Underlying Problems in Surgical Treatment of cT1-2N1 Non-Small Cell Lung Cancer.

Background Obtaining an accurate preoperative diagnosis of N1 in non-small cell lung cancer (NSCLC) is a major difficulty. The aim of this retrospective study was to evaluate the pathological and long-term outcomes of NSCLC patients clinically staged with N1 disease, to aid in the search for better treatment strategies. Materials and Methods We retrospectively reviewed the clinical records of 1,180 consecutive patients with NSCLC who underwent surgery for curative intent from 1991 to 2011 in our department. Data on 96 (8.1%) patients who had cT1-2N1 disease and underwent lobectomy or more extensive surgery were available. Results Only 32% of patients (n = 31) were confirmed to have pathological N1 disease, and 34 and 33% of patients were proven to have pN0 and pN2 disease, respectively. Female gender, ≤ 30 pack-year tobacco smoking history, adenocarcinoma, and left-sided disease were significantly associated with pathological upstaging (χ2 test). Multivariate analysis using logistic regression revealed left-sided disease to be independently associated with upstaging (relative risk 4.00, p = 0.015). Left-sided disease was more likely to be underestimated by clinical N staging than right-sided disease (χ2 test, p = 0.0001). Univariate and multivariate survival analyses demonstrated that left-sided disease was an independent prognostic factor associated with poor outcomes (Cox proportional hazards regression: hazard ratio 2.27, p = 0.037). Conclusion The diagnostic accuracy of clinical N1 status was poor. Left-sided disease appeared to be understaged by the preoperative assessment of N status, and therefore, patients who might benefit from preoperative induction treatment would not receive it.

Prognostic Significance of Expression of the Epithelial-Mesenchymal Transition-Related Factor Brachyury in Intrathoracic Lymphatic Spread of Non-Small Cell Lung Cancer.

BACKGROUND: Brachyury is a transcriptional regulator that plays important roles in epithelial mesenchymal transition (EMT) during development and has been reported to be essential for mesoderm formation in the early human embryo. We investigated Brachyury protein expression in hilar and mediastinal metastatic lymph nodes of non-small cell lung cancer patients and the prognostic significance of Brachyury expression at metastatic sites. METHODS: Expression of Brachyury in 115 surgically resected primary lung cancer and corresponding metastatic lymph node samples was evaluated by immunohistochemical staining. The relationships between Brachyury protein expression and the patient's clinicopathological factors and prognosis were analyzed. RESULTS: Brachyury expression in metastatic lymph nodes was significantly higher than that in the primary tumor (p = 0.012). Patients with high Brachyury expression in the metastatic lymph nodes had significantly poor prognoses (p = 0.0236) compared with patients with low expression. In addition, patients with larger differences in Brachyury expression between metastatic lymph nodes and the primary tumor had significantly poorer prognoses compared with patients with smaller differences (p = 0.0146). The Brachyury protein expression level in metastatic lymph nodes was significantly associated with the protein expression levels of other EMT-related factors (E-cadherin [inverse association], p = 0.0265; Slug, p = 0.029; and interleukin-8, p = 0.0135). CONCLUSIONS: High expression of Brachyury protein in metastatic carcinoma cells in the intrathoracic lymph nodes was associated with poor prognosis of lung cancer patients. Increased Brachyury expression during the metastatic process may confer further potential for invasion and metastasis of cancer cells.

Clinical Significance of Detecting Somatic Gene Mutations in Surgically Resected Adenosquamous Cell Carcinoma of the Lung in Japanese Patients.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) inhibitors are effective and useful agents for treating patients who harbor EGFR-TKI-sensitive mutations or EML4-ALK rearrangement. Therefore, the importance of determining the presence of these somatic mutations when treating lung adenocarcinomas is widely accepted. However, genetic mutations are rarely evaluated in patients with adenosquamous cell carcinoma of the lung, a relatively infrequent histologic type of lung cancer, because of limited knowledge and the unclear value of assessing these oncogenic mutations in these patients. Therefore, we investigated the clinical implications of somatic mutations in surgically resected adenosquamous cell carcinoma of the lung in Japanese patients. METHODS: We retrospectively analyzed 32 patients with adenosquamous cell carcinoma of the lung who underwent surgical resection at two institutes in Japan. EGFR mutations and EML4-ALK rearrangement were assessed in all of the patients. RESULTS: Overall, 7 (21.9 %) of 32 patients had EGFR mutations: three patients had an exon 19 deletion and 4 had an exon 21, L858R mutation. There were no T790 M mutations. The median relapse-free survival was 766 days and the median overall survival was 1,152 days in the total cohort. Relapse-free survival and overall survival were not significantly different between patients with or without EGFR mutations. CONCLUSIONS: Detecting EGFR mutations in patients with adenosquamous cell carcinoma is clinically important, especially in patients with disease recurrence because EGFR-TKIs may be effective in this histologic type of lung cancer.

