Masaomi Yamane

Prognostic impact of cancer stem cell-related markers in non-small cell lung cancer patients treated with induction chemoradiotherapy

The expression of several cancer stem cell (CSC)-related markers has been confirmed in non-small cell lung cancer (NSCLC). The aim of this study was to clarify the clinical role of CSC-related markers in patients with NSCLC undergoing induction chemoradiotherapy (CRT). Fifty patients with clinically diagnosed N2 or N3 NSCLC who underwent induction CRT with docetaxel and cisplatin concurrently with thoracic radiation followed by surgery were examined in this study. The expressions of CSC related markers (CD133, ALDH1, ABCG2, and Bmi-1) were examined using immunohistochemical staining in surgically resected specimens. Among the 50 patients, 20 patients had no residual tumor cells in the resected specimen when examined pathologically; CSC-related marker expressions and their correlation to survival were evaluated in the other 30 patients. After a median follow-up period of 72 months, the 5-year overall survival rate of the patients with CD133-positive or ALDH1-positive specimens was significantly worse than that of the patients with both CD133-negative and ALDH1-negative expressions (44.9% vs. 90.0%, respectively; P = 0.042). In a multivariate analysis, CD133 and ALDH1 negativity (P = 0.047) and cN2-3 single station metastasis (P = 0.03) were significant independent prognostic factors for prolonged survival. The expressions of CSC-related markers after CRT were significantly correlated with a poor prognosis in patients with NSCLC. The development of therapeutic strategies including adjuvant therapy that take CSC-related marker positivity into consideration is likely to be a key factor in further improvements of the prognosis of patients undergoing trimodality therapy.

Molecular oncology of lung cancer.

Progress in genetic engineering has made it possible to elucidate the molecular biological abnormalities in lung cancer. Mutations in KRAS and P53 genes, loss of specific alleles, and DNA methylation of the tumor suppressor genes were the major abnormalities investigated between 1980 and the 2000s. In 2004, mutations in the epidermal growth factor receptor (EGFR) gene that cause oncogene addiction were discovered in non-small-cell lung cancers (NSCLCs), especially in adenocarcinomas. Because they are strongly associated with sensitivity to EGFR-tyrosine kinase inhibitors (EGFR-TKIs), a great deal of knowledge has been acquired in regard to both EGFR and other genes in the EGFR family and their downstream genes. Moreover, in 2007 the existence of the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene was discovered in NSCLC; and the same as EGFR-TKIs, ALK inhibitors are being found to be highly effective in lung cancers that have this translocation. These discoveries graphically illustrate that molecular biological findings are directly linked to the development of clinical oncology and to improving the survival rates of lung cancer patients. Here, we review the remarkable progress in molecular biological knowledge acquired thus far in regard to lung cancer, especially NSCLC, and the future possibilities.

Risk Factors for Recurrence and Unfavorable Prognosis in Patients with Stage I Non-small Cell Lung Cancer and a Tumor Diameter of 20 mm or Less

Background: The purpose of this study was to identify risk factors for disease recurrence and unfavorable prognosis after surgical resection for stage I non-small cell lung cancer in patients with tumor diameters of ≤20 mm. Methods: One hundred sixty-three patients who had pathologic stage I non-small cell lung cancer with tumor diameters ≤20 mm and who had undergone a lobectomy with mediastinal lymph node dissection were retrospectively reviewed. The relationships between clinicopathologic factors and clinical outcomes, including recurrence and survival, were then examined. The clinicopathologic factors examined in this study were age, sex, smoking status, preoperative serum carcinoembryonic antigen level, pathologic tumor size, histologic subtype, histologic grade, and visceral pleural invasion. Results: Among the clinicopathologic factors that were examined, the histologic grade of the carcinoma status was significantly related to a high risk of recurrence when analyzed using univariate (p = 0.01) and multivariate analyses (p = 0.049). Regarding survival, patients with poorly differentiated carcinomas showed a significantly unfavorable overall survival (p < 0.001), disease-specific survival (p = 0.003), and disease-free survival (p = 0.002) compared with patients with well-/moderately differentiated carcinomas according to univariate analyses. A Cox proportional hazards model indicated that a poorly differentiated carcinoma status was the only independent factor for an unfavorable overall survival (p = 0.02), disease-specific survival (p = 0.046), and disease-free survival (p = 0.04). Conclusions: Poor differentiation of tumor was the only risk factor for recurrence and an unfavorable prognosis for stage I non-small cell lung cancer patients with tumor diameters of ≤20 mm.

