[show abstract][hide abstract] ABSTRACT: Epidermal growth factor receptor (EGFR) mutations are a potential predictor of the effectiveness of EGFR inhibitors for the treatment of lung cancer. Although EGFR mutations were reported to occur with high frequency in nonsmoking Japanese adenocarcinoma patients, the exact nature has not been fully elucidated. We examined EGFR gene mutations within exons 18-21 and their correlations to clinico-pathological factors and other genetic alterations in tumour specimens from 154 patients who underwent resection for lung cancer at Kyoto University Hospital. Epidermal growth factor receptor mutations were observed in 60 tumours (39.0%), all of which were adenocarcinoma. Among the patients with adenocarcinoma (n=108), EGFR mutations were more frequently observed in nonsmokers than former smokers or current smokers (83.0, 50.0, 15.2%, respectively), in women than men (76.3 vs 34.0%), in tumours with bronchio-alveolar component than those without bronchio-alveolar component (78.9 vs 42.9%), and in well or moderately differentiated tumours than poorly differentiated tumours (72.0, 64.4, 34.2%). No tumours with EGFR mutations had any K-ras codon 12 mutations, which were well-known smoking-related gene mutations. In conclusion, adenocarcinomas with EGFR mutation had a distinctive clinico-pathological feature unrelated to smoking. Epidermal growth factor receptor mutations may play a key role in the development of smoking-independent adenocarcinoma.
British Journal of Cancer 09/2005; 93(3):355-63. · 5.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: UFT, an oral 5-fluorouracil derivative, is the only drug that is effective as a postoperative adjuvant therapy for non-small cell lung cancer (NSCLC) [ ], but the mechanism of the action remains unclear. We examined whether UFT and/or its metabolite, gamma-hydroxybutyric acid (GHB) inhibits lung metastases in a mouse model.
Lewis lung carcinoma cells were implanted into the foot pads of C57 BL/6 mice, and mice were treated with UFT or GHB.
Both the mean number of metastatic nodules and the mean lung weight for UFT-treated mice (11.4 and 192.1 mg, respectively) were significantly lower than those for saline-treated mice (41.5 and 415.0 mg, respectively) (p < 0.001 for both). UFT did not inhibit tumor growth at the primary sites (foot pads). No significant body weight loss was documented in UFT-treated mice. GHB did not inhibit development of lung metastases even when a higher dose was used.
UFT inhibits development of lung metastases without any toxicity in mouse model, which may explain the efficacy of postoperative administration of UFT for resected NSCLC.
The Thoracic and Cardiovascular Surgeon 04/2005; 53(2):118-21. · 0.93 Impact Factor
[show abstract][hide abstract] ABSTRACT: To examine the efficacy of UFT, an oral 5-fluorouracil derivative agent, as post-operative adjuvant therapy for pathologic (p-) stage I non-small-cell lung cancer (NSCLC), because a previous randomized study had suggested it was efficacious for early-stage NSCLC patients.
Patients with completely resected p-stage I, adenocarcinoma or squamous cell carcinoma were eligible. A total of 332 patients were randomized to the surgery-alone group (control group) and the treatment group (UFT 400 mg/m(2) for 1 year after surgery, UFT group) after stratification by the histologic types.
For all patients, the 5- and 8-year survival rates for the UFT group were 82.2% and 73.0%, and those for the control group were 75.9% and 61.2%, respectively; no statistically significant improvement of survival was achieved by UFT administration (P=0.105). For Ad patients, the 5- and 8-year survival rates of the UFT group (n=120) were 85.2% and 79.5%, respectively, which seemed better than those of the control group (n=121) (79.2% and 64.0%, respectively; P=0.081). For squamous cell carcinoma patients, there was also no difference in survival between the control group (n=48) and the UFT group (n=43) (P=0.762). For all pT1 patients, the 5- and 8-year survival rates of the UFT group were 83.6% and 82.1%, respectively, significantly better than those of the control group (77.9% and 57.6%, respectively, P=0.036); UFT was not significantly effective for pT2 patients. For pT1 adenocarcinoma patients, UFT administration markedly improved the survival (P=0.011).
