Prognosis of non-small cell lung cancer with postoperative regional lymph node recurrence.

BACKGROUND: Regional lymph node recurrence after radical surgery for non-small cell lung cancer (NSCLC) is an oligo-recurrent disease; however, no treatment strategy has been established. In the present study we aimed to determine the clinical outcomes of postoperative regional lymph node recurrence and identify prognostic predictors in the era of molecular-targeted therapy. METHODS: We retrospectively analyzed data on clinical characteristics and outcomes of patients with regional lymph node recurrence after surgery who underwent treatment for NSCLC between 2002 and 2022. RESULTS: A total of 53 patients were included in this study. The median time between surgery and detection of recurrence was 1.21 years. Radiotherapy (RT) alone and chemoradiotherapy (CRT) were performed in 38 and six patients, respectively. Driver gene alterations were detected in eight patients (EGFR: 6, ROS1:1, and BRAF: 1) and programmed death-ligand 1 (PD-L1) expression was examined in 22 patients after 2016. Median progression-free survival (PFS) and overall survival (OS) after lymph node recurrences were 1.32 and 4.34 years, respectively. Multiple lymph node recurrence was an independent prognostic factor for PFS, whereas driver gene alteration was the only prognostic factor for OS. There was no significant difference in the OS between patients stratified according to the initial treatment modality for lymph node recurrence. CONCLUSION: Our results suggest that the number of tumor recurrences may correlate with PFS, while detection of driver gene alterations could guide decision-making for the appropriate molecular-targeted therapy to achieve longer OS.

Anatomy of the lung revisited by 3D-CT imaging.

The anatomy of the lung was originally described based on data acquired from cadaveric studies and surgical findings. Over time, computed tomography (CT) and three-dimensional (3D) imaging techniques have been developed, allowing for reconstruction and understanding of lung anatomy in a more intuitive way. The wide adoption of 3D-CT imaging technology has led to a variety of anatomical studies performed not only by anatomists but also by surgeons and radiologists. Such studies have led to new or modified classification systems, shed light on lung anatomy from a useful surgical viewpoint, and enabled us to analyze lung anatomy with a focus on particular anatomical features. 3D images also allow for enhanced pre- and intra-operative simulation, improved surgical safety, enhanced educational utility, and the capacity to perform large-scale anatomical studies in shorter time frames. We will review here the key features of 3D-CT imaging of the lung, along with representative anatomical studies regarding (I) general lung anatomy, (II) anatomy of the right and left lobes, and (III) features of interlobar vessels. The current surge of 3D imaging analysis shows that the field is growing, with the technology continuing to improve. Future studies using these new and innovative methodologies will continue to refine our understanding of lung anatomy while enhancing our ability to perform safe and effective surgical resections.

Autoimmune alopecia areata due to thymoma without myasthenia gravis: a case report.

BACKGROUND: Thymoma is associated with autoimmune diseases. Myasthenia gravis is frequently associated with thymoma, but cases of thymoma complicated by alopecia areata are very rare. In this report, we present a case of thymoma associated with alopecia areata, but without Myasthenia gravis. CASE PRESENTATION: A 60-year-old woman had a complaint of rapid progression of alopecia areata. A hair follicular biopsy was performed, which showed the infiltration of CD8-positive lymphocytes. She was prescribed topical steroids for 2 months prior to surgery, but her hair loss was not improved. Screening computed tomography showed a mass in the anterior mediastinum, which was suspected to be a thymoma. Myasthenia gravis was ruled out because she had no relevant symptoms or physical findings, and no anti-acetylcholine receptor antibodies were detected in serum. We performed a transsternal extended thymectomy based on a diagnosis of thymoma Masaoka stage I, without myasthenia gravis. Pathological examination showed Type AB thymoma, Masaoka stage II. The chest drainage tube was removed on postoperative day 1, and the patient was discharged on postoperative day 6. The patient has continued topical steroids and showed improvement 2 months postoperatively. CONCLUSIONS: Although alopecia areata is a rare complication in thymoma cases without myasthenia gravis, thoracic surgeons need to keep this condition in mind because alopecia reduces the patient's quality of life.