Less Maintenance Immunosuppression in Lung Transplantation Following Hematopoietic Stem Cell Transplantation From the Same Living Donor

Living‐donor lobar lung transplantation (LDLLT) is one of the final options for saving patients with pulmonary complications after hematopoietic stem cell transplantation (HSCT). We retrospectively investigated 19 patients who had undergone LDLLT after HSCT in Japan. Eight patients underwent LDLLT after HSCT in which one of the donors was the same living donor as in HSCT (SD group), while 11 received LDLLT from relatives who were not the HSCT donors (non‐SD group). In the SD group, three patients underwent single LDLLT. The 5‐year survival rate was 100% and 58% in the SD and non‐SD groups, respectively. In the SD group, postoperative immunosuppression was significantly lower than in the non‐SD group. Two patients died of infection and one died of post‐transplant lymphoproliferative disease (PTLD) in the non‐SD group, while only one patient died of PTLD 7 years after LDLLT in the SD group. Hematologic malignancy relapsed in two patients in the non‐SD group. For the three single LDLLTs in the SD group, immunosuppression was carefully tapered. In our study, LDLLT involving the same donor as for HSCT appeared to have advantages related to lower immunosuppression compared to LDLLT from relatives who were not the HSCT donors.

Sirolimus Ameliorated Post Lung Transplant Chylothorax in Lymphangioleiomyomatosis

We report a successful case of sirolimus treatment for chylous pleural and peritoneal effusions of lymphangioleiomyomatosis after lung transplantation. A 32-year-old woman underwent living donor lung transplantation. Persistent chylous pleural and peritoneal effusions were seen postoperatively. Pleurodesis by intrathoracic injection of OK-432, minomycin, and somatostatine analog failed to control chylous effusions. However, sirolimus treatment reduced the amount of chylous drainage and improved both chylous pleural and peritoneal effusions.

Suppression of Inflammatory Cytokines During Ex Vivo Lung Perfusion With an Adsorbent Membrane

BACKGROUND Lung grafts can be perfused ex vivo for 2 hours without edema formation; however, prolonged ex vivo lung perfusion (EVLP) eventually induces lung injury. This study evaluated the change in proinflammatory cytokines of the perfusate during EVLP and investigated the effect of cytokine removal using an adsorbent membrane. METHODS Porcine heart-lung blocks were harvested after electrically induced cardiac arrest and underwent 12-hour EVLP with an adsorbent membrane (membrane group: n = 5) and without an adsorbent membrane (control group: n = 6). RESULTS In the control group, both tumor necrosis factor-alpha and interleukin 8 levels were elevated in the perfusate 2 hours after perfusion. Although tumor necrosis factor-alpha and interleukin 8 levels were significantly lower in the membrane group than in the control group during the EVLP period, there was no significant difference in oxygenation, pulmonary vascular resistance, edema formation, or myeloperoxidase activity between the two groups. CONCLUSIONS Tumor necrosis factor-alpha and interleukin 8 levels of the perfusate were elevated during EVLP. Although adverse effects of these inflammatory cytokines were anticipated, removal of inflammatory cytokines by the adsorbent membrane did not improve lung function during prolonged EVLP. Factors other than the cytokines may play a major role in causing lung injury during EVLP. Further research is needed to investigate the real mechanism of lung graft injury during prolonged EVLP and to establish longer EVLP duration for graft treatment. This strategy could contribute to the salvage of potentially damaged lungs, especially from cardiac death donors, and to expansion of the donor pool.

