Feasibility and Safety of Uniportal Thoracoscopic Segmentectomy Using a Unidirectional Dissection Approach without Dissecting a Fissure.

Background: Few original articles describe the perioperative outcomes of uniportal thoracoscopic segmentectomy using a unidirectional dissection approach. In this retrospective study, we evaluated the feasibility and safety of this procedure. Methods: This study included 119 patients who underwent uniportal thoracoscopic segmentectomy in our department between February 2019 and December 2022. The patients were divided into unidirectional (group U, n = 28) and conventional (group C, n = 91) dissection approach groups. While the dominant pulmonary vessels and bronchi were transected at the hilum without dissecting a fissure in the unidirectional (U) group, the dominant pulmonary artery was exposed and divided at a fissure in the conventional (C) group. Patient characteristics and perioperative outcomes were compared between groups U and C. Results: The proportions of simple and complex segmentectomies were statistically similar between the groups. The operating time was shorter (group U: 110 [interqurtile range: 90-140] min, group C: 135 [interqurtile range: 105-166] min, p = 0.012) and there was less blood loss (group U: 0 [interqurtile range: 0-0] g, group C: 0 [interqurtile range: 0-50] g, p = 0.003) in group U than in group C. However, there were no significant intergroup differences in other perioperative outcomes. Conclusions: The unidirectional dissection approach in uniportal thoracoscopic pulmonary segmentectomy is safe and feasible and enables a smoother operation.

Uniportal thoracoscopic mediastinal lymphadenectomy using appropriate surgical steps.

Background: Although lymphadenectomies play an important role in the surgical treatment of patients with non-small cell lung cancer (NSCLC), the quality of lymphadenectomies via a uniportal approach has only been evaluated in a few studies. We describe the surgical steps for a mediastinal lymphadenectomy via uniportal video-assisted thoracoscopic surgery (uVATS) and compare the quality of mediastinal lymphadenectomies using uVATS versus multiportal video-assisted thoracoscopic surgery (mVATS). Methods: Between April 2017 and January 2023, we analyzed data from 304 patients with NSCLC who underwent (bi-)lobectomy with nodal dissection (ND)2a-1 or greater lymphadenectomy via uVATS or mVATS. We compared patient characteristics and perioperative results, including the number of harvested lymph nodes (LNs), between the two approaches. In addition, the factors associated with N-upstage were identified. Results: No significant differences in the total number of harvested LNs were detected between the two approaches. Significantly more LN#2R/4R zone LNs were harvested in the uVATS group compared with the number harvested in the mVATS group [uVATS group: 8.5, interquartile range (IQR), 5-12.3; mVATS group: 7, IQR, 5-9, P=0.0177], while no significant differences in total nodes or nodes harvested in other zones were detected. Multivariable analysis revealed that pathologic invasion size [odds ratio: 1.0200, 95% confidence interval (CI): 1.0100-1.0400, P=0.0050], but not approach (uVATS, odds ratio: 0.6240, 95% CI: 0.3160-1.2300, P=0.1750), significantly contributed to N factor upstages. Conclusions: The use of appropriate surgical steps enabled us to achieve similar quality lymphadenectomies via mVATS or uVATS.

Two cases of lower lobe segmentectomy (left and right) using the lung-inverted approach in a robotic operation.

In pulmonary segmentectomy, the dominant pulmonary arteries are conventionally divided at the fissure. However, this approach sometimes leads to accidental injury of the pulmonary artery and prolonged air leaks when the fissure is fused. To overcome these problems, we have adopted the lung-inverted approach without dissection of a fissure for segmentectomy, taking advantage of the good view provided by robotic surgery. We have successfully performed a robotic left S10 or right S6 segmentectomy using the lung-inverted approach. In addition to a good postoperative course, the console time was 72 minutes for the left S10 segmentectomy and 110 minutes for the right S6 segmentectomy; these times were considered relatively short. This approach did not require repeated rotation of the lung, which may have contributed to the short operating time. A clear understanding of the anatomy was required to properly implement this approach, because each branch of the pulmonary vessels and of the bronchi was treated at the hilum. Preoperative 3-dimensional computed tomography broncho-angiography was considered useful because it allowed us to recognize the relative positions of the dominant pulmonary vessels, bronchi and other preserved structures.

Robotic upper division segmentectomy of the left upper lobe without turning the lung.