Successful resection of a giant mediastinal non-seminomatous germ cell tumor showing fluorodeoxyglucose accumulation after neoadjuvant chemotherapy: report of a case.

A 32-year-old man presented with a mediastinal non-seminomatous germ cell tumor showing fluorodeoxyglucose (FDG) accumulation (maximum standardized uptake value = 22.21) and extremely elevated blood alpha-fetoprotein (AFP) level (9203.0 ng/ml). The patient underwent 4 cycles of neoadjuvant chemotherapy (cisplatin, bleomycin, and etoposide), which normalized the AFP level and reduced the tumor size, allowing complete resection without a support of extracorporeal circulation. Despite preoperative positron emission tomography revealing increased FDG uptake in the residual tumor (maximum standardized uptake value = 3.59), the pathologic evaluation revealed that no viable germ cell tumor cells remained. We believe FDG uptake should not be used as a criterion for surgical resection after neoadjuvant chemotherapy. It is appropriate to resect the residual tumor regardless of FDG uptake after induction chemotherapy if a tumor is resectable and the AFP level normalizes.

[A case of surgical treatment for a bilateral pneumothorax that occurred in a patient with severe asbestosis and advanced emphysema].

A 71-year-old male with a history of asbestosis was referred to our department for the treatment of a bilateral pneumothorax. His pulmonary function was severely impaired because of asbestosis and emphysema. Chest computed tomography showed severe emphysema with bilateral multiple bullae. Although chest drainage tubes were placed in the bilateral thorax, the left lung did not completely expand due to a persistent air leak. We performed VATS while retaining the patient's spontaneous respiration under general sedation with regional epidural anesthesia, since one-lung, positive pressure ventilation was considered to be difficult to achieve. After the airway was secured by a laryngeal-mask, the bullae were then thoracoscopically resected. The pneumothorax improved after surgery.

A rare case of a bronchial anomaly running in the hilar region from the right lower lobe to the middle lobe.

A 77-year-old male was referred to our department due to lung cancer (cT3N0M0) of the right lower lobe. During right lower lobectomy, a thin duct structure was recognized in the hilar region between the middle and lower lobes that was identified to be a supernumerary bronchus upon a review of the preoperative chest CT images. Although bronchial anomalies are rare, it is important to carefully view preoperative images for any such anomalies in order to more safely perform surgery.

[Case of pulmonary inflammatory pseudotumor with cysts].

We herein report a case involving a 58-year-old female patient with multiple cystic lesions in the right lobe of the lung. The lesions were revealed on chest computed tomography in 2002 and followed up. Transbronchial lung biopsy showed no malignancy in June 2013. The lesions gradually increased in size and thickness and were associated with fluid-filled cysts. We performed a right lower lobectomy in November 2013. Pathological examination revealed inflammatory pseudotumor. Such a case of inflammatory pseudotumor presenting as a pulmonary cyst has not been previously described. Intractable infection and inflammation are regarded as common causes of inflammatory pseudotumor. This condition should be considered in patients with a medical history consistent with infectious disease and a pulmonary cyst found on chest computed tomography.

[A case of liver metastasis from gastric cancer responding completely to S-1/docetaxel chemotherapy].

A 68-year-old man was introduced to our hospital with right lower abdominal pain. Endoscopic examination and abdominal CT revealed gastric cancer with liver metastasis. We started chemotherapy using S-1(120 mg/body/day), orally administered for 2 weeks followed by a 2-week rest period, and docetaxel(35 mg/m(2)), administered intravenously on day 1 and 15 as 1 course. After 4 courses of chemotherapy, the liver tumor reduced markedly and no new cancerous region was found by examination; therefore total gastrectomy and partial hepatectomy were performed. Histological examination showed an undifferentiated adenocarcinoma remaining as Grade 1b in the resected stomach. A resected specimen of the liver showed necrotic tissue without any cancer cells. This case suggests that S-1/docetaxel chemotherapy may reduce the stage of unresectable liver metastasis from gastric cancer and make a curative operation possible.

[Case of adenocarcinoma in situ accompanied by an intrapulmonary lymph node with a sarcoid-like reaction].

A 65-year-old male underwent a chest CT scan, which revealed an 8 mm nodule on the wall of a bulla in the left lower lobe of the lung, and was thus suspected to be lung cancer. Pulmonary wedge resection of the left lower lobe by means of video-assisted thoracoscopic surgery was thus performed. A specimen of the lung revealed the presence of intrapulmonary lymph node on the wall of a bulla. The histopathological findings of the resected lung specimen showed non-caseating granulomas in the lymph node, and adenocarcinoma in situ. We concluded that the sarcoid-like reaction observed in the intrapulmonary lymph node was therefore related to the adenocarcinoma in situ.

