A comparative study of robot-assisted thoracoscopic surgery and conventional approaches for short-term outcomes of anatomical segmentectomy.

OBJECTIVES: Since anatomical segmentectomy requires meticulous dissection of the segmental pulmonary vessels and bronchus, robot-assisted thoracoscopic surgery (RATS) has been widely adopted in recent years. We investigated the usefulness of RATS segmentectomy by comparing perioperative outcomes with conventional approaches including open thoracotomy or video-assisted thoracoscopic surgery (VATS). We compared perioperative outcomes of segmentectomy between RATS and conventional approaches including open thoracotomy or video-assisted thoracoscopic surgery (VATS). METHODS: This single-institutional retrospective study comprised 231 patients with primary lung cancer who underwent segmentectomy by RATS or conventional approaches between January 2011 and December 2022. Surgical outcomes and postoperative complications were analyzed among patients whose background factors were adjusted by propensity score matching (PSM). RESULTS: Before PSM, there were significant differences in age, smoking status, and types of segmentectomy. After PSM, 126 patients (63 patients in each group) were included in this analysis. The RATS group had significantly shorter operative time (154 vs 210 min; p < 0.01), fewer bleeding amounts (10 vs 40 mL; p < 0.01), and shorter duration of chest drainage (2 vs 2 days; p = 0.04) than the conventional-approach group. There was no significant difference in the incidence of all complications; however, the incidence of postoperative pneumonia was significantly lower than in the conventional-approach group (p = 0.02). CONCLUSIONS: RATS segmentectomy is proposed to be useful. It was suggested that RATS segmentectomy may be useful with better perioperative results than the conventional approach. Further studies on oncological long-term outcomes and cost-benefit comparisons are needed.

Video-Assisted Thoracoscopic Surgery Using Extracorporeal Membrane Oxygenation for Intractable Pneumothorax.

Intractable pneumothorax with poor lung function that has received multiple conservative treatments may occur. Case 1 was a 70-year-old woman with aspergilloma who was admitted for pneumothorax. Case 2 was a 68-year-old man with acute exacerbation of interstitial pneumonia who developed pneumothorax. In both cases, multiple conservative therapies were administered, but the leak continued; thus, operations using veno-venous extracorporeal membrane oxygenation (ECMO) were planned. By video-assisted thoracoscopic surgery (VATS), we obtained the optimal surgical field by lung collapse. We removed many blood clots that were used for pleurodesis, ligated the bulla in case 1, and covered the leak point with strengthening agents in case 2. For cases of intractable pneumothorax, lung collapse by ECMO is advantageous because we can check details and leak points even in blood clots or in poor condition of the lung, and we can maneuver the lung in poor condition with a clear surgical field.

High mRNA expression of POU2F3 in small cell lung cancer cell lines predicts the effect of lurbinectedin.

BACKGROUND: Small cell lung cancer (SCLC) is a progressive disease with a poor prognosis. Recently, a method to classify SCLC by the expression status of four transcription factors, ASCL1, NEUROD1, POU2F3, and YAP1, was proposed. Here, we investigated the potential relationships between expression of these four transcription factors and the effect of lurbinectedin. METHODS: mRNA and protein expression of ASCL1, NEUROD1, POU2F3, and YAP1 were quantified in eight SCLC cell lines and analyzed for potential correlations with drug sensitivity. In addition, ASCL1, NEUROD1, POU2F3, and YAP1 expression were evaluated in 105 resected cases of high-grade neuroendocrine carcinoma of the lung, including 59 resected cases of SCLC. RESULTS: Based on the results of qRT-PCR and western blot analyses, the eight SCLC cell lines examined were classified into NEUROD1, POU2F3, and YAP1 subtypes, as well as five ASCL1 subtypes. There were no correlations between cell line subtype classification and drug sensitivity to cisplatin, etoposide, or lurbinectedin. Next, we compared relative mRNA expression levels of each transcription factor with drug sensitivity and found that the higher the mRNA expression level of POU2F3, the lower the IC50 of lurbinectedin. Evaluation of resected SCLC tissue revealed that the composition of subtypes defined by the relative dominance of ASCL1, NEUROD1, POU2F3, and YAP1 was as follows: 61% ASCL1, 15% NEUROD1, 14% POU2F3, 5% YAP1, and 5% all-negative. CONCLUSION: In our experiments, high mRNA expression of POU2F3 in SCLC cell lines correlated with the effect of lurbinectedin.

