Yuji Hirami

Tumor-Infiltrating Foxp3+ Regulatory T Cells are Correlated with Cyclooxygenase-2 Expression and are Associated with Recurrence in Resected Non-small Cell Lung Cancer

Background: Cyclooxygenase-2 (COX-2) is constitutively overexpressed in a variety of epithelial malignancies and is usually associated with a poor prognosis. COX-2-derived prostaglandin E2 transforms CD4+CD25+ T regulatory (Treg) cells (Tregs), and Tregs are thought to moderate the antitumor immune response. Herein, we investigated the prognostic value of tumor-infiltrating Treg cells and their correlation with COX-2 expression in resected non-small cell lung cancer (NSCLC). Material and Methods: Intratumoral COX-2 and Treg expression were retrospectively assessed using immunohistochemistry in paraffin-embedded samples from 100 patients who had undergone complete resections for NSCLC. The expressions of COX-2 and Foxp3, which was most specific Treg cell marker, were compared with the clinicopathological variables, and the correlation between Foxp3+ Tregs and COX-2 expression was analyzed. Results: The recurrence-free survival (RFS) of patients with elevated COX-2 expression was significantly worse than that of patients without COX-2 expression. Tumor-infiltrating Foxp3-positive lymphocytes were positively correlated with COX-2 expression. The median count for Foxp3-positive lymphocytes was 3 (minimum-maximum, 0–24) in 10 high-power fields. The RFS of patients with tumors containing ≥3 Foxp3-positive cells (Foxp3 expression group) was significantly worse than that of patients with tumors containing <3 Foxp3-positive cells. In a multivariate analysis, only nodal status was an independent predictor of a significantly shorter RFS. However, in node-negative NSCLC, Foxp3 expression was an independent predictor of a significantly shorter RFS. Conclusions: Tumor-infiltrating Foxp3+ Tregs were positively correlated with intratumoral COX-2 expression and were associated with a worse RFS, especially among patients with node-negative NSCLC.

Post-recurrence survival of patients with non-small-cell lung cancer after curative resection with or without induction/adjuvant chemotherapy

OBJECTIVES Recently, the prognosis of patients with non-small-cell lung cancer (NSCLC) has improved, thanks to the standardization of adjuvant chemotherapy and the introduction of molecular-targeted drugs, notably epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and other new anti-cancer agents. However, the survival characteristics and prognosis of patients with recurrent NSCLC after curative resection are not well understood. METHODS Of the 430 consecutive patients with NSCLC who underwent complete surgical resection at our institution between January 2004 and July 2011, we included 76 patients with recurrence whose post-recurrence treatment and outcome could be confirmed. We then retrospectively evaluated the effect of prognostic factors on post-recurrence survival. RESULTS There were 50 men and 26 women, and the median age at recurrence was 74.5 years. The median time from surgical resection to recurrence was 12.7 months. Thirty-eight of the 76 (50%) patients underwent multimodality treatment with surgery and preoperative and/or postoperative chemotherapy as their initial treatment. For recurrence, systemic chemotherapy was administered to 64 (84%) patients, and the disease control rate for first-line chemotherapy was 55%. The 1- and 2-year post-recurrence survival rates were 68.3 and 45.8%, respectively, and the median post-recurrence survival time was 17.7 months. Six independent prognostic factors were identified: wild-type EGFR, no adjuvant chemotherapy for the primary lung cancer, age ≥ 80 years at recurrence, a poor Eastern Cooperative Oncology Group performance status at recurrence, symptomatic at recurrence and no systemic chemotherapy for recurrence, which significantly decreased the post-recurrence survival. CONCLUSIONS The prognosis of patients with NSCLC recurrence after surgery is currently improving. Our results suggested two new prognostic factors, adjuvant chemotherapy and EGFR mutations, neither of which have been previously reported. Treatment strategies for postoperative recurrence should be established based on a more detailed subdivision of factors, such as histology and molecular markers, in the future.

