Shinichiro Shimamatsu

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 Controlling Nutritional Status Score Is a Significant Independent Predictor of Poor Prognosis in Patients With Malignant Pleural Mesothelioma

Introduction Malignant pleural mesothelioma (MPM) is a devastating neoplasm; however, some patients exhibit a good response to chemotherapy or multidisciplinary therapy, including surgery and chemotherapy. It is therefore important to discover the factors that can be used to select patients who will benefit from such treatment. Although the Controlling Nutritional Status (CONUT) score has been used to predict the prognosis in other types of malignancy, its utility in patients with MPM is unknown. The aim of this study was to clarify the clinical significance of the CONUT in patients with MPM. Methods The data of 83 patients, who were treated with surgery, chemotherapy, or multidisciplinary therapy, were analyzed in the present study. A cut‐off CONUT score of 2 was used to classify all of the patients into low or high CONUT groups. Results Fifty‐two of the 83 patients were classified into the low CONUT group. A high CONUT score was significantly correlated with chemotherapy alone (P = .011). The high CONUT group had significantly poorer overall survival (OS) (P < .001) and disease‐ or progression‐free survival (DFS/PFS) (P < .001). The clinical stage and the CONUT score were found to be independent predictive factors for the OS: clinical stage, I/II and III/IV; P = .001 and CONUT score, ≥ 3 and ≤ 2; P = .011, respectively. The clinical stage and the CONUT score were also independent predictive factors for DFS/PFS: clinical stage, I/II and III/IV; P = .006 and CONUT score, ≥ 3 and ≤ 2; P = .013, respectively. Conclusions The CONUT score was an independent predictor of a poor prognosis in the patients with MPM. This score provides useful information for selecting patients who will benefit from the treatment. Micro‐Abstract The aim of this study was to clarify the clinical significance of the Controlling Nutritional Status (CONUT) in malignant pleural mesothelioma. The data of 83 patients were analyzed. The high CONUT group had significantly poorer overall survival (P < .001) and disease‐ or progression‐free survival (P < .001). The CONUT score provides useful information for selecting patients who will benefit from the treatment.

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.

Correlation between CXCR4/CXCR7/CXCL12 chemokine axis expression and prognosis in lymph-node-positive lung cancer patients

The CXCR4/CXCR7/CXCL12 chemokine axis plays important roles in the migration of tumor cells during cancer development by modulating site‐specific distant metastasis including to regional lymph nodes. We investigated the correlation of these chemokine expressions to prognosis in lymph‐node‐positive non‐small‐cell lung cancer (NSCLC) patients. A total of 140 surgically resected specimens of primary site (PS) and metastatic lymph nodes (MLN) of NSCLC involving hilar and/or mediastinal lymph nodes (N1‐2) were collected. CXCR4, CXCR7 and CXCL12 expressions were evaluated. Cox regression analysis was performed to determine whether these chemokines were independent prognostic factors in N1‐2 NSCLC. High expression of CXCR4 in PS and CXCL12 in MLN was associated with poor overall survival (OS) (P = .025 and .033, respectively). Significant correlations between CXCR4 expression in PS and CXCL12 expression in MLN were observed (P = .040). There was significant difference in OS between 2 groups according to expressions of CXCR4 in PS and CXCL12 in MLN (P = .0033). Expression of CXCL12 in MLN was identified as an independent prognostic factor (HR 1.79, 95% CI 1.08‐3.04, P = .023). CXCL12 in MLN was mainly expressed by tumor cells compared with stromal cells (56% vs 25%, respectively, P < .0001). CXCR4/CXCL12 may play roles in tumor progression in MLN and is associated with poor prognosis of lymph‐node‐positive NSCLC patients.

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.

How should we manage small focal pure ground-glass opacity nodules on high-resolution computed tomography? A single institute experience.

BACKGROUND Although the detection of pure ground-glass opacity (p-GGO) nodules on high-resolution chest computed tomography (HRCT) often implies a diagnosis of lung adenocarcinoma, the management of p-GGO nodules remains under discussion. OBJECTIVE To assess the correlation between the radiological and pathological diagnoses of small p-GGO on HRCT. PATIENTS AND METHODS This is a single-institution retrospective study. We analyzed 89 consecutive patients, including 33 patients with resected p-GGO nodule(s) equal or less than 20 mm in maximal diameter on axial images of HRCT. RESULTS Thirty-nine patients underwent locoregional treatment (Treatment group), including surgical resection in 33 and stereotactic body radiation therapy in six. The remaining 50 patients were observed (Observation group) using periodic chest HRCT. The median follow-up time was 30.4 (4.9-102.5) months in the Treatment group and 44.8 (0.4-1125.8) months in the Observation group. During the follow-up period, the p-GGO nodules increased in size in eight patients over a median of 20.6 (12.1-50.6) months, with increased attenuation in three patients over a median of 20.6 (12.1-50.6) months, and either decreased in size or disappeared in four patients over a median of 6.9 (2.0-11.2) months. Thirty-three patients with 47 nodules underwent surgical resection, including 41 adenocarcinomas, one neuroendocrine tumor, three cases of atypical adenomatous hyperplasia and two benign lesions. The frequency of invasive adenocarcinoma was higher among the larger p-GGO nodules. CONCLUSIONS Careful observation and decision making with respect to the timing of intervention in cases of p-GGO nodules are warranted.

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.

Surgical resection of a well-differentiated inflammatory liposarcoma of the middle mediastinum: a case report

Liposarcomas are the most common type of mesenchymal neoplasm in soft tissue sarcomas. Although they frequently develop at the lower limbs or retroperitoneum, cases arising from the mediastinum are rare. Furthermore, the incidence of the inflammatory subtype of well-differentiated liposarcoma is known to be low. We experienced a case of a middle mediastinal liposarcoma in a 68-year-old woman. The tumor, which was completely resected, was 92 mm in diameter. The tumor consisted of two different imaging components that showed different growth and which were diagnosed as the lipoma-like subtype and inflammatory subtype of well-differentiated liposarcoma. To the best of our knowledge, this is the first report of a well-differentiated inflammatory liposarcoma arising from the middle mediastinum.

A case of different EGFR mutations in surgically resected synchronous triple lung cancer

We describe a 77-year-old Japanese woman who presented with three nodule shadows in three different lobes of the right lung, without evidence of lymph node metastasis or distant metastasis. All three tumors were surgically resected. The pathological diagnosis was synchronous multiple primary lung cancer: pT2aN0M0, pStageIB. Based on a differing epidermal growth factor receptor (EGFR) mutation status, no lymph node metastasis, and no distant metastasis, the tumors were characterized as synchronous triple primary rather than intrapulmonary metastases. At eight months after surgery, a new lesion emerged in the right lower lobe. Given that the most advanced tumor had an EGFR del-19 mutation, the patient was orally administered afatinib. Since then, the treatment response of the patient has been assessed as stable disease (SD) for about two years. This is a very rare case of resected triple synchronous primary lung cancer on the same lung side in which the lesions all had a different EGFR mutation status, and this report highlights the clinical utility of surgical resection of multifocal lung nodules without lymph node metastasis or distant metastasis in order to optimize therapy for patients with known driver mutations.

A typical carcinoid tumor of the lung presenting with pure persistent ground-glass opacity on high-resolution computed tomography: a case report

Pure ground-glass opacity nodules (p-GGN) on high-resolution computed tomography (HRCT) generally have been considering typically associated with adenocarcinoma with less invasive nature. We herein reported a patient presenting focal p-GGN on middle lobe of the right lung who underwent surgical resection with its pathological diagnosis turned out to be typical carcinoid tumor.