Kotaro Kameyama

The tumour–stromal interaction between intratumoral c-Met and stromal hepatocyte growth factor associated with tumour growth and prognosis in non-small-cell lung cancer patients

Immunohistochemical analyses of the effects of hepatocyte growth factor (HGF) and c-Met expression on tumour growth and angiogenesis were performed on 88 patients with non-small-cell lung cancers (NSCLCs). In all, 22 carcinomas (25.0%) were intratumoral HGF-positive, 14 carcinomas (15.9%) were stromal HGF-positive, and 36 carcinomas (40.9%) were intratumoral c-Met-positive. None of the carcinomas were stromal c-Met-positive. Examination of tumour growth revealed that the frequency of tumours with a high Ki-67 index was significantly greater for stromal HGF-positive tumours than for stromal HGF-negative tumours (P=0.0197). The frequency of tumours with a high Ki-67 index was also significantly greater for intratumoral c-Met-positive tumours than for intratumoral c-Met-negative tumours (P=0.0301). However, there was no significant difference in tumour vascularity with relation to intratumoral HGF status, stromal HGF status, and intratumoral c-Met status. The survival rate of patients with intratumoral c-Met-positive tumours was significantly lower than for patients with c-Met-negative tumours (P=0.0095). Furthermore, the survival rate of patients with both intratumoral c-Met-positive and stromal HGF-positive tumours was significantly lower than for patients with either positive tumours, and that of patients with both negative tumours (P=0.0183 and P=0.0011, respectively). A univariate analysis revealed that intratumoral c-Met expression was a significant prognostic factor of NSCLC patients (relative risk=2.642, P=0.0029). The present study demonstrates that tumour–stromal interaction between tumour cell-derived c-Met and stromal cell-derived HGF affects tumour growth and the prognosis of NSCLC patients.

Clinical application of biological markers for treatments of resectable non-small-cell lung cancers

We performed a clinical study to identify biological markers useful for the treatment of resectable non-small-cell lung cancers (NSCLCs). In all, 173 patients were studied. By immunohistochemistry, we evaluated the Ki-67 proliferation index, tumour vascularity, thymidylate synthase (TS), vascular endothelial growth factor (VEGF)-A, VEGF-C, and E (epithelial)-cadherin. Concerning the survival of NSCLC patients, tumour vascularity (P<0.01), VEGF-A status (P=0.03), VEGF-C status (P=0.03), and E-cadherin status (P=0.03) were significant prognostic factors in patients with stage I NSCLCs. The Ki-67 proliferation index (P=0.02) and TS status (P<0.01) were significant prognostic factors in patients with stage II–III NSCLCs. In patients with stage II–III NSCLCs, furthermore, the survival of UFT (a combination of tegafur and uracil)-treated patients with TS-negative tumours was significantly better than those of any other patients. Biological markers associated with tumour angiogenesis or metastasis are useful for the detection of aggressive tumours among early-stage NSCLCs. Postoperative chemotherapy might be necessary in such tumours even in stage I. In contrast, tumour proliferation rate and TS status are useful markers for identifying less aggressive tumours in locally advanced NSCLCs. Thymidylate synthase expression is also a useful marker to evaluate responsiveness of UFT-based chemotherapy for these tumours.

E-cadherin expression associated with differentiation and prognosis in patients with non–small cell lung cancer

BACKGROUND E-Cadherin plays a major role in maintaining the intercellular junctions in epithelial tissues. The reduction of E-cadherin expression in cancer cells may be associated with tumor differentiation, metastasis, and a poor prognosis. METHODS Immunohistochemistry for E-cadherin expression was performed on 109 tumors from patients with non-small cell lung cancer who underwent operations. RESULTS With respect to membranous immunostaining, 57 carcinomas were E-cadherin-positive, 39 carcinomas E-cadherin-reduced, and 13 carcinomas E-cadherin-negative. The percentage of poorly differentiated tumors in the impaired E-cadherin expression group was significantly higher than that in the E-cadherin-positive group (p = 0.005). Furthermore, the frequency of lymph node metastases in tumors with impaired E-cadherin expression was significantly higher than that in the E-cadherin-positive tumors (p = 0.011). A Cox regression analysis revealed that E-cadherin expression was a significant factor in the prediction of survival for patients with non-small cell lung cancer (p = 0.002). CONCLUSIONS E-Cadherin expression was associated with tumor differentiation, lymph node metastasis, and prognosis in patients with non-small cell lung cancer.