Post-operative UFT administration did not significantly improve post-operative survival of p-stage I NSCLC patients. Subset analyses suggested that UFT might be effective in pT1N0M0 adenocarcinoma patients.
Annals of Oncology 02/2005; 16(1):75-80. · 7.38 Impact Factor
[show abstract][hide abstract] ABSTRACT: Recent experimental studies have revealed that tumour-associated stromal macrophages as well as tumour cells express vascular endothelial growth factor C (VEGF-C), which plays important roles in lymphangiogenesis, which is a critical factor in the progression of many malignant tumours including non-small-cell lung cancer (NSCLC). However, no clinical study on VEGF-C expression in both stromal macrophages and tumour cells has been reported, and we conducted the present study to address the issue in resected NSCLC. A total of 206 patients with completely resected pathologic stage I-IIIA NSCLC were retrospectively reviewed. Expression of VEGF-C in primary lung tumour was assessed immunohistochemically. Expression of VEGF-C in tumour cells was high in 125 patients (60.7%), and that in stromal macrophages was positive in 136 patients (71.2%). The status of VEGF-C in tumour cells or in stromal macrophages was not correlated with nodal status or angiogenesis. The 5-year survival rate of high tumoral VEGF-C patients (60.7%) was significantly lower than that of low tumoral VEGF-C patients (39.3%) (P=0.046), and a multivariate analysis confirmed that tumoral VEGF-C status was a significant and independent prognostic factor. Moreover, tumour showing high VEGF-A and VEGF-C expression in tumour cells showed the poorest prognosis (5-year survival rate, 45.1%). The status of VEGF-C in stromal macrophages was not correlated with the prognosis. In conclusion, tumoral VEGF-C status, not stromal VEGF-C status, was a significant prognostic factor in resected NSCLC.
British Journal of Cancer 09/2004; 91(3):498-503. · 5.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: The prognosis in cases of advanced lung cancer with poor performance status is poor. We report here a patient with advanced non-small cell lung cancer of performance status 3 who had severe cancer-induced pain, which was not controlable with morphine and radiation therapy. The cancer was successfully treated by oral administration of gefitinib (250 mg/day) without serious adverse effects of worsening of quality of life. Not only was the tumor controlled but rapid relief of severe cancer-induced pain was achieved.
Gan to kagaku ryoho. Cancer & chemotherapy 03/2004; 31(2):223-6.
[show abstract][hide abstract] ABSTRACT: Significant factors in the prognosis of p53 status in non-small cell lung cancer (NSCLC) remain controversial; some clinical studies have documented that p53 abnormality is a significant factor in predicting poor prognosis, and others failed. In the present study, we examined whether or not adjuvant therapy may influence the prognostic significance.
217 patients with pathologic stage I disease were reviewed. As postoperative adjuvant therapy, UFT, an oral 5-fluorouracil derivative, was administered to 73 patients; p53 status was determined immunohistochemically.
The 5-year survival rate for tumor with aberrant p53 expression was 66.4 %--significantly lower than that for tumor without aberrant p53 expression (79.7%, p = 0.023). The prognostic significance of p53 status was enhanced in patients who received UFT; 5-year survival rates for tumor with and without aberrant p53 expression were 68.8 and 94.7%, respectively (p = 0.002). In patients who did not receive UFT, the difference did not reach statistical significance (5-year survival rates: 65.5 and 71.5%, respectively; p = 0.267).
This study demonstrates that postoperative survival is improved by UFT administration in patients with normal p53 function, but not in those without normal p53 function.
The Thoracic and Cardiovascular Surgeon 01/2003; 50(6):355-9. · 0.93 Impact Factor
[show abstract][hide abstract] ABSTRACT: To improve the postoperative results of limited resection for small lung cancer, we have developed a new operative method, pulmonary artery-guided segmentectomy. This resection begins with identification of the pulmonary arterial branches involved in the tumor, then the pulmonary tissue is divided along the pulmonary arteries (i.e. guided by pulmonary arteries) from the hilum toward the periphery by electrocautery. The advantages of this method include the facilitation of securing adequate margin from the tumor, and the feasibility of intralobar lymph node dissection during operation. To examine the efficacy of the new method of segmental resection, we retrospectively reviewed 74 cases of T1N0M0 disease who underwent the pulmonary artery-guided segmentectomy.