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.

Keratin-positive fibrotic extraskeletal myxoid chondrosarcoma: a close mimic of myoepithelial tumour.

AIMS: Extraskeletal myxoid chondrosarcoma (EMC) is a rare form of adult sarcoma with distinct histology and NR4A3 gene fusion. Immunohistochemically, EMCs are variably positive for S100 protein and neuroendocrine markers. Unlike histologically similar soft-tissue myoepithelial tumours, keratin expression is rare. Prompted by two recent EMC cases with diffuse keratin expression, we investigated the expression of epithelial markers in a molecularly confirmed cohort of EMC and identified two additional similar cases. METHODS AND RESULTS: Four keratin-positive EMCs occurred in one man and three women aged 46-59 years. All tumours displayed nonclassic histology with prominent stromal fibrosis, and keratin AE1/AE3 was expressed either diffusely (N = 2) or focally (N = 2). In one tumour, keratin expression was limited to the sclerotic area. All tumours coexpressed epithelial membrane antigen and two additionally expressed S100 protein or glial fibrillary acidic protein. All tumours harboured NR4A3 fusions, including TAF15::NR4A3 (N = 1) and EWSR1::NR4A3 (N = 3). Two cases were initially considered as most consistent with myoepithelial tumours based on widespread stromal fibrosis and keratin expression. DNA methylation analysis classified two tumours tested as EMCs. CONCLUSIONS: We identified a small subset of EMCs characterised by keratin expression and prominent stromal fibrosis. This histological pattern must be recognised in the differential diagnosis of myoepithelial tumours because misclassification may lead to the erroneous prediction of tumour behaviour and may alter patient management. NR4A3 genetic analysis should be considered even in the face of keratin expression and prominent stromal fibrosis.

Sustained antitumor response to lenvatinib with weekend-off and alternate-day administration in chemotherapy-refractory thymic carcinoma: a case report.

Lenvatinib is a multitargeted kinase inhibitor and maintaining its dose intensity has been shown to be beneficial in patients with thyroid and hepatocellular carcinomas. However, most patients require lenvatinib interruption and dose reduction due to the high incidence of adverse events (AEs). Lenvatinib was recently approved in Japan for patients with unresectable thymic carcinoma; however, real-world evidence of its clinical benefit is limited. Here, we report the case of chemotherapy-refractory thymic carcinoma in a patient who was administered a starting dose of lenvatinib using a 5-day on/2-day off (weekend-off) protocol, followed by alternate-day administration after fatigue onset derived from overt or subclinical hypothyroidism. Consequently, the patient exhibited a durable response to lenvatinib, with a 17-month progression-free survival without any severe or intolerable AEs. The present case suggests that maintaining lenvatinib dose intensity using such alternative administration regimens contributes to favorable clinical outcomes in thymic carcinoma.

Durable response to afatinib rechallenge in a long-term survivor of non-small cell lung cancer harboring EGFR L858R and L747V mutations.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors are standard therapeutic agents for non-small cell lung cancer (NSCLC) patients with major EGFR mutations such as exon 19 deletions and a L858R mutation, whereas treatment strategies for cases with uncommon EGFR mutations remain to be fully established. Here, we report a long-term (≥20 years from initial diagnosis) NSCLC survivor carrying EGFR L858R and L747V mutations. The patient received gefitinib monotherapy, systemic chemotherapy/chemoimmunotherapy, and local consolidative therapies for oligometastatic lesions, and responded to afatinib rechallenge with a progression-free survival of 12 months. The current case suggests that afatinib is effective in NSCLC patients with EGFR L858R and L747V mutations and that a therapeutic approach combining appropriately timed systemic therapies with local consolidative therapies for oligometastatic lesions improves long-term survival.

