Inoperable non-small cell lung cancer: a retrospective analysis of 427 patients treated with high-dose radiotherapy

PURPOSE: The influence of patient and treatment characteristics on survival as well as normal tissue toxicity were retrospectively analyzed. METHODS AND MATERIALS: Four hundred twenty seven patients with unresectable non-small cell lung cancer received at least 60 Gy and two-thirds were treated with 70 Gy. RESULTS: Five-year survival rates and median survival time (95% confidence interval) were 2 +/- 2% (mean +/- s.e.) and 11.1 months (9.1-14.5) after 60-66 Gy (median 60 Gy); 8 +/- 2% and 14.9 months (13.3-16.5) after > or = 70 Gy (p = 0.0013). Stage I-II patients had significantly higher survival rates as compared to Stage III patients (p = 0.0015). Within the subgroup of Stage III patients those with Stage IIIA had significantly higher survival rates than Stage IIIB (p = 0.0167). Female patients achieved 5-year survival rates after 70 Gy of 15 +/- 7% as compared to only 7 +/- 2% of their male counterparts. Chemotherapy, histology, Karnofsky status, and age had no influence on survival after univariate and multivariate analysis. Nine percent and 11% of the patients suffered from moderate to severe pneumonitis and esophagitis. CONCLUSION: High-dose radiotherapy of unresectable non-small cell lung cancer with total doses > 60 Gy conventionally fractionated is feasible. With doses of > or = 70 Gy significantly higher survival rates were achieved as compared to 60-66 Gy. Normal tissue toxicity was acceptable. For Stage IIIB patients, however, treatment results are disappointingly low even after 70 Gy with no 5-year survivor.     

The prognostic significance of accumulation of p53 protein in stage III non-small cell lung cancer treated by radiotherapy

In the present study the prognostic significance of accumulation of nuclear p53 protein on survival and freedom from local progression was investigated. Formalin-fixed, paraffin-embedded sections obtained by bronchoscopy or mediastinoscopy were used to examine the expression of nuclear p53 protein using immunohistochemistry. In 37 cases (57%), overexpression of the p53 protein was detected. No relation was found between p53 expression and other pretreatment variables. Response to radiotherapy was found in 11 p53-negative cases (65%) versus 10 p53-positive cases (42%). Freedom from local progression was significantly better in the p53-negative cases as compared with the p53-positive cases. The p53-negative cases who responded to radiotherapy showed an excellent freedom from local progression rate after 2 years of 100%, whereas all p53-positive cases without response to radiotherapy showed local progression within 24 months. Overall survival between p53-negative and -positive cases did not differ, however the disease-specific survival was found to be worse in the p53-positive cases as compared to the negative cases (median survival 8.4 vs. 14.4 months (P < 0.05)). No correlation was found between p53 expression and the frequency of distant metastases. In conclusion, the results of this study suggest that p53 protein expression may be of prognostic value on freedom from local progression in non-small cell lung carcinoma.     

Confirmation of a prognostic index for patients with inoperable non-small cell lung cancer

The surfaces of hydroxyapatite-glass-titanium (HA-G-Ti) functionally gradient composite and titanium bars were treated with electrochemical apatite deposition, and a cathodic current was applied at 62 degrees C in a solution containing calcium and phosphate ions. Specimens with and without the electrochemical surface treatment were implanted in the femurs of Japanese white rabbits. The rabbits were sacrificed at 3, 6, and 9 weeks after implantation, and the bonding strengths of bone to these specimens were determined by a pull-out method. At 3 and 6 weeks after implantation the specimens with the electrochemical surface treatment showed larger values for the Weibull modulus and characteristic strengths than those of untreated specimens, whereas there was no remarkable difference in the results at 9 weeks. Especially the pull-out strengths of surface-treated specimens were significantly larger than the untreated ones at 3 weeks after implantation. Scanning electron microscopy and Fourier transform infrared absorption spectroscopy of the specimen surface after implantation demonstrated that formation of new bone was enhanced by the electrochemical surface treatment. It can be concluded that the electrochemical surface treatment undoubtedly contributes to the early stage fixation between bone and implant.     