From 1993 to 2000, 74 patients with pathological T1N0M0 lung cancer were treated by the pulmonary artery-guided segmentectomy. Forty-one patients (55.4%) who underwent the segmentectomy had been considered suitable candidates for lobectomy (intentional resection group). The other 33 patients (44.6%) were considered poor candidates for lobectomy because of poor cardiopulmonary reserve (compromised resection group).
The overall survival rate at 5 years was 82.0%. The 5-year survivals in the intentional and the compromised resection groups were 81.6 and 77.6%, respectively, and no significant differences were detected between the groups. According to tumor size, the 5-year survival rate for patients with tumors of 20 mm or smaller (92.9%, n=53) was higher than that for the patients with tumors of 21-30 mm (63.0%, n=21), but the difference did not reach statistical significance. Median follow-up time of 27.0 months revealed eight locoregional recurrences and four deaths due to lung cancer. Sixty-three patients (85.1%) are alive with no evidence of disease, and six patients (8.1%) are alive with recurrent disease. Locoregional recurrences occurred in one of 53 patients (1.9%) with tumors 20 mm or smaller and in seven of 21 patients (33.3%) with tumors 21-30 mm, the difference being statistically significant (P<0.01).
Our intermediate results demonstrated that the new pulmonary artery-guided segmentectomy could be an alternative method for selected patients with small lung cancer, particularly with tumors 20 mm or smaller in diameter.
European Journal of Cardio-Thoracic Surgery 05/2002; 21(5):894-9; discussion 900. · 2.67 Impact Factor
[show abstract][hide abstract] ABSTRACT: Angiogenesis is an essential process in the progression of malignant tumors. Whereas pan-endothelial markers, such as CD34, are generally used in evaluation of angiogenesis, pan-endothelial antibodies react with not only "newly forming" vessels but also normal vessels just trapped within tumor tissues. It has been recently reported that anti-CD105 antibody preferentially reacts with "activated" endothelial cells in angiogenic tissues. Thus, the superiority of anti-CD105 monoclonal antibody (mAb) in evaluation of angiogenesis of non-small cell lung cancer (NSCLC) was assessed.
A total of 236 patients with resected NSCLC were retrospectively reviewed. Intratumoral microvessel density (IMVD) was determined with an anti-CD34 mAb (CD34-IMVD) and with an anti-CD105 mAb (CD105-IMVD).
The mean CD34-IMVD and CD105-IMVD were 179.9 and 41.6, respectively. Whereas CD34-IMVD was significantly correlated with the expression of vascular endothelial growth factor (P = 0.003), CD105-IMVD was more closely correlated with vascular endothelial growth factor expression (P < 0.001). The 5-year survival rate of the lower CD105-IMVD patients was 74.9%, significantly higher than that of the higher CD105-IMD patients (60.4%, P = 0.018). Whereas the 5-year survival rate of the lower CD34-IMVD patients seemed higher than that of the higher CD34-IMVD patients (63.7%), the difference did not reach a statistical significance (P = 0.137). Multivariate analysis confirmed that higher CD105-IMVD was a significant factor to predict poor prognosis (P = 0.029), whereas CD34-IMVD was not (P = 0.070).
Anti-CD105 mAb proved to be superior to anti-CD34 mAb in evaluation of angiogenesis in NSCLC.