Complex vs. simple segmentectomy: comparing surgical outcomes in the left upper division.

BACKGROUND: Lung segmentectomy is an option for the treatment of noninvasive or minimally invasive lung cancer. For tumors located in the left upper division (LUD), LUD trisegmentectomy (S1+2 + S3) is frequently performed as a sublobar resection because of its technical simplicity. However, the differences in surgical outcomes between simple and complex segmentectomies remain unclear. METHODS: We compared the surgical outcomes and frequency of postoperative complications of LUD trisegmentectomy (simple group) with those of complex segmentectomy (other than LUD trisegmentectomy; complex group) for pulmonary lesions using three-dimensional computed tomography between 2010 and 2021. RESULTS: In total, 118 patients were included: 65 in the simple group and 53 in the complex group (S1+2: 25, S3: 15, others: 13). There were no significant differences in surgical time or duration of postoperative chest drainage. However, the blood loss volume was significantly smaller in the complex group than in the simple group (12 vs. 36 mL, p = 0.023), and major complications tended to occur less frequently in the complex group than in the simple group (3.8 vs. 13.8%, p = 0.061). Among patients who underwent intentional segmentectomy for primary lung cancer (n = 61), major complications were significantly less common in the complex group (p = 0.006). CONCLUSIONS: Complex segmentectomy can be performed safely under the guidance of three-dimensional CT. Complex segmentectomy itself is not a risk factor for postoperative complications when the intersegmental planes are sufficiently recognized and accurately cut.

Superior Lingular S4 Segmentectomy.

Although segmentectomy has become a routine procedure, atypical segmentectomies are less popular than their typical counterparts, probably because anatomic and surgical data are lacking. The left superior lingular S4 segment is considered relatively small, usually resected along with other segments. However S4 segment size varies among patients, and resection of this single segment can be a valuable lung-preserving procedure in carefully selected patients with tumors located at the border of the upper division and lingular segments. We present here the anatomic and surgical features required for a methodologic left S4 segmentectomy based on our experience and the literature.

Course of postoperative relapse in non-small cell lung cancer is strongly associated with post-progression survival.

BACKGROUND: For early-stage non-small cell lung cancer (NSCLC), surgical resection is considered the most effective treatment strategy and curative treatment. Unfortunately, even after complete resection, almost half of all patients with stage I-IIIA NSCLC relapse and die. Although the possibility of a cure for postoperative recurrence of NSCLC is significantly low, the course of subsequent treatment can possibly affect overall survival (OS). Here, we examined the association of relapse-free survival (RFS) and post-progression survival (PPS) with OS in patients with postoperative recurrence of NSCLC. METHODS: We evaluated 128 patients with NSCLC who underwent complete resection between January 2007 and December 2018. The association between RFS and PPS on OS was examined at the patient level. RESULTS: Spearman's rank correlation and linear regression analyses revealed that PPS was strongly correlated with OS (r = 0.83, p < 0.05, R2  = 0.72), whereas RFS was weakly associated with OS (r = 0.56, p < 0.05, R2  = 0.37). Additionally, the performance status at relapse and administration of tyrosine kinase inhibitors were significantly correlated with PPS. CONCLUSIONS: PPS was significantly more strongly correlated with OS than was RFS in patients with postoperative recurrence of NSCLC. These results suggest that therapy following postoperative recurrence affects OS. Therefore, it is necessary to validate these promising results in a large prospective study.

Comprehensive expressional analysis of chemosensitivity-related markers in large cell neuroendocrine carcinoma of the lung.