Surgery for stage IIIa-N2 non-small cell lung cancer

BACKGROUND: The presence of ipsilateral mediastinal lymph node metastasis (N2 disease) in patients with non-small cell lung cancer presents a formidable challenge to the physician responsible for selecting therapy. The benefit of a surgical approach is controversial; however, it generally is agreed that only complete resection of all known tumor can provide a favorable outcome. This requires selecting patients for whom complete resection is a reasonable surgical objective. METHODS: Retrospective review of a collected data base comprising records for 2883 patients who underwent definitive surgical treatment was accomplished to emphasize the prognostic implications of regional lymph node metastasis. Patients making up the N2 subset (n = 307) were the focus of the investigation, and providing insight to the puzzle of appropriate patient selection was a major goal. RESULTS: Five-year cumulative survival rates for patients with N0, N1, and N2 disease were, respectively, 62%, 43% and 31%. Three factors significantly influenced the outcome: a complete lymph node dissection, the extent of mediastinal lymph node involvement, and apparent complete resection of all tumor. Important survival determinants were the number of nodes involved, the level of involvement (single or multiple levels), and a T1 primary tumor status. Criteria for unresectability and recommendations for patient selection were developed from (1) the end results of the study and (2) the contributions of imaging and invasive techniques to clinical staging and to the histologic verification of nodal disease.     

Serum levels of interleukin-6 as a prognostic factor in advanced non-small cell lung cancer

OBJECTIVE: The purpose of this study was to evaluate pancreatic enhancement with low-dose mangafodipir trisodium (5 mumol/kg) using three different T1-weighted pulse sequences. SUBJECTS AND METHODS: Fifteen patients, six of whom had proven focal pancreatic tumors, underwent T1-weighted gradient-recalled echo imaging, spin-echo imaging, and fat-suppressed spin-echo imaging before and 30 min after injection of 5 mumol/kg of mangafodipir trisodium. Region-of-interest measurements were obtained in the pancreas before and after contrast enhancement. Signal-to-noise ratios were calculated in all 15 patients. Contrast-to-noise ratios were calculated in the six patients with pancreatic tumors. RESULTS: The signal-to-noise ratios of the pancreas increased after injection of mangafodipir trisodium on all three T1-weighted pulse sequences (p < .001). Enhanced fat-suppressed sequences (29 +/- 7.7) and gradient-recalled echo sequences (29 +/- 9.6) had the highest signal-to-noise ratios. Contrast-to-noise ratios between normal pancreatic tissue and pancreatic tumor also increased after contrast administration (p < .05) and were highest on the fat-suppressed (-9.6 +/- 4.0) pulse sequence. CONCLUSION: Mangafodipir trisodium produced marked pancreatic enhancement at a dose of 5 mumol/kg for all three T1-weighted pulse sequences. The enhanced T1-weighted spin-echo fat-suppressed sequence showed the highest signal-to-noise and contrast-to-noise ratios.     

Chemotherapy in non-small cell lung cancer: a review

Lung cancer, of which non-small cell carcinoma is the most common, has been a significant therapeutic challenge for decades and will remain so for decades to come. Despite its prevalence, progress in the management of non-small cell lung cancer has been relatively slow. This is in part due to the pessimism of most physicians treating this disease, which has resulted in a relatively lackadaisical attitude with regards to clinical trials when compared to other solid tumours like breast or colorectal cancers. Nevertheless, the past decade has seen significant progress, specifically with regards to the management of locally advanced disease. Chemotherapy, though shown to be biologically active in non-small cell lung cancer, is considered an ineffective palliative tool in the setting of metastatic disease due to its toxicities and the "less than encouraging" response rates generated by the cisplatin-based combination regimen which is generally considered to be the most active currently available. The advent of new active agents such as paclitaxel and vinorelbine which are potentially less toxic may change this view. Conversely, the response rate of locally advanced disease to chemotherapy is significantly higher and this has resulted in numerous multimodality trials of neoadjuvant chemotherapy prior to surgery and/or radiation. To date, a number of randomised trials have shown that this approach can result in significant survival benefit for patients with locally advanced disease. An alternative approach makes use of the potential synergism between certain chemotherapeutic agents (such as cisplatin) and radiation when used concurrently. However, data on concurrent chemoradiotherapy in locally advanced disease have been largely based on single-arm studies and are inconclusive. Three randomised trials on concurrent chemoradiotherapy have been shown benefit for the use of combined modality in locally advanced disease. Hence, treatment of locally advanced disease should include chemotherapy as part of the combined modality approach. However, the optimal sequencing of these modalities would require well-designed randomised trials to determine.     