Clinical Cancer Research 12/2001; 7(11):3410-5. · 7.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: Surgery is usually not indicated for malignant pleural effusion (PE) due to its poor prognosis. However, PE is first detected at thoracotomy, and it is difficult to judge an appropriate mode of resection. Forty-nine patients with lung cancer were first diagnosed as PE and/or pleural dissemination (PD) at thoracotomy. The histological types were 36 adenocarcinoma, ten squamous cell carcinoma and three large cell carcinoma. Sixteen patients had only PE, 17 had only PD, and 16 had both PE and PD. Ten patients underwent only exploratory thoracotomy, seven partial resection, 27 lobectomy and five panpleuropneumonectomy. The overall survival rate was 26.7% at 3 years. The patients with PE and/or PD seemed to have a poorer survival compared to our previous study. The patients with only PE showed a significantly better prognosis than the patients with only PD (P=0.0001) or with PD+PE (P=0.019). The patients who underwent exploratory thoracotomy showed poor survival. There were significant differences in the survival in relation to the extent of the primary tumor. In conclusion, the patients with T1-2 of primary tumor and only a small amount of PE without PD can be expected to show long-term survival after tumor resection.
Lung Cancer 11/2001; 34(1):75-81. · 3.39 Impact Factor
[show abstract][hide abstract] ABSTRACT: The clinical significance of preoperative induction therapy for non-small cell lung cancer (NSCLC) is reviewed. As the survival rate in locally advanced NSCLC patients remains poor, preoperative therapy has been attempted in order to improve survival. Whereas some prospective phase II and phase III studies have demonstrated that preoperative cisplatin-based chemotherapy with or without concurrent radiation may improve the prognosis, the efficacy has not been established. Recently, some new chemotherapeutic agents such as paclitaxel and gemcitabine have been introduced, and it has been suggested that preoperative therapy using these new drugs may be more effective. To establish effective preoperative therapy regimens, more sophisticated, prospective, randomized studies in sufficient numbers of homogenous populations such as mediastinoscopy-proven stage IIIA, T1-2N2 patients should be conducted.
[show abstract][hide abstract] ABSTRACT: Alteration of homotypic cell-cell adhesion has been suggested to play an important role in tumor progression. The present study examined the relationship between neural cell adhesion molecules and state of proliferation of small cell lung cancer (SCLC) cells.
Seventeen surgically resected specimens of SCLC were immunohistochemically examined, by using monoclonal antibodies against neural cell adhesion molecule (NCAM) and its polysialic acid side chains, and L1 cell adhesion molecule (L1-CAM). Ki-67 labeling indices were also determined immunohistochemically.
All patients were positive for L1-CAM. Fifteen patients (88.2%) were positive for NCAM. Among the fifteen patients, nine (60.0%) were positive for NCAM PSA side chain. The probability of survival of the NCAM without PSA side chain group was significantly higher than that of the NCAM with PSA side chain group (log-rank test; P = 0.500).
The expression of NCAM with PSA side chains might be a prognostic factor and NCAM a marker for SCLC. L1-CAM may be synthesized independent of state of proliferation of individual tumor cell and may affect clinical feature of SCLC.
Journal of Surgical Oncology 06/2001; 77(1):49-54. · 2.64 Impact Factor
[show abstract][hide abstract] ABSTRACT: The structures of N-linked oligosaccharides present in human sera from 12 healthy volunteers and from 14 patients with non-small cell lung cancer (NSCLC) were analyzed by our recently developed partially automated systematic method. Thirty different structures of oligosaccharides were deduced, and these accounted for 84.1% of the total N-linked oligosaccharides present in human sera. All of the quantified oligosaccharide levels in healthy human sera were within twice the standard deviation. The amount of a triantennary trigalactosylated structure with one outer arm fucosylation (A3G3Fo) was found to be markedly increased in NSCLC patients in comparison to that in healthy volunteers (p < 0.01). No significant positive correlation with other clinical data was found. Serum A3G3Fo levels can thus be a novel marker for the diagnosis of NSCLC.