Assessment of Intraoperative Microbiological Culture in Patients with Empyema: Comparison with Preoperative Microbiological Culture.

PURPOSE: Assessing microbiological culture results is essential in the diagnosis of empyema and appropriate antibiotic selection; however, the guidelines for the management of empyema do not mention assessing microbiological culture intraoperatively. Therefore, we tested the hypothesis that intraoperative microbiological culture may improve the management of empyema. METHODS: We performed a retrospective analysis of 47 patients who underwent surgery for stage II/III empyema from January 2011 to May 2019. We compared the positivity of microbiological culture assessed preoperatively at empyema diagnosis versus intraoperatively. We further investigated the clinical characteristics and postoperative outcomes of patients whose intraoperative microbiological culture results were positive. RESULTS: The positive rates of preoperative and intraoperative microbiological cultures were 27.7% (13/47) and 36.2% (17/47), respectively. Among 34 patients who were culture-negative preoperatively, eight patients (23.5%) were culture-positive intraoperatively. Intraoperative positive culture was significantly associated with a shorter duration of preoperative antibiotic treatment (p = 0.002). There was no significant difference between intraoperative culture-positive and -negative results regarding postoperative complications. CONCLUSIONS: Intraoperative microbiological culture may help detect bacteria in patients whose microbiological culture results were negative at empyema diagnosis. Assessing microbiological culture should be recommended intraoperatively as well as preoperatively, for the appropriate management of empyema.

Preoperative prognostic nutritional index level is associated with tumour-infiltrating lymphocyte status in patients with surgically resected lung squamous cell carcinoma.

OBJECTIVES: The prognostic nutritional index (PNI) is an indicator of systemic immune-nutritional condition and is a well-known prognostic biomarker in lung cancer patients. Tumour-infiltrating lymphocytes (TILs) is a specific histological feature of cancers, influencing an individual's immunological tumour responses. However, whether PNI can reflect lung cancer patients' prognosis through local immunity such as TIL is unclear. METHODS: We selected 64 lung squamous cell carcinoma patients who underwent curative operations. We investigated the significance of preoperative PNI level and evaluated the relationship between PNI and immune cells surrounding the lung cancer tissue using immunohistochemical analysis of a cluster of differentiation (CD)3, CD4, CD8 and CD68. RESULTS: A low-PNI level was significantly associated with a worse postoperative prognosis (P = 0.042). The PNI (hazard ratio 2.768, 95% confidence interval 1.320-5.957; P = 0.007) was an independent prognostic factor. The low-PNI group had a significantly shorter recurrence-free survival and overall survival (P = 0.013 and P = 0.002, log-rank test) compared with the high-PNI group. A significant positive correlation between PNI components including preoperative peripheral blood lymphocyte count and serum albumin concentration, and TILs, was observed. Absolute numbers of TILs in the preoperative high-PNI group were significantly increased compared with those in the preoperative low-PNI group (CD3+ cells; P = 0.002, CD4+ cells; P = 0.049 and CD8+ cells; P = 0.024). CONCLUSIONS: The preoperative PNI level was strongly associated with the postoperative outcome in lung cancer patients. Considering the positive relationship between preoperative PNI level and TIL status, preoperative immune-nutritional condition may influence lung cancer patients' postoperative prognosis through local immunity as well as systemic immune response.

LINE-1 Hypomethylation Is Associated With Malignant Traits and Cell Proliferation in Lung Adenocarcinoma.

BACKGROUND/AIM: Long interspersed nuclear element-1 (LINE-1) methylation status is a marker for global DNA methylation. However, the relationship between LINE-1 methylation and the biology of lung adenocarcinoma remains unclear. Here, we aimed to examine the role of LINE-1 in lung cancer. MATERIALS AND METHODS: LINE-1 methylation levels were quantified by bisulfite pyrosequencing of resected tumor specimens from 162 patients with lung adenocarcinoma. The relationships of LINE-1 methylation with clinicopathological factors, gene mutations, and Ki-67 immunoreactivity were investigated. RESULTS: LINE-1 hypomethylation was associated with tumor invasion and advanced stage. TP53 mutations were more frequently detected in the LINE-1 hypomethylation group than in the hypermethylation group. LINE-1 hypomethylation was associated with poor recurrence-free survival, high maximum standardized uptake value in positron-emission tomography, and high Ki-67 expression in tumors. CONCLUSION: LINE-1 hypomethylation was associated with high-grade malignancy and poor prognosis in lung adenocarcinoma, but was not related to driver mutations.

