Hirokazu Kitahara

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.

The prognostic impact of the amount of tobacco smoking in non-small cell lung cancer—Differences between adenocarcinoma and squamous cell carcinoma

BACKGROUNDS The purpose of this study was to investigate the relationship between the level of tobacco smoking and the clinicopathological features of non-small cell lung cancer (NSCLC) patients, individually for adenocarcinoma (Ad) and squamous cell carcinoma (Sq). PATIENTS AND METHODS We retrospectively reviewed the clinical records of 1825 consecutive lung cancer patients who underwent surgery in our department. Among these, the data sets of 750 Ad patients and 364 Sq patients who received lobectomy or more extensive resection were available. RESULTS In Ad patients, those who had never smoked (never-smokers) (n=309) were more likely to be female, to have less advanced stage tumors, and to have a significantly better prognosis than those who had ever smoked (ever-smokers) (n=441) (5-year OS: never-smokers, 67.9%; ever-smokers, 53.7%, p<0.0001). In Sq patients, the never-smokers (n=15) were more likely to be female than the ever-smokers (n=349). Among ever-smokers, the light-smokers (PY≤30; n=56) were associated with more female patients, more advanced stage tumors, and significantly worse prognoses than were the heavy smokers (PY>30; n=292) (p=0.0003). The multivariate survival analysis showed that light smoking was related to a worse prognosis compared with heavy smoking (HR=2.06, 95% CI 1.43-2.98, p=0.0001). CONCLUSIONS The never-smokers had a significantly better prognosis than ever-smokers among Ad patients, whereas the light-smokers had a significantly worse prognosis than heavy smokers among Sq patients. There may be factors other than tobacco carcinogens that influence the development of Sq in never and/or light smokers.

Solitary pulmonary metastasis from malignant melanoma of the bulbar conjunctiva presenting as a pulmonary ground glass nodule: Report of a case.

We herein report a case of solitary pulmonary metastasis from malignant melanoma that presented as a pulmonary ground glass nodule. A 57‐year‐old man who had undergone resection of a malignant melanoma of the right bulbar conjunctiva at the age of 51 was referred to our hospital for management of ground glass opacity in his left lung. Because radiological examination suggested the nodule was an adenocarcinoma in situ, computed tomography (CT) follow‐up was planned. CT examination performed nine months later showed that the nodule had grown from 6 mm to 8 mm. Moreover, CT performed one and a half years after first detection revealed that the nodule had grown up to 10 mm. The patient, therefore, underwent partial resection of the lung for diagnosis and treatment. Pathological examination of the resected specimen revealed atypical cells with melanin granules proliferating in a lepidic‐like fashion. The cells were positive on S‐100 staining, indicating a pulmonary metastasis from malignant melanoma. Thus, metastatic tumors from malignant melanoma can present as ground glass opacities.

Surgical results of resectable small cell lung cancer.

The standard of care for patients with small cell lung cancer (SCLC) is chemotherapy and radiotherapy, even for patients with limited disease. To define the role of surgical resection in patients with limited SCLC, we investigated the outcomes of patients diagnosed with limited‐stage disease (LD) SCLC.

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.

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.

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.