OBJECTIVES: Various drug-sensitivity markers have been reported to be associated with tumor progression and chemotherapy resistance. Detailed expression profiles of sensitivity markers for cytotoxic chemotherapy in pulmonary large cell neuroendocrine carcinoma (LCNEC) remain unclear. Herein, we aimed to clarify the correlation between the expression of drug-sensitivity markers and clinicopathological features, prognostic impact, and status of tumor immunity in patients with LCNEC. METHODS: We retrospectively analyzed the correlation between clinicopathological features and the expression of drug-sensitivity-related markers, including vascular endothelial growth factor 2 (VEGFR2), thymidylate synthase (TS), tubulin beta 3 class III (TUBB3), topoisomerase I (Topo-I), and Topo-II in 92 surgically resected LCNEC samples. Furthermore, we examined the prognostic significance of expression of these and their correlation with the immune cell status. RESULTS: Overall, high expression of TS, TUBB3, VEGFR2, Topo-I, and Topo-II was detected in 50 (54%), 31 (34%), 23 (25%), 65 (71%), and 36 (39%) samples, respectively. Univariate and multivariate analyses revealed that advanced pathological T and N factors, positive lymphatic permeation, and Topo-II expression were independent unfavorable prognosticators for recurrence-free survival, and advanced pathological T and N factors, Topo-II positive expression, and TS positive expression were independent unfavorable prognosticators for overall survival. In terms of correlation with immune cell status, higher expression of VEGFR2 was closely linked to negative PD-L1 expression. CONCLUSIONS: These findings suggest that elevated Topo-II and TS expression may contribute to poor outcomes through protumoral biology in patients with LCNEC, and elevated VEGFR2 expression might negatively impact tumor immune reactions in LCNEC.

Segmentectomy Guided by 3-Dimensional Images Reconstructed From Nonenhanced Computed Tomographic Data.

Three-dimensional (3D) imaging is an essential tool for performing an accurate segmentectomy. However, data acquired from contrast-enhanced computed tomography (CT) are considered necessary when reconstructing 3D pulmonary vascular images. Therefore, 3D images are currently unavailable for patients who cannot undergo contrast-enhanced CT scans due to patient-related issues such as anaphylaxis to the contrast agent, among others. We present here our experience with atypical segmentectomies guided by 3D images reconstructed from nonenhanced CT data.

Spontaneous pneumothorax in a patient with multiple pulmonary arteriovenous malformations caused by hereditary hemorrhagic telangiectasia: a case report.

Spontaneous pneumothorax occurring in patients with pulmonary arteriovenous malformations (PAVMs) caused by hereditary hemorrhagic telangiectasia (HHT) is extremely rare. We report a case of spontaneous pneumothorax in a PAVM patient. A 26-year-old man with previously diagnosed HHT and multiple small PAVMs presented with chest pain and dyspnea and was referred to our hospital. Chest X-ray showed a left-sided pneumothorax. Computed tomography (CT) showed apical bullae on both sides of the upper lobe. We clarified the location of PAVMs by 3D-CT to avoid the massive bleeding caused by careless grasping of PAVMs and unintentional incomplete resection of the PAVMs during the pneumothorax surgery. Considering the risk of exacerbation, the patient underwent bullectomy of the left upper lobe. The postoperative histopathological examination indicated that the pneumothorax occurred spontaneously in the HHT patient. We should clarify the location of PAVMs to avoid bleeding caused by the grasping of PAVMs during surgery.

Right upper lobe segmentectomy guided by simplified anatomic models.