The fissureless technique in lobectomy or the unidirectional dissection technique in segmentectomy is considered useful to avoid a postoperative prolonged air leak if a fissure is fused because it is not dissected. Another advantage of this technique is that it does not require repeated rotation of the lung to obtain a good surgical view, which may result in a shorter operating time. We believe that this technique is suitable for a robotic approach because we sometimes find it difficult to rotate the lung parenchyma in the limited rigid thoracic cavity when using the robotic approach. We demonstrate a robotic upper division segmentectomy of the left upper lobe with an explanation of the nuances of its performance. The console time was 74 minutes with minimal blood loss. The patient's postoperative course was uneventful. On the day of the operation, we removed the chest tube because we found no air leak. The patient was discharged on postoperative day (POD) 2. The final pathology report showed that a sufficient surgical margin was achieved. These good perioperative results indicate the feasibility of this technique.

A robotic left S1+2c subsegmentectomy using preoperative simulation.

Although there are reports describing segmentectomy by a robotic approach, reports describing robotic subsegmentectomy are rare because this procedure requires more precise anatomical knowledge and exposure of subsegmental pulmonary vessels and bronchi. However, the robotic approach has several advantages, including a high-definition 3-dimensional surgical view and precise motion without tremor, which may allow us to perform the subsegmentectomy more easily. Considering these advantages of the robotic approach, we successfully performed a robotic left S1+2c segmentectomy with a short console time and a good postoperative course. We present the surgical steps of this procedure. In addition, the preoperative simulation method was useful to ensure a sufficient surgical margin. Because the robotic approach lacked tactile feedback, it was difficult to locate the target tumour intraoperatively by palpation compared with the conventional thoracoscopic approach. Finally, in this case, we obtained an adequate surgical margin using this preoperative simulation method.

A robotic anterior (S3) segmentectomy of the left upper lobe.

A robotic approach might be more suitable for pulmonary segmentectomy than the conventional thoracoscopic approach, because the high-definition 3-dimensional surgical view and precise motion without tremor allow us to dissect pulmonary vessels and bronchi to the periphery. However, among several types of segmentectomies, the anterior segmentectomy (S3) of the left upper lobe may be one of the most difficult to achieve in the robotic approach because the dissected hilar region tends to be obstructed by the lung parenchyma in the "looking-up" view. We offer two technical tips to achieve robotic left S3 segmentectomy. The first is the proper retraction of the upper lobe using straw gauze, which allows us to get a good surgical view in the dissected hilar area where pulmonary vessels and bronchi are located. Second, when the intersegmental plane is divided by robotic staplers, the lung should be moved to the dividing line because the angulation of the inserted stapler is limited. Taking these two tips into consideration, we have successfully performed a robotic left S3 segmentectomy. We show the surgical steps of this procedure.

Comparison of the Learning Curve between Uniportal and Robotic Thoracoscopic Approaches in Pulmonary Segmentectomy during the Implementation Period Using Cumulative Sum Analysis.

BACKGROUND: The aim of this retrospective study was to compare the learning curve and perioperative outcomes between the two approaches uVATS and RATS during their implementation periods. METHODS: The uVATS group included 77 consecutive uVATS segmentectomies performed by HI between February 2019 and June 2022, while the RATS group included 30 between July 2022 and September 2023. The patient characteristics, perioperative outcomes, and learning curves were compared between the two groups. The learning curve was evaluated using operative time and cumulative sum (CUSUMOT) analysis. RESULTS: Most patient characteristics and perioperative outcomes were equivalent between the two groups. In the uVATS group, after a positive slope was observed until the 14th case (initial period), a plateau was observed until the 38th case (stable period). Finally, a negative slope was observed after the 38th case (proficiency period). In the RATS group, after a positive slope was observed until the 16th case (initial period), a plateau was observed until the 22nd case (stable period). Finally, a negative slope was observed after the 22nd case (proficiency period). CONCLUSIONS: In segmentectomy, a surgeon reached the proficiency period earlier in RATS than in uVATS, although the trends to the stable period were similar.

Completion Pneumonectomy for Second Primary/Primary Lung Cancer and Local Recurrence Lung Cancer.

