently displayed greater potency without adverse events. Taken together, our results demonstrate the feasibility and safety of targeting EGFR-expressing NSCLCs using ligand-based, piggyBac-engineered CAR-T cells. Our data also show that lowering the affinity of CAR molecules is not always beneficial.

Bronchial branching patterns and volumetry in the right upper lobe: impact on segmentectomy planning.

OBJECTIVES: The use of segmentectomy is expected to increase. However, understanding of the segmental bronchial branching is limited. Herein, we aimed to investigate bronchial branching pattern complexity and segmental volumetry of the right upper lung lobe to develop an accurate understanding of segmental anatomy and contribute to the advancement of safe and efficient lung segmentectomy. METHODS: We evaluated chest computed tomography scans of 303 patients and categorized the branching of segmental bronchi (segment 1, apical; segment 2, posterior; and segment 3, anterior) into 4 major types (typical trifurcated, bifurcated non-defective, bifurcated defective and atypical trifurcated) and 11 subtypes. Segmental volumetry was performed to determine the predominant segment in each case (volume difference <5% was considered equal). Branching complexity was evaluated separately for volumetry-predominant and volumetry-non-predominant segments. RESULTS: Trifurcated non-defective was the most frequent branching type (64.4%), followed by bifurcated non-defective (22.1%), bifurcated defective (8.6%) and trifurcated half-defective (4.0%). In terms of segmental volumetry, most cases had a one-segment-predominant distribution (71%) and only 5% of cases had equal distribution (segment 1 = segment 2 = segment 3). More than half of the cases had a segment 3-predominant distribution (52%). Branching complexity analysis revealed that the volumetry-non-predominant segment was associated with a higher risk of complex branching patterns compared with the volumetry-predominant segment (37% vs 19%, respectively; P < 0.005). CONCLUSIONS: Volumetric assessment of the right upper lobe showed a heterogeneous segmental volume distribution. Care should be taken during lung segmentectomy of the volumetry-non-predominant segments because of the high risk associated with complex bronchial branching patterns. CLINICAL TRIAL REGISTRATION: No. 4840.

Long-term outcomes following surgical treatment for thymic epithelial tumor in Japan and an analysis of prognostic factors based on the Japanese Association for Research on the Thymus nationwide database.

PURPOSE: Patients with a thymic epithelial tumor (TET), comprising thymoma, thymic carcinoma (TC), and thymic neuroendocrine neoplasm (TNEN), are rarely encountered. The present study was conducted to determine the recent outcomes of surgical treatment for TET in Japan and clarify the significance of prognostic factors by analyzing a nationwide database created by the Japanese Association for Research on the Thymus (JART). METHODS: The JART database includes records of 2471 thymoma, 285 TC, and 56 TNEN cases surgically treated between 1991 and 2010. At the time of the final follow-up examination, 439 patients had died, with tumor the cause of death in 188. The disease-specific survival was examined using the Kaplan-Meier method, with Cox's proportional hazards model utilized to determine independent prognostic factors. RESULTS: The 10-year survival rate according to TNM-based Stage I, II, IIIA, IIIB, IVA, and IVB classification was 98.7%, 76.8%, 85.0%, 68.9%, 66.2%, and 59.8%, respectively. The T factor, M factor, and tumor size were independent prognostic factors in both thymoma and thymic carcinoma cases, while the N factor had tendency to be a prognostic factor in thymoma but not in thymic carcinoma cases. The WHO histological type was an independent factor in thymoma cases. CONCLUSION: The significance of pathology and TNM classification as prognostic factors was confirmed.

Successful resection after first-line lenvatinib therapy in an advanced thymic carcinoma.