Gene expression profiling using targeted RNA-sequencing to elucidate the progression from histologically normal lung tissues to non-invasive lesions in invasive lung adenocarcinoma.

Lung adenocarcinoma (LUAD) shows heterogeneous morphological features and the stepwise progression from adenocarcinoma in situ to minimally invasive adenocarcinoma to invasive LUAD. Although multiple genetic alterations have been linked to the progression, the differences between the gene expression profiles of non-invasive lesions (non-ILs) and adjacent histologically normal lung (aNL) tissues within invasive LUAD have not been investigated. Herein, we analyzed differentially expressed genes (DEGs) specific to early-stage carcinogenesis in LUAD. Invasive LUAD tissue samples containing both non-ILs and aNL tissues were obtained from seven patients with pathological stage I LUAD, and each component was subjected to microdissection. Gene expression profiles of each component were determined using targeted RNA-sequencing. In total, 2536 DEGs, including 863 upregulated and 1673 downregulated genes, were identified in non-ILs. In non-ILs, the expression of SLC44A5, a choline transporter-like protein-coding gene, was significantly upregulated, and that of TMEM100, a gene encoding a transmembrane protein, was significantly downregulated. Reportedly, SLC44A5 plays an important role in the development and progression of hepatocellular carcinoma, whereas TMEM100 functions as a tumor suppressor in non-small cell lung cancer. Gene set enrichment analysis showed that DEGs in non-ILs were negatively enriched in cell death and immune response. Immunohistochemical analysis revealed that increased SLC44A5 expression and decreased TMEM100 expression were maintained in ILs. A protein-protein interaction (PPI) network analysis identified several upregulated and downregulated hub genes with high degrees in non-ILs. In conclusion, several new DEGs and key PPI network hub genes were identified in non-ILs, contributing to understanding of early-stage carcinogenesis in LUAD.

A rare case of combined thymoma and a multilocular thymic cyst discovered due to chest pain.

BACKGROUND: A thymoma with chest pain and multilocular thymic cysts (MTCs) is very rare. CASE PRESENTATION: A 49-year-old man presented to another hospital complaining of an anterior chest pain. Chest computed tomography (CT) showed an anterior mediastinal tumor 60 × 30 × 55 mm in size. The boundary with the pericardium or left brachiocephalic vein seemed to be partially unclear while enhanced by the contrast medium, and so the tumor could have invaded them. No definitive diagnosis of myasthenia gravis was made although the serum anti-acetylcholine receptor antibody count was high. We performed an extended thymectomy with combined partial resection of left brachiocephalic vein, left upper lobe, and left phrenic nerve. He was discharged with no chest pain and no complications post-surgery. The tumor was pathologically type B2 thymoma with hemorrhage necrosis and MTCs, and we diagnosed Masaoka stage II because of no histological infiltration to the organs. CONCLUSIONS: We speculated that hemorrhagic necrosis due to infarction in tumor caused the inflammation to spread to the surrounding organs, which was related to the chest pain and the development of MTCs.

Comparison between robot-assisted thoracoscopic surgery and video-assisted thoracoscopic surgery for mediastinal and hilar lymph node dissection in lung cancer surgery.