Onychomycosis of the Middle Finger of a Japanese Judo Athlete due to Trichophyton tonsurans

We present a 17-year-old Japanese male high school student, who had applied steroid ointment for atopic dermatitis, with fingernail onychomycosis due to Trichophyton tonsurans. He was found positive for T. tonsurans infection based on hairbrush culture performed due to an epidemic of T. tonsurans infection in his judo club. The hairbrush culture method is very important in screening for this infection, and dermatologists should examine the entire body of athletes who are found positive using this method. For the diagnosis of T. tonsurans infection, other than the skin and hair, the nails should also be checked by dermoscopy because the fingernail may be the origin of this fungus.

PD-L1 Is Upregulated by Simultaneous Amplification of the PD-L1 and JAK2 Genes in Non-Small Cell Lung Cancer.

OBJECTIVES: The programmed death ligand 1(PD-L1)/programmed cell death protein 1 (PD-1) pathway is one of the most important checkpoint pathways for mediating tumor-induced immune suppression through T-cell exhaustion. Recently, targeted therapies using monoclonal antibodies against components of this pathway have been shown to reduce tumor burden in patients with non-small cell lung cancer (NSCLC). However, the prognostic significance of PD-L1 expression is controversial and the precise mechanisms of PD-L1 gene activation in lung cancer have yet to be clarified. METHODS: We investigated copy number alterations (CNAs) in the PD-L1 gene by real-time PCR in 94 surgically resected lung cancer samples to find possible associations between PD-L1 CNA and lung cancer biology. Janus kinase 2 gene (JAK2) CNA and its influence on the PD-L1/PD-1 pathway were also assessed. RESULTS: Five samples were shown to have PD-L1 gene amplification, whereas 89 samples did not. The patients with PD-L1 amplification had worse prognoses than did those without PD-L1 amplification. Genetic amplification of the PD-L1 gene was correlated with JAK2 gene amplification. The lung cancer cell line HCC4006 was found to harbor both JAK2 and PD-L1 amplification. Flow cytometry analyses revealed the level of PD-L1 protein expression to be higher in HCC4006 cells than in other NSCLC cell lines. Expression of the PD-L1 protein was significantly reduced by the JAK2 inhibitor TG-101348 and the signal transducer and activator of transcription 3 (STAT-3) inhibitor BP-1-102, but not by the STAT1 inhibitor fludarabine. CONCLUSIONS: Our data suggest that expression of PD-L1 protein is upregulated by the simultaneous amplification of the PD-L1 and JAK2 genes through JAK-STAT signaling in NCSLC.

Prognostic Impact of EGFR Driver Mutations on Postoperative Disease Recurrence in Lung Adenocarcinoma.

AIM: The purpose of this study was to investigate the prognostic significance of epidermal growth factor receptor (EGFR) sensitizing mutations in patients with lung adenocarcinoma who underwent complete surgical resection. PATIENTS AND METHODS: We retrospectively reviewed the clinical records of 164 patients with lung adenocarcinoma who underwent surgery from 2003 to 2010. Seventy-four patients harbored EGFR mutations; two with exon 18 mutations, 27 with exon 19 mutations, and 45 with exon 21 mutations. RESULTS: There were more female patients and more never-/light smokers among patients with EGFR mutations than among patients without EGFR mutations. Patients with EGFR mutations had a trend for better disease-free survival and overall survival compared to patients without EGFR mutations (p=0.068 and p=0.049, respectively). Patients with exon 21 mutations had significantly better disease-free survival than patients with exon 19 mutations (p=0.027). CONCLUSION: Adenocarcinomas harboring EGFR exon 21 mutation were less malignant than adenocarcinomas harboring exon 19 mutation.

Applicability of Pulmonary Lobectomy in Treating Metastatic Lung Tumors.

PURPOSE: Although metastases to the lung from other organs are usually removed with limited lung resections (e.g., wedge resections or segmentectomies), pulmonary lobectomies are often required to remove whole pulmonary tumors. This study investigated the clinical applicability of pulmonary lobectomies to treat metastatic lung tumors. METHODS: We retrospectively reviewed clinical records of 143 consecutive patients with metastatic tumors in the lung who underwent surgery in our department, including data sets for 100 patients treated for their first metastatic lung tumors. RESULTS: Of the 100 patients, 23 received pulmonary lobectomies, 69 received wedge resections and eight received segmentectomies. Patients in the lobectomy group were more likely to be younger, have larger and/or multiple tumors, and to have tumors of musculoskeletal origin (sarcomas) than those who underwent segmentectomies or wedge resections (the limited resection group). The two groups did not significantly differ in survival (3-year survival rate; lobectomy vs limited resection: 75.2% vs 80.4%, P = 0.15), or post-operative morbidity, although the only post-operative morbidity was associated with post-operative prognosis in the lobectomy group. CONCLUSIONS: Pulmonary lobectomy is a safe and applicable surgical procedure for metastatic lung tumors when long survival is expected after the tumor resection.