Tomohiko Iida

Regulation of Cell Surface Expression of CTLA-4 by Secretion of CTLA-4-Containing Lysosomes Upon Activation of CD4+ T Cells

CTLA-4 is expressed on the surface of activated T cells and negatively regulates T cell activation. Because a low-level expression of CTLA-4 on the cell surface is sufficient to induce negative signals in T cells, the surface expression of CTLA-4 is strictly regulated. We previously demonstrated that the association of CTLA-4 with the clathrin-associated adaptor complex AP-2 induces internalization of CTLA-4 and keeps the surface expression low. However, the mechanism to induce high expression on the cell surface upon stimulation has not yet been clarified. To address this, we investigated the intracellular dynamics of CTLA-4 by analyzing its localization and trafficking in wild-type and mutant CTLA-4-transfected Th1 clones. CTLA-4 is accumulated in intracellular granules, which we identified as lysosomes. CTLA-4 is degraded in lysosomes in a short period, and the degradation process may serve as one of the mechanisms to regulate CTLA-4 expression. Upon TCR stimulation, CTLA-4-containing lysosomes are secreted as proven by the secretion of cathepsin D and β-hexosaminidase in parallel with the increase of surface expression of CTLA-4 and lysosomal glycoprotein 85, a lysosomal marker. These results suggest that the cell surface expression of CTLA-4 is up-regulated upon stimulation by utilizing a mechanism of secretory lysosomes in CD4+T cells.

Cytokine-independent Jak3 Activation upon T Cell Receptor (TCR) Stimulation through Direct Association of Jak3 and the TCR Complex

Jak3 is responsible for growth signals by various cytokines such as interleukin (IL)-2, IL-4, and IL-7 through association with the common γ chain (γc) in lymphocytes. We found that T cells from Jak3-deficient mice exhibit impairment of not only cytokine signaling but also early activation signals and that Jak3 is phosphorylated upon T cell receptor (TCR) stimulation. TCR-mediated phosphorylation of Jak3 is independent of IL-2 receptor/γc but is dependent on Lck and ZAP-70. Jak3 was found to be assembled with the TCR complex, particularly through direct association with CD3ζ via its JH4 region, which is a different region from that for γc association. These results suggest that Jak3 plays a role not only in cell growth but also in T cell activation and represents cross-talk of a signaling molecule between TCR and growth signals.

Spontaneous regression of bone metastasis from renal cell carcinoma; A case report

BackgroundSpontaneous regression of metastatic renal cell carcinoma is rarely observed.Case presentationMetastatic renal cell carcinoma was identified in a 70-year-old male using computed tomography-guided percutaneous needle biopsy. Two months after the diagnosis, a partial resection of the sternal bone was performed. Pathological examination revealed granulated tissue with bleeding and necrosis but no carcinogenic cells.ConclusionWe report a pathologically identified case in which a sternal bone metastasis that was noticed two years after radical nephrectomy regressed completely and spontaneously.

Surgical intervention for non-small-cell lung cancer patients with pleural carcinomatosis: Results from the Japanese lung cancer registry in 2004

Introduction: A subset of non–small-cell lung cancer (NSCLC) patients with malignant pleural effusion and/or malignant pleural nodules is now classified as stage IV and is generally considered a contraindication to surgery. However, several reports have demonstrated that the prognosis of patients with pleural carcinomatosis first detected at thoracotomy is relatively favorable. The aim of this study was to describe the results of surgical intervention in NSCLC patients with pleural carcinomatosis in Japan. Methods: In 2010, the Japanese Joint Committee of Lung Cancer Registry conducted a nationwide registration of lung cancer patients who underwent surgery in 2004. Using this database, we performed a retrospective study focused on pleural carcinomatosis. We examined the clinicopathological features, the current status of therapy, and surgical outcomes in patients with pleural carcinomatosis. Results: Among the 11,420 registered NSCLC patients, 329 (2.9%) patients had pleural carcinomatosis. The median survival time and 5-year survival rate of 313 patients without other metastatic disease were 34.0 months and 29.3%, respectively. Primary tumor resection was performed in 256 (81.8%) patients, and macroscopic complete resection was achieved in 152 (48.6%) patients, with 5-year survival rates of 33.1% and 37.1%, respectively. Multivariate analysis revealed that Eastern Cooperative Oncology Group performance status (p < 0.001), best stage nodal status (p = 0.002), and the presence or absence of gross residual tumor (p = 0.013) were independent predictors of survival. Conclusion: In our surgical registry for NSCLC, patients with pleural carcinomatosis accounted for 2.9%, and macroscopic complete resection for them was associated with better survival.

Changes in diagnostic strategies for hilar-type castleman’s disease: Report of two cases

Castleman’s disease (CD) is rare and difficult to diagnose preoperatively. We report two similar cases of hyaline vascular type CD diagnosed preoperatively using different modalities. In the first case, a biopsy specimen taken during diagnostic thoracoscopy revealed lymphatic structure suggestive of CD. In the second case, endobronchial ultrasound-guided transbronchial needle aspiration enabled sampling of histological cores for histological diagnosis. In both cases, the final diagnosis was established by surgical resection.

