Seiichi Fukuyama

Therapeutic strategy for postoperative recurrence in patients with non-small cell lung cancer

Postoperative recurrence occurs in approximately half of patients with non-small cell lung cancer (NSCLC), even after complete resection. Disease recurrence after surgical resection reduces the patients life expectancy sharply. The prognosis after postoperative recurrence is considered to largely depend on both the mode of first recurrence (distant, locoregional or combined) and the treatment modality: (1) The majority of cases of postoperative recurrence involve distant metastasis with or without locoregional recurrence. Platinum-based systemic chemotherapy is practically accepted as the treatment for these diseases on the basis of evidence for original stage IV disease. The advent of both pemetrexed and molecular-targeted drugs has improved the survival of nonsquamous NSCLC and changed the chemotherapeutic algorithm for NSCLC; (2) Among patients with distant metastatic recurrence without locoregional recurrence at the primary tumor site, the metastasis is often limited in both organ and number. Such metastases are referred to as oligometastases. Local therapy, such as surgical resection and radiotherapy, has been suggested to be the first-line treatment of choice for oligometastatic recurrence; and (3) While locoregional recurrence is likely to cause troublesome symptoms, it is a potentially limited disease. Therefore, providing local control is important, and radiation is usually beneficial for treating local recurrence. In order to obtain better control of the disease and provide treatment with curative intent in patients with limited disease, the administration of concurrent platinum-based chemoradiotherapy is recommended according to the results of originally nonresectable stage IIIA and IIIB disease.

Serum Tissue Inhibitors of Metalloproteinase-1 and -2 in Patients with Non-Small Cell Lung Cancer

PurposeIn view of the increasing number of patients diagnosed with lung cancer every year worldwide, there is an urgent need for an effective screening marker to improve its early detection.MethodsWe quantified the level of immunoreactive proteins for the tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 in the sera of 54 patients with non-small cell lung cancer (NSCLC) and 25 healthy control subjects, by using enzyme-linked immunosorbent assays with specific monoclonal antibodies.ResultsThe TIMP-1 level was significantly higher, and the TIMP-2 level was significantly lower in the patients with NSCLC than in the controls. Furthermore, both TIMP-1 and TIMP-2 were significantly higher in patients with squamous cell carcinoma than in those with adenocarcinoma. The TIMP-1 level in patients with stage III/IV disease was significantly higher than that in those with stage I/II disease. The TIMP-1/TIMP-2 ratio was significantly higher in the patients with NSCLC, and the receiver-operating characteristic curves analysis revealed that the TIMP-1/2 ratio, but not TIMP-1 or -2 alone, was a better screening marker for NSCLC than carcinoembryonic antigen (P < 0.0001). Patients with a high TIMP-1 value had significantly shorter disease-free survival (P = 0.0479), but those with a high TIMP-1/2 ratio did not.ConclusionThe TIMP-1/2 ratio may be a good screening marker of NSCLC; however, it was less effective than TIMP-1 as a prognostic factor.

Blockage of the macrophage migration inhibitory factor expression by short interference RNA inhibited the rejection of an allogeneic tracheal graft

We investigated the inhibitory effect of blocking the macrophage migration inhibitory factor (MIF) on the fibrous obstruction of a transplanted allograft in a murine model of obstructive bronchiolitis (OB). Tracheal grafts from C57BL/6 mice were transplanted into a subcutaneous pouch of BALB/c. Three days after transplantation, liposome including short interference (si) RNA for MIF was injected into the lumen of the grafts. The allografts were then harvested 7, 14 or 28 days after transplantation for an evaluation of the morphological changes. The MIF expression, which was ubiquitously recognized in the epithelium of allografts, decreased after the in vivo transfection of MIF siRNA. OB formation was therefore inhibited significantly more by the treatment with MIF siRNA than the allografts injected with empty liposome on the 14th day, however, no difference was observed between them on the 28th day. Treatment with MIF siRNA inhibits the destruction of tracheal allografts and OB formation in the early phase, and MIF was thus found to be one of the major cytokines involved in the rejection of the allogeneic trachea.

Elective video-assisted thoracoscopic lung biopsy for interstitial lung disease.