BACKGROUND: Completion pneumonectomy (CP) for second primary/primary lung cancer (SPLC) and local recurrence lung cancer (LRLC) is still controversial. Although several case series on such a practice exist, the oncological benefit is under debate. The purpose of this study was to review available literatures on CP for SPLC and LRLC and evaluate postoperative and long-term outcomes. METHODS: MEDLINE, SCOPUS, and Web of Science were reviewed for eligible studies in January 2021. Studies were included if they indicated outcomes of patients with lung cancer undergoing CP. Overall survival (OS) was defined as the primary endpoint; secondary endpoints included operative morbidity and 30-day mortality. Random-effects meta-analysis based on a binomial distribution was used to create pooled estimates. RESULTS: Thirty-two eligible studies including 1157 patients were identified. These studies were uniformly retrospective reports. Pooled estimates for 3-year and 5-year OS were 50.6% (95% confidence interval [CI], 34.7%-66.5%) and 38.9% (95% CI, 32.2%-46.1%) in SPLC patients. When the SPLC was a stage I tumor, pooled 5-year OS was favorable with 60.7% (95% CI, 43.2%-75.9%). In LRLC, pooled 3-year and 5-year OS were 47.6% (95% CI, 36.1%-59.4%) and 33.8% (95% CI, 26.8%-41.5%), respectively. Pooled morbidity and 30-day mortality was reported in 38.2% (95% CI, 32.0%-44.9%), and 10.0% (95% CI, 8.1%-12.3%), respectively. CONCLUSIONS: CP for SPLC and LRLC is a challenging procedure with significant perioperative morbimortality. However, published evidence indicates good long-term survival for selected patients. Further studies are needed to identify patient subgroups which benefit most from CP.

Inhibition of Cell-surface Molecular GPR87 With GPR87-suppressing Adenoviral Vector Disturb Tumor Proliferation in Lung Cancer Cells.

BACKGROUND/AIM: GPR87 is a member of the cell surface molecular G protein-coupled receptors (GPCR) family and suggested to contribute to the viability of human tumor cells. Its tumor-specific expression and cell surface location make it a potential molecule for targeted therapy. In the present study, we aimed to examine the effect of silencing GPR87 expression and explore the possibility of establishing gene therapy against GPR87-overexpressing lung cancer. MATERIALS AND METHODS: Twenty malignant cell lines were investigated and GPR87-overexpressing H358 and PC9 lung cancer cells were subjected to inhibiting experiments. A short hairpin siRNA targeting the GPR87 gene was transformed into an adenoviral vector (Ad-shGPR87). Real-time RT-PCR and western blot analyses were performed to evaluate gene and protein expression. Tumors derived from human H358 cells were subcutaneously implanted in nude mice for in vivo experiments. RESULTS AND CONCLUSION: About 50% (10/20) malignant cells showed GPR87-overexpression, especially for lung cancer cells (70%, 7/10). Ad-shGPR87 effectively down-regulated the GPR87 expression, and significantly inhibited the cell proliferation in GPR87-overexpressing H358 and PC9 cells. Treatment with Ad-shGPR87 exerted a significant antitumor effect against the GPR87-expressing H358 xenografts. In addition, the gene expression of H3.3, a recently proved activator for GPR87 transcription, was positively correlated with GPR87 gene expression. Furthermore, a significant decrease of KRAS and c-Myc expression was observed in both cell lines after Ad-shGPR87 infection. In conclusion, GPR87 may play a critical role in cancer cell proliferation, and indicate its potential as a novel target for lung cancer treatment.

Solid predominant subtype in lung adenocarcinoma is related to poor prognosis after surgical resection: A systematic review and meta-analysis.

BACKGROUND: Recent studies have indicated that solid predominant (SP) subtype of lung adenocarcinoma (LADC) may be associated with early recurrence and worse prognosis. Hence, a systematic review and meta-analysis were performed to evaluate the association between LADC subtype and survival. METHODS: The MEDLINE, SCOPUS, Web of Science and Cochrane Libraries were reviewed for eligible studies in December 2017. Studies were included if they compared outcomes of patients with and without SP subtype in resection specimens of LADC patients after surgical treatment by using multivariate Cox regression analysis. A meta-analysis for overall survival (OS) and disease-free survival (DFS) was performed. The hazard ratios (HR) or odds ratios with 95% confidence intervals (CIs) from each study were used to calculate pooled HRs. Statistical analyses were performed using Review Manager 5.3. RESULTS: In total, 14 eligible studies including 12,137 LADC patients were identified, which assessed the impact of SP subtype on OS and DFS in patients treated with pulmonary resection. SP subtype was reported in 1246 (10.2%) patients and was associated with significantly worse OS (pooled HR, 1.51; 1.29-1.75) and DFS (pooled HR, 1.26; 1.14-1.40). CONCLUSIONS: SP subtype is associated with significantly worse OS and DFS in patients with LADC after pulmonary resection. These data provide evidence for the integration of the distinct histological LADC subtyping into prognostic tools and guidelines for adjuvant treatment after complete surgical resection.

[Surgical Resection of T4 Category Lung Cancer].