Journal of Biochemistry 05/2001; 129(4):537-42. · 2.72 Impact Factor
[show abstract][hide abstract] ABSTRACT: Polysialic acid (PSA) is a carbohydrate attached mainly to the neural cell adhesion molecule. Because PSA is composed of a linear homopolymer of alpha-2-8-linked sialic acid residues and has a large negative charge, the presence of PSA attenuates the adhesive property of neural cell adhesion molecule and increases cellular motility. In an earlier study, we demonstrated that PSA and STX, a polysialyltransferase, were associated with tumor progression in non-small cell lung cancer (NSCLC) (F. Tanaka et al., Cancer Res., 60: 3072-3080, 2000). Therefore, in the present study, to assess the prognostic significance of PSA in resected NSCLC, a total of 236 patients who underwent complete resection for pathological (p)-stage I-IIIa disease were reviewed retrospectively. PSA was expressed in 44 of 236 (18.6%) patients, and the expression was correlated with p-stage disease. For all p-stage patients, 5-year survival rates for those with PSA-positive and PSA-negative tumors were 52.1% and 71.3%, respectively, demonstrating a significantly worse prognosis for the PSA-positive patients (P = 0.012). Analysis for only p-stage I patients also demonstrated a significantly worse prognosis for the PSA-positive patients; 5-year survival rates of the PSA-positive and the PSA-negative patients were 45.1% and 83.5%, respectively, (P < 0.001). In addition, there proved to be no difference in the postoperative survival among p-stage I, II, and IIIa patients when PSA expression was positive. Multivariate analysis confirmed that PSA expression was an independent factor to predict poor prognosis in resected NSCLC. These results suggested that PSA could be an important clinical marker and that preoperative induction and/or postoperative adjuvant therapies should be performed for PSA-positive NSCLC, even if the disease is classified as p-stage I.
Cancer Research 03/2001; 61(4):1666-70. · 8.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: Caspase-3 is a cysteine protease that plays an important role in the process of apoptotic cell death. Whereas many studies on the clinical significance of apoptosis in the therapy of malignant tumors have been reported, little has been studied clinically on caspase-3. In the present study, the clinical significance of caspase-3 expression in resected nonsmall-cell lung cancer (NSCLC) and its correlation with incidence of apoptosis were examined. A total of 118 consecutive patients who had undergone complete resection for pathologic Stage I NSCLC were retrospectively reviewed. Caspase-3 expression was examined immunohistochemically using a polyclonal antibody that recognized uncleaved caspase-3. The 5-year survival rate for patients with strong expression of caspase-3 (66.6%) was significantly lower than that for patients with weak expression (82.1%, P = 0.021). Expression of caspase-3 was not correlated with incidence of apoptosis, proliferative activity, or p53 status. Multivariate analysis confirmed that strong expression of caspase-3 was a significant factor to predict poor prognosis. These results suggest that enhanced expression of "uncleaved" caspase-3, that is, inactivated caspase-3, was correlated with poor prognosis in resected NSCLC.
International Journal of Cancer 02/2001; 96 Suppl:54-60. · 6.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: To examine whether efficacy of postoperative oral administration of UFT, a 5-fluorouracil derivative chemotherapeutic agent, may be influenced by incidence of apoptosis (apoptosis index) or apoptosis-related gene status (p53 and bcl-2) of the tumour, a total of 162 patients with pathologic stage I non-small cell lung cancer were retrospectively reviewed. UFT was administrated postoperatively to 44 patients (UFT group), and not to the other 118 patients (Control group). For all patients, 5-year survival rate of the UFT group (79.9%) seemed higher than that of the Control group (69.8%), although without significant difference (P = 0.054). For patients with higher apoptotic index, 5-year survival rate of the UFT group (83.3%) was significantly higher than that of the Control group (67.6%, P = 0.039); for patients with lower apoptotic index, however, there was no difference in the prognosis between these two groups. Similarly, UFT was effective for patients without p53 aberrant expression (5-year survival rates: 95.2% for the UFT group and 74.3% for the Control group, P = 0.022), whereas not effective for patients with p53 aberrant expression. Bcl-2 status did not influence the efficacy of UFT. In conclusion, apoptotic index and p53 status are useful factors to predict the efficacy of postoperative adjuvant therapy using UFT.
British Journal of Cancer 02/2001; 84(2):263-9. · 5.08 Impact Factor