Chemotherapy in the treatment of non-small cell lung cancer

Non-small cell cancers of the lung include squamous cell carcinoma, adenocarcinoma and large cell carcinoma. These tumors have traditionally been considered to be quite resistant to both chemotherapy and radiation therapy. Although surgery has offered the best chance for cure, the tumor has usually spread too far for effective surgery by the time it is discovered. Several newer chemotherapeutic agents show improved survival rates in the treatment of these tumors. These agents include paclitaxel, carboplatin and vinorelbine. These drugs may be used as single agents or in combination and have also been used in combination with radiation. Although further study will be required before the optimal regimen is determined, it appears that use of these agents can improve the survival of patients with inoperable non-small cell cancer of the lung.     

Cyclin B1和survivin在非小细胞肺癌中的表达和意义

Objective: We studied the expression of cyclin B1 and survivin in human non-small cell lung cancer (NSCLC), and the relationship between such expression and clinicopathological features of NSCLC. Methods: One hundred cases of tissue specimen including NSCLC, neighboring noncancerous tissue and normal lung tissue were collected at random. These specimens were detected by immunohistochemical methods. Results: The expression of cyclin B1 and survivin showed significant difference (P < 0.01) between NSCLC tissues, proliferating epithelial cells of bronchioles and small bronchi in neighboring noncancerous tissues, and normal lung tissues. Compared with normal lung tissues, there was an overexpression of cyclin B1 and survivin in NSCLC and an enhancing expression of cyclin B1 and survivin in proliferating epithelial cells of bronchioles and small bronchi in neighboring noncancerous tissues. Significantly positive correlation was found between the overexpression of cyclin B1 and that of survivin in 100 NSCLC cases (P < 0.01). The significantly positive correlation was also found between the enhancing expression of cyclin B1 and that of survivin in proliferating epithelial cells of bronchioles and small bronchi in neighboring noncancerous tissues (P < 0.01). No statistical significance was found between the different histological types, the differentiated degree, lymphatic metastasis and the expression of cyclin B1 and survivin (P > 0.05) in NSCLC. Statistical significance was marked between different clinical stages of NSCLC and the expression of cyclin B1 and survivin (P < 0.05). Conclusion: The overexpression of cyclin B1 and survivin was found in NSCLC. The expression of cyclin B1 and survivin might be up-regulated during an early step of tumorigenesis and during the development of NSCLC. The progression of cell cycle could be efficiently connected with the control of apoptosis by the interrelations between the overexpression of cyclin B1 and that of survivin in NSCLC during the G2/M phase. The overexpression of cyclin B1 and survivin might be used as marker in showing the dividing and proliferating ability, and the inhibiting apoptosis ability (lengthening cell lifespan) of NSCLC. Moreover, the overexpression of cyclin B1 and survivin was associated with the clinic stages of NSCLC.     

Smac在非小细胞肺癌表达的临床意义

Objective:The aim of our study was to investigate the clinical significance of Smac (second mitochondria-derived activator of caspase) expression on non-small cell lung cancer (NSCLC). Methods:The expression of Smac was evaluated on RNA and protein level in tumor tissues. The expression of Smac mRNA was examined by RT-PCR in 59 samples of tumor tissues and matched normal lung tissues. The expression of Smac protein was examined by IHC in 213 cancer tissues. Results:The positive rate of Smac mRNA was found in 59.3% of cancer tissues, but only in 30.5% of matched normal tissues (P < 0.05). The positive rate of Smac protein was 76.5%. The expression of Smac in stage II disease was significantly higher than that in stage I disease (P = 0.001). The survival of patients with Smac overexpression was significantly shorter than those who were negative. Conclusion:Smac might be involved in the progression of NSCLC, the biologic significance of Smac in primary lung cancer needs further study.     