Sirolimus Amelioration of Clinical Symptoms of Recurrent Lymphangioleiomyomatosis After Living-donor Lobar Lung Transplantation

In this study we report the case of a 28-year-old female patient with recurrent lymphangioleiomyomatosis (LAM) in the allografts after bilateral living-donor lobar lung transplantation. Although her post-operative course under immunosuppression with tacrolimus and prednisolone had been uneventful without rejection episodes, she had developed shortness of breath and a progressive chylous effusion with diffuse cystic changes in both lungs 5 years after transplantation. In spite of a diagnosis of having a recurrence of LAM based on radiologic findings and deteriorating pulmonary function, her clinical symptoms, which included dyspnea and chylothorax, were significantly improved after treatment with sirolimus. Although a beneficial effect of sirolimus in the treatment of LAM has not been definitively determined, this report may provide useful information for management of recurrent LAM after lung transplantation.

Experimental orthotopic lung transplantation model in rats with cold storage

This report describes a new experimental procedure, a rat unilateral, orthotopic lung transplantation with cold storage, and evaluates its relevancy and reliability to study the early events during cold ischemia/reperfusion (I/R) injury. This model, using the cuff technique, does not require extensive training and is relatively easy to be established. The model can induce reproducible degrees of pulmonary graft injury including impaired gas exchange, proinflammatory cytokine upregulation, or inflammatory infiltrates, depending on the preservation time. The results are consistent with the previous clinical evidence, thus suggesting that this model is a valid and reliable animal model of cold I/R injury.

Outcome of living-donor lobar lung transplantation using a single donor

OBJECTIVE Living-donor lobar lung transplantation usually requires 2 healthy donors who donate either a right or a left lower lobe; however, finding 2 healthy donors is difficult. Several case reports have been published on successful living-donor lobar lung transplantation using a single donor; however, little is known about its outcome. METHODS We retrospectively investigated 14 critically ill patients who had undergone single living-donor lobar lung transplantation at 3 lung transplant centers in Japan. There were 10 female and 4 male patients, including 10 children and 4 adults. Size matching was assessed by estimated graft forced vital capacity and 3-dimensional computed tomography volumetry. The diagnoses included complications of allogeneic hematopoietic stem cell transplantation (n = 6), pulmonary hypertension (n = 4), and others (n = 4). RESULTS At a mean follow-up of 45 months (range, 2-128), the 3- and 5-year survival rate was 70% and 56%, respectively. There were 4 early deaths, for a hospital mortality of 29%, with 1 additional death at 40 months. The main cause of early death was primary graft dysfunction, most likely related to size mismatching. The survival among these 14 patients was significantly worse than the survival in a group of 78 patients undergoing bilateral living-donor lobar lung transplantation during the same period (P = .044). CONCLUSIONS Single living-donor lobar lung transplantation provides acceptable results for sick patients who would die soon otherwise. However, bilateral living-donor lobar lung transplantation appears to be a better option if 2 living donors are found.

Living-Donor Lobar Lung Transplantation for Pulmonary Complications After Hematopoietic Stem Cell Transplantation

Background. The indication of lung transplantation for patients with pulmonary complications of hematopoietic stem cell transplantation (HSCT) remains controversial, and only few such cases have been reported. We reviewed our experiences regarding living-donor lobar lung transplantation (LDLLT) in patients with pulmonary complications of HSCT. Methods. We reviewed and assessed seven patients (age, 6–45 yr) who underwent LDLLT at Okayama University Hospital for pulmonary complications of HSCT (HSCT group). Their characteristics and postoperative results were compared with those of 41 LDLLT without HSCT patients (non-HSCT group). In the HSCT group, indications for LDLLT included bronchiolitis obliterans (n=6) and pulmonary fibrosis (n=1) that had developed after treatments involving HSCT. Preexisting hematologic diseases included acute lymphocyte leukemia (n=4), acute promyelocystic leukemia (n=1), myelodysplastic syndrome (n=1), and aplastic anemia (n=1). Results. In the HSCT group, two patients died due to infectious complications, whereas five are currently alive (an overall survival of 71.4%) without any recurrence of the hematologic diseases (mean follow-up period, 35.7 months). The mean of acute rejection episodes was 1.1 per patient in the HSCT group and 1.8 in the non-HSCT group. One of the seven HSCT (14.4%) and 10 non-HSCT (24.4%) patients have currently developed bronchiolitis obliterans syndrome. Conclusion. Our results showed that LDLLT for patients with respiratory failure because of pulmonary complications of HSCT could be an effective approach with less rejection episodes; however, it has a possibly higher risk of the development of infectious complications.