MRP-1/CD9 gene transduction downregulates Wnt signal pathways

Motility-related protein-1 (MRP-1/CD9) is a transmembrane glycoprotein that has been implicated in cell adhesion, motility, proliferation, and differentiation. It has a functional role as a tumor metastatic suppressor. During tumor progression, a reduction of MRP-1/CD9 gene expression results in tumor cells with a high metastatic potential. However, the mechanism of action of MRP-1/CD9 is still unclear. We studied changes of gene expression in relation to MRP-1/CD9 gene transduction into tumor cell lines, HT1080 and A549, using microarray assays and real-time PCR. Consequently, we have demonstrated that MRP-1/CD9 gene transduction can downregulate expression of several Wnt family genes, such as Wnt1, Wnt2b1 and Wnt5a, and their target genes, including WISP-1 (Wnt-1 induced secreted protein 1), WISP-3, c-Myc, vascular endothelial growth factor-A, and matrix metalloproteinase-26. Western blot analyses also showed that MRP-1/CD9 gene transduction downregulated expression of Wnt1 protein and its target proteins. In addition, a neutralizing anti-MRP-1/CD9 monoclonal antibody inhibited the downregulation of Wnt signal pathways in MRP-1/CD9-transfected cells. The present study has revealed that the MRP-1/CD9 signal is located upstream of the Wnt signal pathways. Therefore, MRP-1/CD9 could suppress cell transformation including epithelial to mesenchymal transition through downregulation of Wnt1, and might suppress tumor metastasis through downregulation of Wnt5a.

Evaluation of the new TNM staging system proposed by the International Association for the Study of Lung Cancer at a single institution

OBJECTIVE The seventh TNM Classification of Malignant Tumours will be published in 2009. The International Association for the Study of Lung Cancer has proposed a revision of the current pathologic staging system. We illustrated the effects of this new system and pointed out potential problems using a retrospective study of surgical cases of non-small cell lung cancer at our institution. METHODS Subjects were 1532 patients for whom current pathologic staging was possible. These data were migrated into the new staging system. The numbers of patients at various stages determined by using the current and new staging systems were, respectively, as follows: IA (n = 700, n = 700), IB (n = 338, n = 249), IIA (n = 49, n = 164), IIB (n = 129, n = 116), IIIA (n = 204, n = 234), IIIB (n = 77, n = 17), and IV (n = 35, n = 52). Prognoses were compared by using the current and the new systems. RESULTS By using the new staging system, 5-year survivals by T classifications were as follows: T1a, 82.6%; T1b, 73.3%; T2a, 63.5%; T2b, 50.1%; T3, 40.6%; and T4, 34.6%. There were significant differences between the new T1a and T1b (P = .0026), T1b and T2a (P = .0027), and T2a and T2b (P = .0062) classifications. In the current system 5-year survivals based on pathologic stages were as follows: IA, 84.8%; IB, 72.9%; IIA, 53.8%; IIB, 53.7%; IIIA, 31.8%; IIIB, 34.0%; and IV, 27.1%. There were significant differences between stages IA and IB (P < .0001) and stages IIB and IIIA (P = .0006). In the new system these were as follows: IA, 84.8%; IB, 75.2%; IIA, 62.4%; IIB, 52.1%; IIIA, 32.4%; IIIB, 15.2%; and IV, 30.6%. There were significant differences between stages IA and IB (P = .0004), IB and IIA (P = .0195), IIA and IIB (P = .0257), IIB and IIIA (P = .0040), and IIIA and IIIB (P = .0399). CONCLUSION Although the outcomes for stages IIIB and IV were reversed, the new pathologic staging system was considered valid based on our single-institution evaluation.

Neural-cadherin expression associated with angiogenesis in non-small-cell lung cancer patients.

An immunohistochemical analysis for E(epithelial)-cadherin and N(neural)-cadherin expression in relation to tumour angiogenesis was performed in 150 patients with nonsmall cell lung cancer (NSCLC). In all, 71 carcinomas (47.3%) were E-cadherin-negative. Epithelial-cadherin-negative tumours had lymph node metastases significantly more frequently than E-cadherin-positive tumours (P=0.0100). On the other hand, 46 carcinomas (30.7%) were N-cadherin-positive. Regarding tumour vascularity, there was no significant correlation between E-cadherin expression and tumour vascular. In contrast, the frequency of hypervascular tumours was significantly higher for N-cadherin-positive carcinomas than for N-cadherin-negative carcinomas (P=0.0373). Regarding prognosis, the 5-year survival rate of patients with E-cadherin-negative NSCLCs was significantly lower than that of patients with E-cadherin-positive NSCLCs (P=0.0146). In contrast, of the patients with large cell carcinomas, the 5-year survival rate of patients with N-cadherin-positive tumours was significantly lower than that of patients with N-cadherin-negative tumours (P=0.0013). A multivariate analysis demonstrated that E-cadherin status (P=0.0339) and tumour vascularity (P=0.0295) were significant indicators for survival. In conclusion, E-cadherin expression and tumour vascularity are significant prognostic factors of NSCLC patients. Furthermore, N-cadherin expression is associated with tumour angiogenesis, and its expression is one of prognostic factors of patients with large cell carcinomas. Thus, N-cadherin also might play a specific role in undifferentiated large cell carcinomas.