BACKGROUND: To standardize the technical strategy for right upper lobe (RUL) segmentectomy, we previously developed simplified 3-dimensional (3D) anatomic models that classify the RUL anatomy into 14 patterns according to the branching pattern of bronchi and veins. We aimed to study the surgical outcome of RUL segmentectomy guided by these simplified anatomic models. METHODS: Patients were classified into the anatomic models, and the approach to the intersegmental veins was selected accordingly. The intersegmental vein and corresponding intersegmental plane were as follows: V1b (the apicoanterior plane), V2a (the apicoposterior plane), and V2c (the posteroanterior plane). Clinicopathologic characteristics and short- and long-term outcomes were analyzed retrospectively. RESULTS: Thirty-four consecutive patients who underwent thoracoscopic RUL segmentectomy guided by simplified anatomic models between January 2016 and December 2019 at Gunma University were analyzed. All the patients were classified into a model: anterior + central Iab type (47%), anterior + central Ib type (41%), anterior II type (12%), or central III type (0%). The standard approaches to intersegmental veins were an anterior approach for V1b, a posterobronchial approach for V2a, and an interlobar approach for V2c. The approach to intersegmental or intrasegmental veins was modified according to the anatomic model in 4 cases (12%). The median operative time, blood loss, and hospital stay were 222 minutes, 19 grams, and 7 days, respectively. Prolonged air leakage was observed in 1 patient. CONCLUSIONS: Segmentectomy guided by simplified anatomic models promotes anatomic classification, development of a standardized approach for segmental vein identification, and acceptable outcomes, which can facilitate the implementation of RUL segmentectomy.

Clinicopathological features of small-sized peripheral squamous cell lung cancer.

Recent advances in imaging technology have enhanced the detection rate of small-sized peripheral lung cancers. The present study aimed to identify the clinicopathological differences between patients with small-sized peripheral squamous cell carcinoma (SCC) and adenocarcinoma (ADC). Patients with lung cancer who underwent radical surgical resection at Gunma University Hospital between July 2007 and October 2012 were retrospectively analyzed. Patients who exhibited small-sized peripheral tumors (pathological size, ≤2 cm) located within the outer-third of the lung field on preoperative computed tomography were enrolled in the present study. A total of 26 patients were diagnosed with SCC and 214 with ADC. The results revealed that patients with SCC exhibited higher rates of pleural invasion, vascular invasion and lymphatic invasion compared with ADC patients. Additionally, the rate of postoperative recurrence was higher in patients with SCC compared with ADC patients. Patients with ADC were subsequently into two groups: Solid ADCs (sADC) and non-solid ADCs (nsADC), which included pure ground glass nodules and part-solid ADCs. The results revealed that the incidence of pleural invasion, vascular invasion and lymphatic invasion, and the rate of postoperative recurrence in patients with sADCs were similar to those with SCC, but were also significantly higher when compared with nsADC patients. The present study concluded that patients with SCC and sADC may not be suitable candidates for sublobar resection, despite exhibiting small tumors that are located in the peripheral lung.

Carbonic anhydrase 9 expression is associated with poor prognosis, tumor proliferation, and radiosensitivity of thymic carcinomas.

INTRODUCTION: Thymic epithelial tumors (TETs) comprise several histologies of thymoma and thymic carcinomas (TCs), and TC frequently metastasizes and causes death. We therefore aimed here to identify key molecules closely related to prognosis and their biological roles in high-risk TETs, particularly TCs. RESULTS: RNA sequence analysis demonstrated that hypoxia-related genes were highly expressed in TETs. The expression of the hypoxia-related gene CA9 was noteworthy, particularly in TCs. Immunohistochemical analysis revealed that CA9 was expressed in 81.0% of TCs and 20.7% of all TET samples. CA9 expression was significantly associated with Masaoka stage, WHO classification, and recurrence-free survival after tumor resection (P = 0.005). The down-regulation of CA9 transcription in TC cell lines by small interfering RNAs significantly inhibited CA9 expression, which inhibited proliferation and increased sensitivity to irradiation. CONCLUSIONS: CA9 expression may serve as a significant prognostic marker of TETs and therefore represents a potential target for the development of novel drugs and radiation-sensitizing therapy designed to improve the outcomes of patients with TCs. MATERIALS AND METHODS: We performed comprehensive transcriptome sequencing of 23 TETs and physiologic thymic specimens to identify genes highly and specifically expressed in high-risk TETs, particulary TCs. We performed immunohistochemical analysis of 179 consecutive surgically resected TETs to evaluate the significance of the association of protein expression with clinicopathological features and prognosis. The biological significance of the most promising prognostic marker was further studied using the TC cell lines, Ty-82 and MP57.

