Jitsuo Usuda

Conclusions. Endoscopic tumor ablation is a valuable option for inoperable postoperative laryngotracheal intraluminal invasion of well-differentiated thyroid carcinoma (DTC). Objectives. To investigate whether DTC invasion to the laryngotracheal mucosa can be controlled by ‘simple’ tumor ablation considering its relatively slow-growing nature. Patients and methods. Twenty-two consecutive patients underwent endoscopic tumor ablation caused by DTC for local control of intraluminal lesions with no significant extrinsic laryngotracheal compression in symptomatic or asymptomatic patients in whom radical operations were contraindicated. Debulking by Nd:YAG laser was followed by electrocoagulation and microwave coagulation for the residual tumor base. Results. The critical complication, post-treatment supraglottic stenosis, was managed by prophylactic minitracheotomy. During the follow-up period of up to 125 months, 6 of 22 patients died (median survival 50 months), mainly of lung metastases, but all had a patent airway at death. Post-surgical extraluminal lesion growth is indolent and since relapse of the intraluminal lesion is the main cause of symptoms, satisfactory local control could be obtained by re-ablation of the mucosal lesion every few years. Lesions requiring retreatment within 1 year after initial treatment usually have high-grade malignancy, causing extrinsic compression, and prognosis is unfavorable.

Non-small cell lung cancer (NSCLC) constitutes approximately 85% of all lung cancers, with patients having a poor prognosis. Approximately one third of NSCLC patients present with early-stage disease in which potentially curative resection and multi-modality therapy. Although adjuvant chemotherapy is the standard practice for patients with stages I-III breast and colorectal cancer, the therapeutic efficacy of adjuvant chemotherapy, following complete surgical resection of early stage NSCLC, has not been fully established. Several prospective randomized trials for patients with early stage NSCLC (stages I-IIIA) have confirmed a survival benefit with cisplatin-based adjuvant chemotherapy, as demonstrated in the 1995 meta-analysis performed by the NSCLC Collaborative Group. Studies from Japan have reported that adjuvant therapy with uracil-tegaful (UFT) afforded an improvement of 4% in the 5-year survival rate and a relative risk reduction of 26% in mortality at 5 years among patients with T1-2N0 (stage I) disease. In particular, the Japan Lung Cancer Research Group has demonstrated an improvement in the 5-year survival rate of 11%, favoring chemotherapy with UFT in the subset of patients with T2N0 (stage IB) disease. Two published meta-analyses based on abstracts have estimated a relative risk reduction in mortality of 11-13% at 5 years. The Lung Adjuvant Cisplatin Evaluation (LACE), which was based on a pooled analysis of five randomized trials, has demonstrated that cisplatin-based adjuvant chemotherapy improved survival in patients with completely resected NSCLC. This benefit depended on stage, being greatest in patients with stage II or IIIA disease. This analysis has suggested that platinum-based adjuvant chemotherapy may have no benefit for patients with stage IA and only a marginal benefit for patients with stage IB. Thus, the information available at the current time supports the administration of adjuvant chemotherapy for patients who have undergone complete resection of stages IB-IIIA NSCLC. Further research is needed to define the role of adjuvant platinum-based chemotherapy and its use, in conjunction with chest radiotherapy as the treatment for patients with resected stages IB and IIIA NSCLC.

ATX-s10 is a novel and second-generation photosensitizer for photodynamic therapy (PDT). In order to conduct clinical trials of ATX-s10-PDT and/or extend its clinical applications, it is very important to elucidate the mechanisms of the action of ATX-s10-PDT. We examined the apoptic response against ATX-s10-PDT using a Bcl-2 or Bcl-2 mutant overexpressing cells. Using fluorescent microscopy, ATX-s10 localized not only to mitochondria but also to lysosomes and possibly other intracellular organelles, but not to the plasma membrane or the nucleus. These results suggest that ATX-s10-PDT can damage mitochondria and lysosomes. By Western blot analysis, ATX-s10-PDT damaged Bcl-2, which localized preferentially at mitochondrial membranes, and caused Bcl-2 to cross-link immediately after laser irradiation. However, ATX-s10-PDT was not able to rapidly induce morphologically typical apoptosis (i.e. chromatin condensation and fragmentation) as PDT using mitochondria targeted photosensitizers, such as phthalocyanine 4 (Pc 4). Pharmacological inhibitions of lysosomal cytokine protease cathepsins, such as cathepsin B and D, protected MCF-7c3 cells (human breast cancer cells expressing stably transfected procaspase-3) from apoptosis caused by ATX-s10-PDT. Overexpression of wild-type Bcl-2 or Bcl-2Delta33-54 resulted in relative resistance of cells to ATX-s10-PDT, as assessed by the degree of morphological apoptosis or loss of clonogenicity. We conclude that lysosomal damage by ATX-s10-PDT can initiate apoptotic response and this apoptotic pathway can be regulated by photodamage to Bcl-2 via mitochondrial damage.

Photodynamic therapy (PDT), a treatment for cancer, uses a photosensitizer and laser irradiation to produce reactive oxygen in cells. In Japan, the United States, and many other countries, PDT is a treatment option for stage 0 (TisN0M0) and stage I (T1N0M0) centrally located early stage lung cancer. PDT can preserve lung function, can be repeated, and can be combined with other therapeutic modalities such as chemotherapy. Recently, mono-l-aspartyl chlorine e6 (NPe6, Laserphyrin), a second-generation photosensitizer with lower photosensitivity than Photofrin (porfimer sodium), was approved by the Japanese government and a phase II clinical study using NPe6 with a new diode laser demonstrated an excellent antitumor effect and low skin photosensitivity. We expect PDT to be widely employed in many fields and the applications of PDT to be extended because of the decreasing cost of laser equipment and lower systemic photosensitivity induced by the photosensitizer. The purpose of this review is to introduce not only recent clinical trials of PDT for centrally located early lung cancer, but also new applications of PDT for cases of peripheral-type, early-stage lung cancers. We also discuss the applications of PDT for advanced lung cancer and combined therapy using PDT and other treatments for lung cancer.

Inactivation of the p16 and ESR1 tumor suppressor genes by promoter lesion methylation has been reported in many tumor types, including lung cancer. We examined the blood of 95 non-small cell lung cancer patients (66 cases of adenocarcinoma, 23 of squamous cell carcinoma and 6 of large cell carcinoma) and 30 controls consisting of normal subjects and benign disease patients to determine the methylation ratios of p16 and ESR1 using real-time PCR. For both genes, there was a statistically significant difference in the methylation ratio between non-small cell lung cancer patients and controls (p16; p<0.01, ESR1; p<0.001). In addition, there was a strong correlation between the methylation ratio of each gene and old age (p16; p<0.01, ESR1; p<0.001 and p16 or ESR1; p<0.001), and between p16 or ESR1 methylation rate and smoking history (p<0.01). Moreover in Stage I cases, the methylation positive rate of each gene (p16, ESR1 and p16 or ESR1) was higher than the CEA positive rate (p<0.05, p<0.001, p<0.001). Evaluation of p16 and ESR1 promoter methylation in blood using real-time PCR appears to be very useful for lung cancer diagnosis and there is some possibility that these methylated genes might come to represent useful biomarkers for the early detection of lung cancer. Our study results also suggested that comparative evaluation of the methylation ratio before and after surgery might be a powerful tool to predict the prognosis of lung cancer patients.