OBJECTIVES: Lymph node dissection (LND) with robot-assisted thoracoscopic surgery (RATS) in lung cancer surgery has not been fully evaluated. The aim of this study was to compare LND surgical results between video-assisted thoracoscopic surgery (VATS) and RATS. METHODS: We retrospectively compared perioperative parameters, including the incidence of LND-associated complications (chylothorax, recurrent and/or phrenic nerve paralysis and bronchopleural fistula), lymph node (LN) counts and postoperative locoregional recurrence, among 390 patients with primary lung cancer who underwent lobectomy and mediastinal LND by RATS (n = 104) or VATS (n = 286) at our institution. RESULTS: The median total dissected LN numbers significantly differed between the RATS and the VATS groups (RATS: 18, VATS: 15; P < 0.001). They also significantly differed in right upper zone and hilar (#2R + #4R + #10L) (RATS: 12, VATS: 10; P = 0.002), left lower paratracheal and hilar (#4L + #10L) (RATS: 4, VATS: 3; P = 0.019), aortopulmonary zone (#5 + #6) (RATS: 3, VATS: 2; P = 0.001) and interlobar and lobar (#11 + #12) LNs (RATS: 7, VATS: 6; P = 0.041). The groups did not significantly differ in overall nodal upstaging (P = 0.64), total blood loss (P = 0.69) or incidence of LND-associated complications (P = 0.77). CONCLUSIONS: In this comparison, it was suggested that more LNs could be dissected using RATS than VATS, especially in bilateral superior mediastinum and hilar regions. Accumulation of more cases and longer observation periods are needed to verify whether RATS can provide the acceptable quality of LND and local control of lung cancer.

Podoplanin expression in cancer-associated fibroblasts predicts unfavorable prognosis in node-negative breast cancer patients with hormone receptor-positive/HER2 - negative subtype.

BACKGROUND: Podoplanin expression in cancer-associated fibroblasts (CAFs) has been proposed as an indicator for poor prognosis in patients with invasive breast carcinomas, but little is known about its clinical significance in node-negative breast cancer patients with hormone receptor (HR) + /HER2 - subtype, who are expected to have a favorable prognosis. METHODS: Immunohistochemical analyses were performed on 169 resected specimens of node-negative invasive carcinoma of no special type with HR + /HER2 - subtype using antibodies for podoplanin. When more than 10% of CAFs showed immunoreactivity with podoplanin as strong as that of internal positive controls, the specimens were judged as podoplanin-positive. RESULTS: Podoplanin-positive status in CAFs was observed in 16.0% (27 of 169 cases) and it associated with high Ki67 labeling index (LI) (> 30%) (p = 0.03), higher stromal tumor-infiltrating lymphocytes (p < 0.001) and progesterone receptor-negative status (p = 0.045). Log-rank test showed that podoplanin-positive status in CAFs correlated with shorter disease-free survival (DFS) (p = 0.007) and disease-specific survival (DSS) (p < 0.001). Univariate analysis showed a significant correlation between shorter DFS and podoplanin-positive status in CAFs (hazard ratio [HR] = 3.380; p = 0.012), the presence of lymphatic invasion (HR = 5.621; p < 0.001), high Ki67 LI (HR = 5.217; p < 0.001), and histological grade III (HR = 3.748; p = 0.008). According to Cox multivariate analysis, podoplanin-positive status in CAFs had the most significant effect on shorter DSS (HR = 37.759; p = 0.003) followed by high Ki67LI (HR = 27.664; p = 0.007). CONCLUSION: Podoplanin expression in CAFs could be an independent predictor for poor prognosis in node-negative breast cancer patients with HR + /HER2 - subtype.

Transformation from adenocarcinoma to squamous cell carcinoma associated with long-term administration of EGFR-TKIs.

Although patients with non-small cell lung cancer exhibiting EGFR mutations generally respond to tyrosine kinase inhibitors (TKIs), the majority of patients acquire resistance ~1 year after treatment. EGFR T790M mutations, MET or HER2 amplifications and phenotypic transformations contribute to the mechanism of EGFR-TKI resistance. The transformation of small cell lung cancer frequently occurs, although few convert to squamous cell carcinoma associated with the administration of EGFR-TKIs. The current study reports a case of EGFR-mutated adenocarcinoma of the lung that transitioned to squamous cell carcinoma in association with long-term EGFR-TKIs administration.