Comparative Study of Tc-99m MIBI and Tl-201 SPECT in Predicting Chemotherapeutic Response in Non–Small-Cell Lung Cancer

PURPOSE Tc-99m MIBI can be excluded from cytosol against its concentration gradient as a suitable transport substrate by P-glycoprotein. Tc-99m MIBI has also been shown to be more effective than TI-201 chloride for evaluating the response to chemotherapy in patients with small-cell lung cancer. The relation between Tc-99m MIBI accumulation by the tumor and its response to chemotherapy were evaluated in patients with non-small-cell lung cancer (NSCLC) and compared with the same parameters achieved using TI-201 chloride. METHODS Thirty-eight patients with NSCLC were examined before chemotherapy was begun. They were classified according to the results of a follow-up computed tomogram into two groups: responders were patients in whom there was a > or =50% decrease and nonresponders were patients in whom there was a <50% decrease in the sum of the product of the maximum perpendicular diameters of all measurable lesions. All patients underwent dual-isotope imaging with TI-201 chloride and Tc-99m MIBI just before chemotherapy. Regions of interest were placed over the tumor uptake (T) and contralateral normal lung tissue (N) areas on one coronal view with a clearly defined lesion, and the T:N ratio and retention index were calculated. RESULTS The delayed T:N ratio and retention index for Tc-99m MIBI in the responder group were significantly greater (P<0.05) than those in the nonresponder group. There was no significant correlation between the T:N ratio and retention index and tumor response using TI-201 chloride. CONCLUSION Tc-99m MIBI SPECT may be more effective than TI-201 chloride SPECT for evaluating the response to chemotherapy in patients with NSCLC.

Cartilage regeneration using slow release of bone morphogenetic protein-2 from a gelatin sponge to treat experimental canine tracheomalacia: A preliminary report

We investigated whether saber sheath-type tracheomalacia could be treated by the slow release of bone morphogenetic protein (BMP)-2 from a gelatin sponge. A 1 cm gap was made in the middle portion of each of 10 consecutive tracheal cartilage rings in the canine cervix (control group, n = 3), then a gelatin sponge containing 12 &mgr;g of BMP-2 solution was implanted in the gap (12 &mgr;g group, n = 3). In another group (120 &mgr;g + P group, n = 3), the implanted gelatin sponge contained 120 &mgr;g of BMP-2 solution, and the gap was covered with periosteum. All of the control dogs developed saber sheath-type tracheomalacia, whereas tracheomalacia was not observed in the 12 &mgr;g and 120 &mgr;g + P groups. In the 12 &mgr;g group, fibrous cartilage was observed at the ends of the cartilage stumps. In the 120 &mgr;g + P group, newly formed bone and cartilage were observed to form a bridge between the cartilage stumps. The regeneration of cartilage or bone induced by the slow release of BMP-2 from a gelatin sponge might be useful for treatment of tracheomalacia.

Surgical treatment for non-small cell lung cancer in octogenarians--the usefulness of video-assisted thoracic surgery.

The purpose of this study was to investigate whether surgical treatment for non-small cell lung cancer (NSCLC) confers a survival benefit in octogenarians, and whether video-assisted thoracic surgery (VATS) is effective in terms of postoperative morbidity, mortality, and quality of life (QOL). Among 1684 patients with primary NSCLC who underwent pathologically complete resection, 95 were octogenarians. Operation was performed by the VATS approach (VATS group, n=58) or the standard thoracotomy (ST group, n=37). Although postoperative cardiopulmonary complications occurred in 20 cases (21.1%), all were manageable. In the ST group cardiopulmonary complications occurred more frequently than in the VATS group (P=0.030). The overall 5-year survival rate of the 95 octogenarians, including deaths from all causes, was 54.4%. The overall 5-year survival rate of patients with stage IA disease was 65.2%. These outcome data were not significantly worse than those for patients aged 79 years or under (P=0.136). There was no significant difference in overall 5-year survival rates between the ST group and the VATS group (P=0.144). The VATS approach for pulmonary resection is recommended for octogenarians with NSCLC. Surgical resection is the optimal treatment for stage IA NSCLC, and therefore, advanced age is not a contraindication for curative resection.

Pulmonary embolism after lung resection: diagnosis and treatment

Pulmonary embolism after lung resection (PEALR) has a high mortality rate, and it is one of the most severe complications after lung resection. Early diagnosis and treatment are essential for PEALR. Here we present 3 cases of severe PEALR. In these cases, transthoracic Doppler echocardiography was useful for confirming the diagnosis of PEALR. Thrombolysis with recombinant tissue plasminogen activator (r-tPA) was used to treat the embolism, and these patients were subsequently discharged. Thus echocardiography may become a primary procedure to confirm the diagnosis of severe PEALR, and thrombolysis with second-generation r-tPA may be the preferred choice for treatment.