Lung biopsy is often required for the definitive subtype classification of interstitial lung disease. The video-assisted thoracoscopic approach has been advocated as an alternative to standard open lung biopsy because it is less invasive; however, whether it makes a positive contribution to treatment strategy remains contentious. We investigated the safety and efficacy of the video-assisted approach in a retrospective review of 30 consecutive patients who underwent the procedure in an elective setting after being diagnosed with interstitial lung disease by chest radiography and computed tomography. The mean age of the patients was 56.7 years. The preoperative vital capacity and forced expiratory volume in 1 second were 80.0% and 83.6%, respectively. There was no operative mortality, but 2 cases of respiratory failure and 1 of prolonged air leak occurred. The diagnostic yield was 100%, and treatment was changed in 57% of the cases as a result of the histological diagnosis. The rate of treatment change was higher for patients with nonspecific interstitial pneumonia than for those with idiopathic pulmonary fibrosis. We conclude that video-assisted biopsy is effective in the subtyping of interstitial lung disease and is a safe procedure when performed electively at the early stage of the disease.

Operative results of clinical stage I non-small cell lung cancer

BACKGROUND Clinical stage (c-stage) I non-small cell lung cancer (NSCLC) is generally indicated for surgery, however, surgical exploration sometimes reveals advanced disease, thus resulting in incomplete resection. PATIENTS AND METHODS A total of 645 consecutive patients were investigated in which 347 were diagnosed to have c-stage IA in 347 and 298 were diagnosed to have IB disease. All cases underwent operation and were investigated for resectability and the cause of an incomplete resection. RESULTS The c-Stage IA patients included 16.6% of T3/4 and 10.4% of N2 whereas clinical stage IB patients included 14.4% of T3/4 and 18.8% of N2/3. A complete resection was performed in 594 patients (91%). In 347 c-stage IA patients, the complete resection rates were 93% in adenocarcinomas (235/252), 100% in squamous cell carcinomas (76/76), and 89% in others (17/19). In 298 c-stage IB patients, the complete resection rates were 86% in adenocarcinomas (141/164), 90% in squamous cell carcinomas (90/100), and 94% in others (31/33). The 5-year survival rates of the c-stage IA and IB patients who underwent a complete resection were 66.4 and 48.3%, respectively. However, the same rates were 18.4 and 14.7% for c-stage IA and IB patients who underwent an incomplete resection. The reasons for an incomplete resection in 54 patients were malignant pleurisy in 38 (70.4%), extranodal invasion of mediastinal nodal metastasis in ten (19%), an incomplete bronchial margin in three (5.6%), and ipsilateral pulmonary metastases in two (3.7%), and ipsilateral adrenal metastasis in one (1.3%). In 13% of the c-stage IB adenocarcinomas, pleural metastasis was discovered during thoracotomy. CONCLUSIONS Pleural dissemination was the most frequent cause of an incomplete resection, and its prevalence was high in c-stage IB adenocarcinomas.

Prognostic factors in previously treated non-small cell lung cancer patients with and without a positive response to the subsequent treatment with gefitinib

Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has been reported to have a certain anti-tumor effect in previously treated patients with non-small cell lung cancer (NSCLC). However, the prognostic factors in those patients with and without a positive response to gefitinib treatment remain unclear. A retrospective chart review was performed in 131 advanced NSCLC patients who received 250 mg of gefitinib as either a second-line or even later stage treatment from July 2002 to December 2005. The clinical factors including age, gender, performance status (PS), stage, histology, the number of prior types of chemotherapy, and the response to first-line chemotherapy were analyzed. One and 38 patients experienced a complete and partial response, respectively, to gefitinib treatment with an overall response rate of 30%. The median survival time (MST) of all patients receiving gefitinib treatment was 10 months while the MST was 28 months in the 39 gefitinib responders and 6 months in the 92 non-responders. Among the 39 gefitinib responders, the predominant prognostic factor was found to be the effectiveness of the first-line chemotherapy. The MST of the 20 patients with a response to the first-line chemotherapy was 32 months while the MST of the 19 patients without a response to the chemotherapy was 22 months (p=0.025). Among the 92 gefitinib non-responders, the predominant prognostic factor was the PS (p<0.001). The effectiveness of the first-line chemotherapy was therefore found to be a prognostic factor in the gefitinib responders with previously treated NSCLC, while the PS was shown to be a prognostic factor in the gefitinib non-responders.