Clinical analysis in patients undergoing extended resection of pT3 non-small cell lung cancer

Among pT3 cases there contain various subgroups in terms of the organ which is involved in. We analyzed medical records of 85 consecutive patients who underwent extended surgery with diagnosis of pT3 excluding interlober invasion. As regards to the site of invasion, there are not significant differences in survival between pleural invasion, chest wall involvement, pericardial invasion, and diaphragmatic invasion. However, survival of patients who showed involvement of main bronchus seemed better than other groups. Survival of pT3 cases are in part determined by lymph node involvement, N0 group showed 36.0% 5 year survival rate whereas N1 group 20.0%, and there are no patient with N2 disease who survived 5 years. Among pleural and chest wall involvement group, N0 group showed 34.2% 5 year survival and there are no survival in N1 and N2 group. As regards to histologic subgroups, there are not significant differences between each group. Thus we conclude that in pT3 cases, N0 cases are the best candidate for surgical resection, and that adjuvant therapy is necessary for those with N1 or N2 involvement. Cases with bronchial extension should not be argued in the same field of locally invasive lung cancer because of better survival.     

The prognostic value of NCAM, p53 and cyclin D1 in resected non-small cell lung cancer

Expression of the neural cell adhesion molecule, NCAM, in frozen sections has been associated with decreased postoperative survival in non-small cell lung carcinoma. Of the various isoforms of NCAM described, the highly sialylated isoform plays a role in the migration of embryonal cells from the neural crest and is expressed by highly malignant tumours such as small cell lung carcinomas. We investigated the clinical significance of expression of this NCAM isoform as a prognostic factor in a series of 96 non-small cell lung carcinomas resected with curative intent. We also evaluated the effect of microwave pre-treatment of formalin-fixed, paraffin-embedded sections on the NCAM immunostaining and related the outcome to the postoperative clinical course of disease. In addition, in an attempt to extend our search for possible molecular markers of unfavourable prognosis in lung cancer, we evaluated increased immunostaining for p53 and cyclin D1 in the same series. We did not find a significant relation between expression of NCAM or its highly sialylated isoform and the length of postoperative survival. The numbers of positive cases (9 and 14, respectively) were relatively low. Increased p53 and cyclin D1 immunostaining (50 and 55 of the 96 tumours) failed to show a significant relation with postoperative survival. In our material, tumour stage was the only significant prognostic factor.     

Recent advances in the treatment of non-small cell lung cancer

Non-small cell lung cancer (NSCLC), which represents the bulk of primary carcinomas of the lung, is an aggressive malignancy. The majority of patients with NSCLC present with advanced disease, not curable by surgery, at the time of diagnosis. Recent randomized trials have shown an improvement in survival for patients with loco-regional disease treated with combination, platinum-based, chemotherapy and curative irradiation. Similarly, randomized studies of good performance status patients with metastatic disease have documented a survival advantage, albeit a modest advantage, for those receiving chemotherapy. New chemotherapy agents with activity in NSCLC have been studied in phase II trials. These agents need to be evaluated, in loco-regional and metastatic disease, in large randomized phase III trials before conclusions can be drawn about their role in treatment. Novel treatments which among other include gene therapy, anti-angiogenic and anti-metastatic agents are currently being assessed in early phase I and II studies. Gene therapy will likely be combined with standard chemotherapy and radiation in the treatment of NSCLC, whereas anti-angiogenic and anti-metastatic agents may play a role in prevention and maintenance therapy. Finally, regardless of the approach or modality, new interventions will need to be assessed for their impact on overall survival and the quality of life of patients with NSCLC.     