Surgery still remains the main stream in the multimodality treatment for locally advanced lung cancer. On the other hand, more than 50% of non-small cell lung cancer are excluded for surgical indications, especially T4 category of lung cancer. In this study, we showed 5 year overall survival rate of both 50 clinical T4 cases and 30 pathological T4 cases are 35.6% and 41.9% respectively. Those could be compared with the non-surgical treatment results in the literature. Through this study and analysis of other reports, we might consider surgical indications for T4 category lung cancer are as follows;invasion to mediastinum, spine, trachea, carina and additional nodules in ipsilateral different lobes with N0-1 status(esophagus is not included in this study). For obtaining R0 resection to improve survival and reducing postoperative morbidity and mortality rate, prudent evaluations for patients' selection including pre-operative staging before surgery are mandatory.

Customized Adjuvant Chemotherapy Based on Biomarker Examination May Improve Survival of Patients Completely Resected for Non-small-cell Lung Cancer.

AIM: Adjuvant platinum-based chemotherapy is recommended for patients with completely resected stage II (N1) or III (N2) non-small cell lung cancer (NSCLC). However, the optimal chemotherapy regimen is difficult to predict for individual patients. Our previous prospective study on individualized treatment according to biomarker status, such as excision repair cross-complementing 1 (ERCC1), class III ß-tubulin (tubulin), thymidylate synthase (TYMS) and ribonucleotide reductase M1 (RRM1), achieved encouraging results in patients with advanced NSCLC. The present study further examined the effect of biomarker-based adjuvant chemotherapy in patients with completely resected NSCLC. PATIENTS AND METHODS: Between January 2006 and December 2014, 66 patients with localized (stage I-IIIA) NSCLC who underwent R0 operation received 2-4 cycles of platinum doublet adjuvant chemotherapy: Platinum plus docetaxel, platinum plus pemetrexed for adenocarcinoma, and platinum plus tegafur/gimeracil/oteracil combination (TS-1) for squamous cell carcinoma (SCC) were selected according to the registered protocol at each period. Immunohistochemistry was used to evaluate the biomarkers: ERCC1 status for platinum, tubulin for docetaxel, and TYMS for pemetrexed and TS-1. A matched chemotherapy regimen meant that platinum plus docetaxel was administered in patients negative for ERCC1 and negative for tubulin, platinum plus pemetrexed in patients with adenocarcinoma positive for tubulin, negative for ERCC1 and negative for TYMS, and platinum plus TS-1 in those with SCC positive for tubulin, negative for ERCC1 and negative for TYMS. RESULTS: The 5-year survival rate was 77.5% considering all 66 patients, and 85.7%, 71.8%, and 78.8% for those with p-stage I, II, and III, respectively. Patients who received a matched chemotherapy regimen (n=13; platinum plus docetaxel in eight, platinum plus pemetrexed in five) had significantly better 5-year survival than patients with unmatched biomarker status (n=53) (100% vs. 71.0%, p=0.0011). CONCLUSION: Customized adjuvant chemotherapy based on biomarker examination significantly improved the survival of patients with NSCLC, regardless of p-stage.

Tumor Spread Through Air Spaces Is an Independent Predictor of Recurrence-free Survival in Patients With Resected Lung Squamous Cell Carcinoma.

Tumor spread through air spaces (STAS) is a newly recognized pattern of invasion in lung adenocarcinoma. However, clinical significance of STAS has not yet been characterized in lung squamous cell carcinoma. In this study, we investigated whether STAS could determine clinical outcome in Japanese patients with lung squamous cell carcinoma. We reviewed tumor slides from surgically resected lung squamous cell carcinomas (n=216). STAS was defined as tumor cells within air spaces in the lung parenchyma beyond the edge of the main tumor. Tumors were evaluated for histologic subtypes, tumor budding, and nuclear diameter. Recurrence-free survival (RFS) was analyzed using the log-rank test and the Cox proportional hazards model. Tumor STAS was observed in 87 patients (40%), increasing incidence with lymph node metastasis (P=0.037), higher pathologic stage (P=0.026), and lymphatic invasion (P=0.033). All cases with STAS showed a solid nest pattern. The 5-year RFS for patients with STAS was significantly lower than it was for patients without STAS in all patients (P=0.001) and in stage I patients (n=134; P=0.041). On multivariate analysis, STAS was an independent prognostic factor of a worse RFS (hazard ratio=1.61; P=0.023). Patients with STAS had a significantly increased risk of developing locoregional and distant recurrences (P=0.012 and 0.001, respectively). We found that tumor STAS was an independent predictor of RFS in patients with resected lung squamous cell carcinoma, and it was associated with aggressive tumor behavior.

Spontaneous torsion of the right upper lung lobe: a case report.