Gene expression profiling by targeted RNA sequencing in pathological stage I lung adenocarcinoma with a solid component.

OBJECTIVES: Solid predominant adenocarcinoma is considered an independent predictor of an unfavorable prognosis in patients with stage I lung adenocarcinoma (LUAD). Furthermore, solid minor components are related to poor prognosis in patients with stage I LUAD. Therefore, it is imperative to elucidate the molecular determinants of the malignant potential of solid components (SC). Several studies reported the gene expression profiling specific for lepidic predominant adenocarcinoma or solid predominant adenocarcinoma, however; there is no report identifying the differentially expressed genes (DEGs) between SC and acinar component (AC) within the same tumor tissue in pathological (p)-stage I LUAD patients. MATERIALS AND METHODS: LUAD tissue samples containing both SC and AC were obtained from 8 patients with p-stage I LUAD and each component was microdissected. Targeted RNA sequencing was performed by a high-throughput chip-based approach. RESULTS: In total, 1272 DEGs were identified, including 677 upregulated genes and 595 downregulated genes in SC compared with AC. The most highly upregulated gene was TATA binding protein associated factor 7 (TAF7) and the most highly downregulated gene was homeobox B3 (HOXB3), which acts as a metastasis suppressor. A protein-protein interaction (PPI) network analysis of upregulated genes in SC identified ribosomal protein S27a (RPS27a) as a hub gene with the highest degree. First neighbors of RPS27a included PSMA6, which is a highly promising target for lung cancer. The subnetwork of PD-L1 had 10 first neighbors, including CMTM6, which enhances the ability of PD-L1-expressing tumor cells to inhibit T cells. The staining score for PD-L1 in SC was significantly higher than that in AC by immunohistochemistry (p = 0.001). CONCLUSION: Our results revealed several new DEGs and key PPI network in SC compared to AC, contributing to understanding the biological features of SC and providing therapeutic targets for early-stage LUAD with SC in the future.

Comparison of medium-term survival outcomes between robot-assisted thoracoscopic surgery and video-assisted thoracoscopic surgery in treating primary lung cancer.

OBJECTIVES: Robot-assisted thoracoscopic surgery (RATS) for primary lung cancer has been spreading rapidly in Japan. While RATS has various technical advantages over video-assisted thoracoscopic surgery (VATS), the quality of surgery from an oncologic viewpoint must be maintained, and the evaluation of medium- to long-term survival outcomes is momentous. METHODS: This study included 299 patients with primary lung cancer (VATS, n = 246; RATS, n = 53) who underwent lobectomy and mediastinal lymph node dissection at our hospital. We reviewed and compared perioperative factors, the number of dissected lymph nodes, and postoperative recurrence between the VATS and RATS groups. We also compared the postoperative survival rates among 98 patients (49 patients in each group) whose background factors were adjusted by propensity score matching (PSM). RESULTS: After PSM, a significant difference was found in the total operative time between the two groups (p < 0.01); however, no difference was found between the RATS console time and VATS total operative time (p = 0.68). Postoperative recurrence was not significantly different between the groups (VATS, 14%; RATS, 6%; p = 0.18). The 3-year recurrence-free survival rate was not significantly different between the groups (VATS, 91.7%; RATS, 91.2%; p = 0.21). CONCLUSIONS: RATS had promising survival results, which were similar to those of VATS even after PSM. Further case series and longer observation periods are needed to determine what technical benefits of RATS may affect the prognosis of lung cancer.

Pure high-grade fetal adenocarcinoma of the lung: a case report.