Comparison of the prognostic values of preoperative inflammation-based parameters in patients with breast cancer

Peripheral blood-derived inflammation-based markers, including C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR) are indicators of prognosis in various malignant tumors. The present study aimed to identify the inflammation-based parameters that are most suitable for predicting outcomes in patients with breast cancer. Two hundred ninety-six patients who underwent surgery for localized breast cancer were reviewed retrospectively. The association between clinicopathological factors and inflammation-based parameters were investigated. Univariate and multivariate Cox regression analyses were performed to identify independent prognostic indicators associated with disease-free survival (DFS). The NLR level correlated significantly with tumor size (P<0.05). The PLR level correlated with the expression of estrogen receptor and lymph node involvement (P<0.05). Univariate analysis revealed that lower CRP and PLR values as well as tumor size, lymph node involvement, and nuclear grade were significantly associated with superior DFS (CRP: P<0.01; PLR, tumor size, lymph node involvement, and nuclear grade: P<0.05). On multivariate analysis, CRP (hazard ratio [HR]: 2.85, 95% confidence interval [CI]: 1.03–7.88, P<0.05), PLR (HR: 2.61, 95% CI: 1.07–6.36, P<0.05) and nuclear grade (HR: 3.066, 95% CI: 1.26–7.49, P<0.05) were significant prognostic indicators of DFS in patients with breast cancer. Neither LMR nor NLR significantly predicted DFS. Both preoperative CRP and PLR values were independently associated with poor prognosis in patients with breast carcinoma; these were superior to other inflammation-based scores in terms of prognostic ability.

Prognosis and therapeutic response according to the World Health Organization histological classification in advanced thymoma.

PurposeThe clinical efficacy of the World Health Organization (WHO) classification of thymoma has been reported to be a prognostic factor for patients with thymomas. This study focuses on the relationship between the therapeutic response and the WHO histological classification in patients with advanced thymoma.MethodsA retrospective review was performed on 22 patients with Masaoka stage III and IV thymoma treated from 1975 to 2007. There were 1, 1, 7, 3, and 10 patients with WHO histological subtypes A, AB, B1, B2, and B3, respectively.ResultsSurgery was performed on 10 patients. There were 2 complete resections, 2 incomplete resections, and 6 exploratory thoracotomies. Of 18 patients with unresectable tumors, 8, 5, and 5 were treated with radiotherapy, chemotherapy, and chemoradiotherapy as the initial therapy, respectively. The response rate in 9 patients with type A-B2 was significantly better than that in 9 patients with type B3 regardless of treatment modality (100% vs 11.1%, P = 0.0001). Only the WHO classification was significantly associated with survival, with type B3 having a worse prognosis than A-B2 (P = 0.01).ConclusionsType B3 thymoma showed a lower response rate to treatments and thus shorter survival. The WHO classification is a good predictive factor for therapeutic response in advanced thymoma.

Non-small cell lung carcinoma of the superior sulcus: The evolution of treatment outcomes with multimodality treatment at a single institution.

We evaluated the efficacy of the multimodality approach in treating superior sulcus non‐small cell lung carcinoma (SS NSCLC).

Intrapleural Hypotonic Cisplatin Treatment for Malignant Pleural Mesothelioma : In Vitro Experiments and Clinical Application

PurposeWe studied the inhibitory effects of hypotonic cisplatin on the growth of malignant pleural mesothelioma (MPM) cell lines in vitro, and assessed the effectiveness of intraoperative intrapleural hypotonic cisplatin treatment combined with extrapleural pneumonectomy for patients with this tumor.MethodsIn the in vitro experiments, mesothelioma cell lines were exposed to various concentrations of cisplatin in either saline solution or distilled water for up to 5 min. After 48 h incubation, we calculated the inhibition of cell growth. In the clinical study, five patients with MPM underwent intraoperative intrapleural hypotonic cisplatin treatment combined with extrapleural pneumonectomy.ResultsThe hypotonic cisplatin treatment inhibited cell growth at a significantly greater rate than the isotonic cisplatin treatment. Just 1–5 min exposure to 10 µg/ml of hypotonic cisplatin inhibited growth by more than 80%. Clinically, no recurrence was found in four of the five patients after a median follow-up period of 27 months (range: 16–36 months), although contralateral multiple pulmonary metastases were found in one patient 10 months after surgery.ConclusionHypotonic cisplatin treatment is effective against MPM, and should be investigated further.