Recent improvement of survival prognosis after pulmonary metastasectomy and advanced chemotherapy for patients with colorectal cancer

OBJECTIVES New chemotherapeutic regimens (i.e. FOLFOX or FOLFIRI with molecular targeted drugs) have improved the prognosis of patients with unresectable or recurrent colorectal cancer. To estimate the prognostic impact of these chemotherapies, we examined the chronological change in survival rates of patients who underwent pulmonary metastasectomy for colorectal cancer metastasis. METHODS Using a large database, we conducted a retrospective, multi-institutional study to collect data of 1223 eligible patients from 26 institutions who had undergone pulmonary metastasectomy with curative intent. We divided those patients who underwent metastasectomy in different time periods according to the major trend of chemotherapy regimens for recurrent colorectal cancer: those who underwent metastasectomy between 1990 and 1999 ( N  = 451, Group A), between 2000 and 2004 ( N  = 433, Group B) or between 2005 and 2007 ( N  = 339, Group C). RESULTS Five-year overall survival rates after metastasectomy were 45% in Group A, 56% in Group B and 66% in Group C ( P  < 0.0001) whereas rates after metastasectomy plus chemotherapy were 32% in Group A, 47% in Group B and 70% in Group C ( P  = 0.0059). The prognosis of patients who underwent both metastasectomy and chemotherapy in Group C was significantly better than that of the other two groups. Overall survival of patients who did not receive chemotherapy was not significantly different between the groups. CONCLUSION Survival rates of patients after pulmonary metastasectomy for colorectal cancer metastasis who underwent chemotherapy have increased over the years. It implies that newer chemotherapy regimens might have had a positive impact on these patients.

What factors determine the survival of patients with an acute exacerbation of interstitial lung disease after lung cancer resection

PurposesAcute exacerbation of interstitial pneumonia (AEIP) is a leading cause of death after lung cancer resection in patients with interstitial lung disease.MethodsWe retrospectively analyzed 1763 patients with non-small cell lung cancer with a clinical diagnosis of interstitial lung disease (ILD) who underwent lung cancer resection between 2000 and 2009 at 61 hospitals in Japan. AEIP occurred in 164 of 1763 (9.3%) patients with a mortality rate of 43.9% (72/164). Univariate and multivariate analyses were carried out to identify possible risk factors of fatal AEIP. We then analyzed the 164 patients who developed postoperative AEIP and identified the preoperative and postoperative risk factors.ResultsA multivariate regression analysis identified that the sex, percent vital capacity, neoadjuvant radiation, preoperative history of AEIP, preoperative use of steroids, usual interstitial pneumonia pattern on CT, and surgical procedures were independent preoperative risk factors for death due to AEIP. ILD patients with emphysema somehow showed a lower risk of fatal AEIP than those without emphysema in this study.ConclusionsThis study revealed eight risk factors for fatal AEIP.

Chylopericardium following thoracoscopic resection of a mediastinal cyst: A case report

Highlights • A resection of a thoracic duct cyst in the right upper mediastinum resulted in post-operative chylopericardium.• Chylous complications in thoracic duct cysts are frequent when intraoperative diagnosis is not reached, such as in cases with anomalous cyst location.• A review on post-surgical chylopericardium is performed, which will provide information for future management of this rare complication.

Thoracoscopic surgery versus open surgery for lung metastases of colorectal cancer: a multi-institutional retrospective analysis using propensity score adjustment†

OBJECTIVES Thoracoscopic surgery for lung metastasectomy remains controversial. The study aimed at determining the efficacy of thoracoscopic surgery for lung metastasectomy. METHODS This was a multi-institutional, retrospective study that included 1047 patients who underwent lung metastasectomy for colorectal cancer between 1999 and 2014. Prognostic factors of overall survival were compared between the thoracoscopic and open thoracotomy groups using the multivariate Cox proportional hazard model. The propensity score, calculated using the preoperative covariates, included the era of lung surgery as a covariate. A stepwise backward elimination method, with a probability level of 0.15, was used to select the most powerful sets of outcome predictors. The difference between the radiological tumour number and the resected tumour number (delta_num) was also evaluated. RESULTS The c -statistics and the P -value of the Hosmer-Lemeshow Chi-square of the propensity score model were 0.7149 and 0.1579, respectively. After adjusting for the propensity score, the thoracoscopy group had a better survival rate than the open group (stratified log-rank test: P  = 0.0353). After adjusting for the propensity score, the most powerful predictive model for overall survival was that which combined thoracoscopy [hazard ratio (HR): 0.468, 95% CI: 0.262-0.838, P  = 0.011] and anatomical resection (HR: 1.49, 95% CI: 1.134-1.953, P  = 0.004). Before adjusting for the propensity score, the delta_num was significantly greater in the open group than in the thoracoscopy group (thoracoscopy: 0.06, open: 0.33, P  = 0.001); however, after adjustment, there was no difference in the delta_num (thoracoscopy: 0.04, open: 0.19, P  = 0.114). CONCLUSIONS Thoracoscopic metastasectomy showed better overall survival than the open approach in this analysis. The thoracoscopic approach may be an acceptable option for resection of pulmonary metastases in terms of tumour identification and survival outcome in the current era.