Minimally Invasive Open-Window Thoracostomy Using Wound Edge Protectors.

We report the technical details of minimally invasive open-window thoracostomy using wound edge protectors for postoperative pyothorax caused by a bronchopleural fistula with acute exacerbation of idiopathic pulmonary fibrosis under epidural and local anesthesia.

Prognostic significance of PD-L1 expression and tumor infiltrating lymphocytes in large cell neuroendocrine carcinoma of lung.

OBJECTIVES: Since large cell neuroendocrine carcinoma (LCNEC) is a relatively rare histologic type of primary lung cancer, little is known about the immunological status of patients with LCNEC. We aimed to clarify the expression and prognostic impact of programmed cell death ligand 1 (PD-L1), CD8, CD4, and Forkhead box protein P3 (Foxp3) in LCNEC. METHODS: We retrospectively analyzed PD-L1, CD8, CD4, and Foxp3 expressions in 95 surgically resected LCNEC. PD-L1 positive staining was determined in tumors with more than 1% of tumor cells stained to any intensity, and CD8, CD4, and Foxp3 positivity was determined in tumors with more than 5% of lymphocytes stained. RESULTS: Positive expression of PD-L1, CD8, CD4, and Foxp3 was observed in 70 (74%), 52 (55%), 76 (80%), and 43 (45%) tumors, respectively. The expression of PD-L1 was significantly correlated with positive lymphatic permeation. Positive correlations were mutually observed among tumor infiltrating immune cells. Univariate and multivariate analyses showed that positive pleural invasion and Foxp3 negative expression were independent unfavorable prognostic factors for overall survival (OS). Advanced pathological stage, positive pleural invasion, CD4 negative expression in cancer stroma, and Foxp3 negative expression were identified as independent unfavorable prognostic factors for recurrence free survival (RFS). CONCLUSIONS: Foxp3 positive tumor infiltrating lymphocytes (TILs) were an independent favorable prognostic factor for both OS and RFS, whereas CD4 positive TILs were an independent significant unfavorable prognostic factor for RFS. The high frequency of PD-L1 expression could support the use of anti-programmed cell death 1 antibody in the treatment of LCNEC.

The impact of histology and ground-glass opacity component on volume doubling time in primary lung cancer.

BACKGROUND: Correlations between volume doubling time (VDT) of primary lung cancer (PLC), histology, and ground glass opacity (GGO) components remain unclear. The purpose of this study was to evaluate and compare VDT of PLC in terms of histology and presence or absence of GGO components. METHODS: A total of 371 surgically resected PLCs from 2003 to 2015 in our institute were retrospectively reviewed. The VDT was calculated both from the diameters of the entire tumor and of consolidation by using the approximation formula of Schwartz. RESULTS: The median VDTs of adenocarcinoma, squamous cell carcinoma, and others (large cell neuroendocrine carcinomas, small cell lung carcinomas, pulmonary pleomorphic carcinomas, and large cell carcinomas combined) were 261, 70, and 70 days, respectively; these differ significantly (P<0.001). All PLCs with GGO were adenocarcinomas. The VDT of adenocarcinomas with GGO was significantly longer than that of those without GGO (median VDT: 725 and 177 days, respectively), squamous cell carcinomas, and others. When the VDT calculated from the maximum diameter of consolidation component was compared, adenocarcinomas with GGO also showed significantly slower growth than those without GGO (median VDT: 248 versus 177 days, respectively, P=0.040). CONCLUSIONS: The VDT of PLCs is longest for adenocarcinomas. VDT was significantly longer in adenocarcinomas with GGO components than in those without such components, irrespective of VDT calculated on the basis of either the entire tumor diameter or consolidation diameter.