Efficacy of neoadjuvant chemotherapy in primary non-small cell lung cancer

PURPOSE: To examine the changes in ciliary body thickness after topical application of pilocarpine, cyclopentolate hydrochloride, and PhXA41, a prostaglandin F2alpha analog. METHOD: We used high-frequency Humphrey UBM840 ultrasound biomicroscope to examine 36 healthy young Japanese subjects. RESULTS: The mean ciliary body thickness increased from 0.67 +/- 0.07 mm to 0.073 +/- 0.08 mm (P < .01) after application of 2% pilocarpine; 1% cyclopentolate hydrochloride and 0.005% PhXA41 decreased the mean ciliary body thickness from 0.75 +/- 0.07 mm to 0.69 +/- 0.05 mm (P < .05) and from 0.78 +/- 0.06 mm to 0.75 +/- 0.06 mm (P < .01), respectively. CONCLUSIONS: Our ultrasound study clearly indicates that pilocarpine increased comparative thickness of the ciliary body by 8.3%, whereas PhXA41 decreased comparative thickness by 3.3% in a manner similar to cyclopentolate hydrochloride.     

Tumour cell kinetics as prognostic factor in surgically-treated-non-small cell lung cancer

The gene encoding myosin VIIA is responsible for the mouse shaker-1 phenotype, which consists of deafness and balance deficiency related to cochlear and vestibular neuroepithelial defects. In humans, a defective myosin VIIA gene is responsible for Usher syndrome type IB, which associates congenital deafness, vestibular dysfunction and retinitis pigmentosa. In an attempt to progress in the understanding of the function(s) of myosin VIIA, we studied the expression of the myosin VIIA gene during mouse embryonic development. Embryos from day 9 (E9) to E18 were analyzed by in situ hybridization and immunohistofluorescence. The myosin VIIA mRNA and protein were consistently detected in the same embryonic tissues throughout development. Myosin VIIA was first observed in the otic vesicle at E9, and later in a variety of tissues. The olfactory epithelium and the liver express it as early as E10. In the retinal pigment epithelium, choroid plexus, adrenal gland and tongue, expression begins at E12 and in the testis and the adenohypophysis at E13. In the small intestine, kidney and hair follicles of the vibrissae, expression of myosin VIIA starts only at E15. Myosin VIIA expression was observed only in epithelial cell types, most of which possess microvilli or cilia. Interestingly, myosin VIIA expression seems to be concomitant with the appearance of these structures in the epithelial cells, suggesting a role for this myosin in their morphogenesis. The cellular location of myosin VIIA within sensory hair cells and olfactory receptor neurons also argues for a role of this protein in the synaptic vesicle trafficking.     

The prognostic significance of tumor cell detection in intraoperative pleural lavage and lung tissue cultures for patients with lung cancer

METHODS: Three hundred forty-two patients with lung cancer and 99 patients with nonneoplastic lung diseases (control group) underwent intraoperative pleural lavage with 300 ml physiologic saline solution before (lavage I) and after resection (lavage II). RESULTS: Studies of the lavage fluid in all control patients were negative, that is, there were no false positive findings. Tumor cells were found in lavage I in 132 patients (38.6%) and also in lavage II in 99 of them. In stage I (pT1 N0, pT2 N0) lung cancer, tumor cell detection was possible in 47 patients (28.6%). The 4-year survival of patients with resected non-small-cell lung cancer was 24% (95% confidence interval, 16% to 32%) if lavage I results were positive and 52% (95% confidence interval, 45% to 59%) if lavage I results were negative (all stages, p = 0.007). For patients with stage I disease (n = 164) the 4-year survival was 35% (95% confidence interval, 18% to 52%) if lavage I results were positive (n = 47), and 69% (95% confidence interval, 60% to 78%) if lavage I results were negative (n = 117) (p = 0.037). On multivariate analysis the positive cytologic result in intraoperative pleural lavage was an additional prognostic factor for our patients. To prove how the tumor cells enter the pleural cavity, we performed tissue cultures of tumor-free parenchyma in 23 cases of lung cancer. Tumor cell detection by histology and immunohistology was possible in 16 cases (69.6%). Detection of tumor cells in pleural lavage fluid before resection proves that tumor cells have spread into the pleural cavity. CONCLUSION: The positive result in pleural lavage seems to be a prognostic predictor for patients with lung cancer.