Shuhei Hakiri

Functional differences between wild-type and mutant-type BRCA1-associated protein 1 tumor suppressor against malignant mesothelioma cells

Malignant mesothelioma (MM) shows inactivation of the BRCA1‐associated protein 1 (BAP1) gene. In this study, we found BAP1 mutations in 5 (26%) of the 19 cell lines that we established from Japanese MM patients, and examined functional differences between the WT and mutant BAP1. First, we studied the subcellular localization of BAP1, demonstrating that the WT primarily resides in the nucleus and that the mutant BAP1 is found in the cytoplasm of the cells. Transduction of the WT BAP1 vector into MM cells with homozygous deletion at the BAP1 3′ side resulted in both inhibition of cell proliferation and anchorage‐independent cell growth, whereas BAP1 mutants of a missense or C‐terminal truncated form showed impaired growth inhibitory effects. Next, we studied how BAP1 is involved in MM cell survival after irradiation (IR), which causes DNA damage. After IR, we found that both WT and mutant BAP1 were similarly phosphorylated and phospho‐BAP1 localized mainly in the nucleus. Interestingly, BRCA1 proteins were decreased in the MM cells with BAP1 deletion, and transduction of the mutants as well as WT BAP1 increased BRCA1 proteins, suggesting that BAP1 may promote DNA repair partly through stabilizing BRCA1. Furthermore, using the MM cells with BAP1 deletion, we found that WT BAP1, and even a missense mutant, conferred a higher survival rate after IR compared to the control vector. Our results suggested that, whereas WT BAP1 suppresses MM cell proliferation and restores cell survival after IR damage, some mutant BAP1 may also moderately retain these functions.

Clinical evaluation of a new tumour–node–metastasis staging system for thymic malignancies proposed by the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee and the International Thymic Malignancy Interest Group

OBJECTIVES The tumour-node-metastasis classification has been widely used as a guide for estimating prognosis, and is the basis for treatment decisions in patients with malignant tumours. The International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee and the International Thymic Malignancy Interest Group have proposed a new staging system for thymic malignancies. However, its validity has not been fully established. In this study, we assessed the systems utilities and drawbacks. METHODS We reviewed 154 consecutive patients with thymic epithelial tumours who underwent complete resection at our institution, and compared their characteristics and outcomes when classified according to the proposed system with those when classified under the Masaoka-Koga system. RESULTS The proportion of patients with Stage I disease increased remarkably to 77.3% when using the proposed system because of the reclassification of Masaoka-Koga stages II and III diseases. Among 69 patients with Type A, AB or B1 thymoma, 68 tumours (98%) were reclassified as Stage I disease. Moreover, the proportion of Stage III and IV tumours increased in concordance with Types B2, B3 thymomas and thymic carcinoma. Under the proposed new system, the recurrence-free survival rates showed significant deterioration with increasing stage, while the overall survival curves did not. CONCLUSIONS The newly proposed classification for thymic malignancies does not serve as a prognostic prediction model for overall survival but served as a significant imbalance of stage distribution in our cohort. However, it appears to be beneficial, especially in clinical settings and recurrence-free survival analysis.

Marginal pulmonary function is associated with poor short- and long-term outcomes in lung cancer surgery

ABSTRACT We sought to determine the short- and long-term prognoses among ‘marginal-risk’ non-small cell lung cancer patients who have a predicted postoperative- (ppo) forced expiratory volume in the first second (FEV1) of 30–60% and/or a ppo-diffusing capacity of the lung for carbon monoxide (DLCO) of 30–60%. The present study included 73 ‘marginal-risk’ and 318 ‘normal-risk’ patients who underwent anatomical resection for clinical stage I lung cancer between 2008 and 2012. The rates of postoperative morbidity, prolonged hospital stay, and overall survival were assessed. Postoperative morbidity occurred in 35 (48%) ‘marginal-risk’ patients and 66 (21%) ‘normal-risk’ patients, and 17 (23%) ‘marginal-risk’ patients and 20 (6%) ‘normal-risk’ patients required a prolonged hospital stay. The three- and five-year survival rates were 79% and 64% in the ‘marginal-risk’ patients and 93% and 87% in the ‘normal-risk’ patients, respectively. A ‘marginal-risk’ status was a significant factor in the prediction of postoperative morbidity (odds ratio [OR] 2.97, p < 0.001), the rate of prolonged hospital stay (OR 3.83, p < 0.001), and overall survival (hazard ratio 2.07, p = 0.028). In conclusion, ‘Marginal-risk’ patients, who are assessed based on ppo-values, comprise a subgroup of patients with poorer short- and long-term postoperative outcomes.