BACKGROUND: Pure high-grade fetal adenocarcinoma of the lung (H-FLAC) is a very rare tumor. CASE PRESENTATION: An annual check-up revealed an abnormal shadow in the left middle lung field of a 63-year-old Japanese man. Chest computed tomography (CT) showed a 3.6 × 2.8 cm pulmonary lesion with clear boundary in the left upper lobe. A transbronchial lung biopsy revealed non-small cell carcinoma. A left upper lobectomy and mediastinal lymph node dissection were performed. Histologically, the tumor consisted of solid proliferation of atypical cell with clear cytoplasm. Another histological component and morulae were not contained. Immunohistochemically, the tumor was focally positive for alpha-fetoprotein (AFP) and beta-catenin in the cell membrane. Accordingly, we made the diagnosis of pure H-FLAC, pT2aN2M0, stage IIIA. Two courses of adjuvant chemotherapy (cisplatin and vinorelbine) were administered but then the treatment was discontinued due to the patient's adverse reaction. At 25 months after the surgery, the patient had relapsed. CONCLUSIONS: We report a very rare case of pure H-FLAC. This histology has been considered to predict an extremely poor prognosis; therefore, the elucidation of genetic abnormalities and effective treatment is awaited.

Cushing's syndrome caused by ACTH-producing thymic typical carcinoid with local invasion and regional lymph node metastasis: a case report.

BACKGROUND: Ectopic ACTH-producing thymic carcinoid tumors are rare, but often behave aggressively with local invasion and distant metastasis. We herein report a case of ACTH-producing thymic typical carcinoid tumor with lymph node metastasis treated by surgery and postoperative radiation therapy. CASE PRESENTATION: A 61-year-old woman was admitted to be evaluated for hypoglycemia and hypokalemia. Laboratory data revealed elevation of serum cortisol and ACTH levels. Overnight administration of 8 mg dexamethasone did not suppress plasma ACTH. Chest CT demonstrated a tumor of 30 mm in diameter and enlargement of the lymph node at the anterior mediastinum. Ectopic ACTH syndrome was suspected and total thymectomy and lymph node dissection were performed. The histopathological examination indicated typical carcinoid tumor and mediastinal lymph node metastasis, and immunohistochemical staining was positive for ACTH. The plasma ACTH level decreased immediately after surgery. She received postoperative radiation therapy of 60 Gy. CONCLUSION: Ectopic ACTH-producing thymic typical carcinoid tumors are rare, and it is important to consider this disease and perform appropriate treatment.

Initial Results of Robotic Surgery for Primary Lung Cancer: Feasibility, Safety and Learning Curve.

BACKGROUND: At the end of 2016, robot-assisted thoracoscopic surgery (RATS) was still not covered by Japanese national health insurance. Therefore, few institutions in Japan perform RATS and even fewer have reported procedures as they occurred earlier. So, we decided to focus on the initial results of RATS for primary lung cancer. METHODS: We retrospectively reviewed 44 patients who underwent RATS for primary lung cancer from January 2011 to August 2016. After mastering the initial procedure, we introduced a completely portal robotic pulmonary resection procedure using a carbon dioxide insufflation system. Cases were divided into 2 groups: the early period (20 cases) and the later period (24 cases). RESULTS: There was no case of conversion to video-assisted thoracoscopic surgery or thoracotomy. In the 44 cases of primary lung cancer, median operating time was 239.5 min, console time was 179 min, blood loss was 10 mL, drainage period was 2 days, morbidity of Grade 2 or more (Clavien-Dindo classification) was 18.2%, morbidity of Grade 3 or more was only 4.6%, and there was no 30-day mortality. Median operating and console times were significantly shorter in the later period (215 min and 159.5 min, respectively) than in the initial period (300.5 min and 228 min, respectively). Median blood loss was significantly lower in the later period (5 mL) than in the initial period (50 mL). Five-year overall and disease-free survival rates were 100% and 88.9%, respectively. CONCLUSION: RATS for primary lung cancer is feasible and safe, has a faster learning curve, and provides satisfactory. Studies with longer follow-ups and larger numbers of cases are necessary.