Thymic carcinoma is a highly malignant tumor and treatment options are limited. Lenvatinib, a novel multitargeted kinase inhibitor, has recently been approved for the treatment of unresectable thymic carcinoma. There are no reports of complete surgical resection after the administration of first-line lenvatinib in advanced thymic carcinoma. A 50-year-old man visited our hospital because a computed tomography (CT) scan of the chest showed a large thymic squamous cell carcinoma. We suspected malignant pericardial effusion, invasion of the left upper lobe of the lung, and left mediastinal lymph node metastases. The patient was diagnosed with WHO classification stage IVb disease. Lenvatinib therapy was started at 24 mg/day as first-line therapy. Gradual dose reduction to 16 mg/day was required because of hypertension, diarrhea, and palmar-plantar erythrodysesthesia syndrome as side effects. Chest CT findings after 6 months of lenvatinib therapy showed reduction of the main tumor, disappearance of the mediastinal lymph node metastases, and pericardial effusion. Complete salvage resection was successfully performed a month after discontinuation of lenvatinib. The patient has been disease-free for 1 year without adjuvant therapy. Lenvatinib therapy is one of the promising therapeutic options for thymic carcinoma and may make salvage surgery increasingly useful for advanced thymic carcinoma.

Risk factors for late-onset pulmonary fistula after pulmonary segmentectomy.

Background: Late-onset pulmonary fistula (LOPF) is a well-described complication after segmentectomy, but the precise incidence and risk factors are still unclear. We aimed to determine the incidence of, and risk factors for, LOPF development after segmentectomy. Methods: A single-institution retrospective study was performed. A total of 396 patients who underwent segmentectomy were enrolled. Perioperative data were analyzed to identify the risk factors for LOPF requiring readmission according to univariate and multivariate analyses. Results: The overall morbidity rate was 19.4%. The incidence rates of prolonged air leak (PAL) in the early phase and LOPF in the late phase were 6.3% (25/396) and 4.5% (18/396), respectively. The most common surgical procedures with LOPF development were segmentectomy of the upper-division (n=6) and S6 (n=5). With a univariate analysis, presence of smoking-related diseases did not affect LOPF development (P=0.139). Conversely, segmentectomy with cranial side free space (CSFS) in the intersegmental plane and use of electrocautery to divide the intersegmental plane were associated with a high risk of LOPF development (P=0.006 and 0.009, respectively). A multivariate logistic regression analysis showed that segmentectomy with CSFS in the intersegmental plane and use of electrocautery were independent risk factors for LOPF development. Approximately 80% of patients who developed LOPF recovered by prompt drainage and pleurodesis without reoperation, whereas the remaining patients developed empyema due to delayed drainage. Conclusions: Segmentectomy with CSFS is an independent risk factor for LOPF development. Careful postoperative follow up and rapid treatment are necessary to avoid empyema.

Clinicopathological features and surgical outcomes of lobectomy combined with segmentectomy: a cohort study.

Background: Segmentectomy is a standard procedure, and there is considerable data on routine segmentectomies. However, there are only few reports on lobectomy performed in combination with segmentectomy (lobectomy + segmentectomy). Thus, we aimed to clarify the clinicopathological features and surgical outcomes of lobectomy + segmentectomy. Methods: We reviewed patients who underwent lobectomy + segmentectomy between January 2010 and July 2021 at Gunma University Hospital, Japan. We comparatively analyzed clinicopathological data of patients who underwent lobectomy + segmentectomy and those who underwent lobectomy in combination with wedge resection (lobectomy + wedge resection). Results: We collected data from 22 patients who underwent lobectomy + segmentectomy and 72 who underwent lobectomy + wedge resection. Lobectomy + segmentectomy was mainly performed to treat lung cancer, and the median number of resected segments was 4.5 and the median number of lesions was 2. Lobectomy + segmentectomy was associated with a higher rate of thoracotomy and a longer operation time. Incidence of overall complications, including pulmonary fistula and pneumonia was higher in the lobectomy + segmentectomy group. However, there were no significant differences in the length of drainage, major complications, and mortality. For lobectomy + segmentectomy, the only left-sided procedure was a left lower lobectomy + lingulectomy, whereas procedures were diverse on the right side, mostly combining a right upper or middle lobectomy with atypical segmentectomies. Conclusions: Lobectomy + segmentectomy was performed for (I) multiple lung lesions, (II) lesions invading an adjacent lobe, or (III) lesions with a metastatic lymph node invading the bronchial bifurcation. Although lobectomy + segmentectomy is a lung-preserving procedure that can benefit patients with multiple or advanced diseases involving two lobes, this procedure should still be performed following a careful patient selection process.