The diffusing capacity of the lung for carbon monoxide is associated with the histopathological aggressiveness of lung adenocarcinoma

OBJECTIVES The diffusing capacity of the lung for carbon monoxide (DLCO) is an indicator of lung damage. We sought to determine whether DLCO is associated with the aggressiveness of lung adenocarcinoma using histopathological indexes, such as tumour differentiation, scar grade, nuclear atypia and the mitotic index. METHODS Fifty-seven patients with low DLCO (≤80% of predicted) and 466 patients with normal DLCO (>80% of predicted) who underwent R0 resection of lung adenocarcinoma between 2005 and 2012 were retrospectively reviewed. The relationships between the DLCO status and each histopathological index as well as the overall survival were evaluated. RESULTS Low DLCO had significant relationships with moderate/poor differentiation (79% vs 57% [low DLCO vs normal DLCO]), scar grade 3/4 (37% vs 18%), nuclear atypia 3 (65% vs 30%) and the mitotic index 3 (26% vs 8%). After adjusting for the age, sex, forced expiratory volume in 1 s, smoking status and tumour size, a low DLCO still showed a significant correlation with the histopathological indexes. These histopathological indexes were all significant factors for the overall survival on log-rank tests. In a multivariable Cox regression analysis with 13 clinicopathological variables, moderate/poor differentiation and nuclear atypia Grade 3 were significant histopathological factors for the overall survival (hazard ratios: 2.16 and 1.84; 95% confidence intervals: 1.10-4.51 and 1.06-3.21; P = 0.024 and 0.029, respectively). CONCLUSIONS Our findings regarding the relationship between DLCO and the histopathological indexes of lung adenocarcinoma suggest that lung damage may be associated with carcinogenesis and progression.

The Role of 18F-fluorodeoxyglucose Positron Emission Tomography-Computed Tomography for Predicting Pathologic Response After Induction Therapy for Thymic Epithelial Tumors

BackgroundWe investigated the role of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) in predicting the effect of induction therapy in patients with thymic epithelial tumors.MethodsFourteen patients with thymic epithelial tumors who underwent PET-CT before and after induction therapy were retrospectively analyzed. The relationship between the change in the maximum standardized uptake value (SUVmax) in PET-CT, the response evaluation criteria in solid tumors and the pathologic response (Ef0, no necrosis of tumor cells; Ef1, some necrosis of tumor cells with more than one-third of viable tumor cells; Ef2, less than one-third of tumor cells were viable; and Ef3, no tumor cells were viable) was analyzed.ResultsThe study cohort consisted of 5 males and 9 females. Nine of the patients had thymoma, and 5 had thymic carcinoma. The induction therapy included chemotherapy in 9 cases, chemoradiation therapy in 4 cases and radiation therapy in 1 case. Among the 8 patients with a pathologic response of Ef0/1, 5 were clinically evaluated as having stable disease (SD), while 3 were found to have had a partial response (PR). The SUVmax was elevated in 2 cases, unchanged in 1 and decreased in 5. On the other hand, 3 of the 6 patients with a pathologic response of Ef2, 3 were classified as having SD, while the other 3 had a PR. The SUVmax decreased in all of the patients.ConclusionsIn comparison with CT, PET-CT seems to be useful for predicting the pathologic response to induction therapy in patients with thymic epithelial tumors.

Metachronous Germ Cell Tumors of the Mediastinum

We report a rare case of mediastinal nonseminomatous germ cell tumor arising after 2 complete resections of mediastinal mature teratomas 18 and 10 years prior. After three cycles of chemotherapy for the mediastinal nonseminomatous germ cell tumor, the serum α-fetoprotein and β-human chorionic gonadotropin levels were normalized. However, chest radiography revealed that the mediastinal tumor had remarkably increased in size, and thus growing teratoma syndrome was diagnosed. The patient underwent urgent resection of the tumor, and a pathologic examination showed an encapsulated mature teratoma without any malignant viable cells. The patient was well without disease 54 months after the third operation.