[Two Surgical Cases of Müllerian Cyst Arising From the Posterior Mediastinum].

We experienced 2 cases of Müllerian cyst. Case 1 was a 48-year-old woman with a paravertebral cystic tumor. The tumor grew from 23 to 31 mm in diameter for the 3 years. She underwent video-assisted thoracic surgery(VATS) for the excision of the tumor. Case 2 was a 40-year-old woman with a paravertebral cystic tumor, who underwent VATS. The Histological finding showed that the tumors of both cases were the cysts lined by non-stratified cuboidal to columnar epithelium and epithelial cells were positive in the nucleus with estrogen receptor immunohistochemically. The resected cysts were finally diagnosed as Müllerian cyst. Twenty four published cases of Müllerian cyst were reported before, including symptomatic and growing cases. There were some reports of malignant transformation in cases of pelvic origin.

Prognostic Factors for Post Recurrence Survival in Resected Pathological Stage I Non-small Cell Lung Cancer.

Background: Recurrence of lung cancer after surgical resection is a major obstacle in the cure and long-term survival of patients and has become the most common cause of death. However, prognostic factors and efficacy of therapy after recurrence remain controversial. We evaluated the prognostic factors of post recurrence survival (PRS) in patients of resected stage I non-small cell lung cancer (NSCLC). Methods: Of the 551 patients who underwent surgery for stage I NSCLC between 2005 and 2013, we reviewed 89 (16.2%) patients who had recurrence. We examined PRS using the Kaplan-Meier method and multivariate Cox regression analyses. Results: The median follow-up period after recurrence was 21.0 months. The median recurrence free interval (RFI) was 16.8 months. The 1-year PRS and 3-year PRS were 65.6% and 44.7%, respectively. Multivariate analysis revealed that size of primary lesion > 25 mm (P = 0.048), RFI ≤ 17 months (P = 0.048) and no treatment for recurrence (P < 0.001) were independent poor-prognosis factors of PRS. We further examined PRS in 66 patients who underwent any post recurrence therapy. For the patients who underwent treatment after recurrence, bone metastasis (P = 0.025) and treatment without epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) (P = 0.049) were independent poor prognostic factors. Conclusion: PRS may be associated with characteristics of a recurrent lesion, including the biology of the recurrent tumor, RFI, recurrent site, the treatment for recurrence, rather than characteristics of primary lesion. Although further validation is needed, this information is important for the design of clinical trials for post-recurrence therapy.

Excellent prognosis of lepidic-predominant lung adenocarcinoma: low incidence of lymphatic vessel invasion as a key factor.

AIM: To clarify the prognostic value of predominant histological subtypes for small-sized lung adenocarcinoma. MATERIALS AND METHODS: Sixty-four specimens of resected invasive lung adenocarcinoma less than 20 mm in diameter with no lymph node metastasis were studied. These specimens were microscopically classified into predominant histological subtypes (21 lepidic, 16 acinar, 24 papillary, and three solid) according to the International association for the study of lung cancer/American thoracic society/European respiratory society adenocarcinoma classification. The relationships between tumor relapse and predominant histological subtypes were statistically analyzed. In addition the relationships between several pathological factors and predominant histological subtypes were statistically assessed. RESULTS: Kaplan-Meier relapse-free curves showed a five-year relapse-free rate of 100% in 64 patients with lepidic-predominant adenocarcinoma, compared with a rate of 73.7% (p=0.035 by log rank test) in patients with non-lepidic-predominant adenocarcinoma (papillary, acinar, and solid). The only statistically significant pathological factor between lepidic-predominant and non-lepidic-predominant histological subtypes was lymphatic vessel invasion as assessed by logistic regression analysis. CONCLUSION: In small-sized lung adenocarcinoma, lepidic-predominant histological subtype is the best prognostic factor, and a low incidence of lymphatic vessel invasion in the histological subtype is a key factor for an excellent prognosis.