The efficacy of a machine learning algorithm for assessing tumour components as a prognostic marker of surgically resected stage IA lung adenocarcinoma.

BACKGROUND: The importance of the stromal components in tumour progression has been discussed widely, but their prognostic role in small size tumours with lepidic components is not fully understood. Applying digital tissue image analysis to whole-slide imaging may enhance the accuracy and reproducibility of pathological assessment. This study aimed to evaluate the prognostic value of tumour components of lung adenocarcinoma by measuring the dimensions of the tumour consisting elements separately, using a machine learning algorithm. METHODS: Between September 2002 and December 2016, 317 patients with surgically resected, pathological stage IA adenocarcinoma with lepidic components were analysed. We assessed the whole tumour area, including the lepidic components, and measured the epithelium, collagen, elastin areas and alveolar air space. We analysed the prognostic impact of each tumour component. RESULTS: The dimensions of the epithelium and collagen areas were independent significant risk factors for recurrence-free survival (hazard ratio, 8.38; 95% confidence interval, 1.14-61.88; P = 0.037, and hazard ratio, 2.58; 95% confidence interval, 1.14-5.83; P = 0.022, respectively). According to the subgroup analysis when combining the epithelium and collagen areas as risk factors, patients with tumours consisting of both large epithelium and collagen areas showed significantly poor prognoses (P = 0.002). CONCLUSIONS: We assessed tumour components using a machine learning algorithm to stratify the post-operative prognosis of surgically resected stage IA adenocarcinomas. This method might guide the selection of patients with a high risk of recurrence.

Anatomical resection for right B3 downwards-shifting malformation.

The right B3 downwards-shifting malformation is rare. This malformation often leads to the following complications: abnormal pulmonary arteries that accompany the downward-displaced B3, and complete fusion of the upper and middle lobes into one lobe, with no horizonal fissure. When performing pulmonary anatomical resection in the right upper or middle lobes in patients with this malformation, careful preoperative planning and surgical technique are required, with which the surgeon should be familiar. Herein, we present the anatomical features necessary for anatomical resection of the right B3 downwards-shifting malformation based on our technical experiences with anatomic segmentectomy and lobectomy techniques.

Significance of the evaluation of tracheal length using a three-dimensional imaging workstation.

Background: Limited information is available on the total tracheal length and its other characteristics for tracheal surgery. This study aimed to investigate the reference value of tracheal length and assess its relationship with physiological variables. Methods: We measured the tracheal length of 215 patients (107 men and 108 women) who underwent contrast-enhanced computed tomography before thoracic surgery using a three-dimensional imaging workstation. Pearson correlation analysis and multiple linear regression analysis were performed to investigate the relationship between the total tracheal length (cervical and thoracic) and common physiological parameters. Results: The mean total tracheal length was 11.5±1 cm (range, 8.8-14.4 cm); 8% of the patients had a total tracheal length <10 cm. The cervical trachea was significantly shorter in men than in women (2.9±1.3 vs. 3.8±1.3 cm, P<0.001), whereas the thoracic trachea was significantly longer in men than in women (8.9±1.1 vs. 7.4±1.1 cm, P<0.001). Correlation analysis showed that the total tracheal length was positively associated with height in both sexes, while the height was positively associated with only cervical tracheal length. In the multiple linear regression analysis, the total tracheal length was influenced most by height, while cervical and thoracic tracheal lengths were influenced most by sex. Older age was also an independent contributor to a shorter cervical trachea and longer thoracic trachea in both sexes. Conclusions: The total tracheal length ranged from short to long in individuals, and characteristics of tracheal length varied with height, age, sex, and part of the trachea. We should thus be aware of the tracheal length of each patient for appropriate tracheal management.