BACKGROUND: Pulmonary torsion is usually caused by thoracic surgery or trauma. Spontaneous pulmonary torsion caused by tumor and pleural effusion is very rare. CASE PRESENTATION: A 76-year-old Asian male with a chronic cough and suspected lung or pleural tumor presented with sudden dyspnea. Computed tomography showed that the right upper lung lobe contained a large tumor in the region of S1-3; the tumor had shifted to the posterior thoracic space and rotated 90° counterclockwise, potentially impeding blood flow. The patient underwent emergency right upper lobectomy for torsion of the right upper lung lobe. He recovered uneventfully and was discharged without complications. CONCLUSIONS: We experienced a rare case of spontaneous torsion of the right upper lung lobe caused by a large tumor and massive pleural effusion.

Potent effect of adenoviral vector expressing short hairpin RNA targeting ribonucleotide reductase large subunit M1 on cell viability and chemotherapeutic sensitivity to gemcitabine in non-small cell lung cancer cells.

BACKGROUND: Ribonucleotide reductase large subunit (RRM1) is the main enzyme responsible for synthesis of the deoxyribonucleotides used during DNA synthesis. It is also a cellular target for gemcitabine (GEM). Overexpression of RRM1 is reportedly associated with resistance to GEM and the poor prognosis for many types of malignant tumours. Aim of the present study is to establish gene therapy against RRM1-overexpressing tumours. METHOD: An adenoviral vector that encoded a short hairpin siRNA targeting the RRM1 gene (Ad-shRRM1) was constructed. Two RRM1-overexpressing non-small cell lung cancer (NSCLC) lines, MAC10 and RERF-LC-MA, were used. Finally, a human tumour xenograft model in nude mice was prepared by subcutaneously implanting tumours derived from RERF-LC-MA cells. RESULTS: Ad-shRRM1 effectively downregulated RRM1 mRNA and protein in both types of NSCLC cells and significantly reduced the percentage of viable cells as detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay (p<0.005). Caspase 3/7 analysis revealed that transfection with Ad-RRM1 increased the percentage of apoptotic cells in culture containing either type of RRM1-overexpressing cell (p<0.001). Treatment with Ad-shRRM1 exerted a potent antitumour effect against the RRM1-overexpressing RERF-LC-MA xenografts (p<0.05). Furthermore, Ad-shRRM1-mediated inhibition of RRM1 specifically increased sensitivity to gemcitabine of each type of RRM1-overexpressing tumour cell. Combination treatment with Ad-shRRM1 and GEM exerted significantly greater inhibition on cell proliferation than Ad-shRRM1 or GEM treatment alone. CONCLUSION: RRM1 appeared to be a promising target for gene therapy, and Ad-shRRM1 had strong antitumour effects, specifically anti-proliferative and pro-apoptotic effects, against NSCLC cells that overexpressed RRM1. Combination therapy with Ad-shRRM1 and GEM may become a new treatment option for patients with NSCLC.

Overexpression of G protein-coupled receptor 87 correlates with poorer tumor differentiation and higher tumor proliferation in non-small-cell lung cancer.

G protein-coupled receptor 87 (GPR87) is a newly deorphanized member of the transmembrane G protein-coupled receptor family. Recently, GPR87 was suggested to contribute to the viability of human tumor cells and overexpression of GPR87 mRNA was detected in a number of malignant tumors, including lung cancer. We performed a retrospective study of GPR87 expression in association with clinical characteristics and biological markers in non-small-cell lung cancer (NSCLC). We investigated a total of 123 patients with NSCLC who underwent surgery between 1999 and 2004 (58 adenocarcinomas, 53 squamous cell carcinomas and 12 others). Immunohistochemistry was used to evaluate the intratumoral expression of GPR87 and the Ki-67 proliferation index. The TUNEL method was also used to investigate tumor apoptosis. A total of 63 tumors (51.2%) were found to be GPR87-positive. These tumors were more frequently encountered among squamous cell carcinomas rather than among adenocarcinomas (62.3 vs. 43.1%, respectively; P=0.044) and were significantly more frequently poorly and moderately differentiated rather than well differentiated (P=0.029). Moreover, the Ki-67 index was significantly higher in GPR87-positive compared to GPR87-negative tumors (57.0 vs. 40.0%, respectively; P=0.002). The overall survival was significantly worse for patients with GPR87-positive compared to those with GPR87-negative tumors (P=0.029). The Cox regression analyses also demonstrated that the GPR87 status was a significant prognostic factor for NSCLC patients [hazard ratio=2.053; P=0.018). The present study demonstrated that in NSCLC, the overexpression of GPR87 is significantly associated with poorer differentiation and higher proliferation. During the progression of NSCLC, GPR87 overexpression may be associated with the acquisition of a more aggressive phenotype and, therefore, is a potentially useful target for prognostication and treatment.