Influence of vascular endothelial growth factor single nucleotide polymorphisms on non-small cell lung cancer tumor angiogenesis

Vascular endothelial growth factor (VEGF) plays an important role in tumor angiogenesis. Several studies have reported that genomic VEGF polymorphisms may influence VEGF synthesis. To evaluate the role of VEGF single nucleotide polymorphisms (SNPs), we examined the expression of several angiogenesis-related proteins [VEGF, hypoxia-inducible factor-1α (HIF-1α) and delta-like ligand 4 (Dll4)] and the spread of microvessels in resected non-small cell lung cancer (NSCLC). Blood and tumor tissue from 83 patients with NSCLC were examined for VEGF −460T/C (rs833061) and VEGF +405G/C (rs2010963) SNPs using the SNaPshot method. Immunohistochemical staining was performed to measure protein expression and microvessel density (MVD). VEGF −460T/C and +405G/C SNPs showed no association with VEGF or HIF-1α expression and MVD. Patients with VEGF −460TT and the TC genotype had significantly higher MVD compared to those with the CC genotypes. Furthermore, patients with the VEGF −460TT genotype had significantly higher Dll4 expression compared to those with the TC or CC genotypes, while the VEGF +405G/C SNP displayed no association with Dll4 expression and MVD. These findings indicate that the VEGF −460T/C SNP may have a functional influence on tumor angiogenesis in NSCLC. We hypothesize that VEGF SNPs may influence angiogenesis through Dll4.

Teratoma with malignant transformation in the anterior mediastinum

References 1. Oey IF, Jeyapalan K, Entwisle JJ, Waller DA. Pseudo-tumours of the lung after lung volume reduction surgery. Ann Thorac Surg. 2004;77: 1094-6. 2. Dumon JF, Cavaliere S, Diaz-Jimenez JP, et al. Seven year experience with the Dumon prosthesis. J Bronchol. 1996;3:6-10. 3. Hocwald E, Sichel JY, Dano I, Meir K, Eliashar R. Adverse reaction to surgical sutures in thyroid surgery. Head Neck. 2003;25: 77-81. 4. Baughman RP, Lower EE, du Bois RM. Sarcoidosis. Lancet. 2003;361: 1111-8. 5. MacEwen C, Gregson R. Complications of strabismus surgery: how to avoid and manage them. In: Manual of strabismus surgery. Oxford: Butterworth-Heinemann; 2003. p. 181. Figure 2. Granulation tissue seen over the distal end of the Y-stent at the left bronchial arm 1 week after placement (A) and 3 months after the commencement of steroid treatment (B). Brief Communications

Maximal Standardized Uptake Value on FDG-PET Is Correlated With Cyclooxygenase-2 Expression in Patients With Lung Adenocarcinoma

BACKGROUND Cyclooxygenase-2 (COX-2) is constitutively overexpressed in a variety of epithelial malignancies and is usually associated with a poor prognosis. Fluorodeoxyglucose positron emission tomography (FDG-PET) has become an important tool for the diagnosis and staging of non-small-cell lung cancer. The maximal standardized uptake values (SUVmax) of primary tumors on FDG-PET have been shown to be correlated with some clinicopathologic factors. In this study, we investigated the prediction of intratumoral COX-2 expression by FDG-PET in cases of lung adenocarcinoma. METHODS We conducted a retrospective review of the data of 60 patients with lung adenocarcinoma measuring less than 3 cm in diameter. Immunohistochemical staining for COX-2 and other biological factors that might influence cancer progression was performed, and the correlations of the selective tumor marker expression with the SUVmax were evaluated. RESULTS A significant correlation was observed between the SUVmax and the expressions of COX-2, Ki-67, and vascular endothelial growth factor (VEGF). Multiple stepwise regression analysis revealed significant relationships between the SUVmax and the expression of COX-2 (p<0.001) and Ki-67 (p=0.016). Of the 2, COX-2 expression was the stronger determinant of the SUVmax, which increased in proportion to the score for COX-2 expression. The recurrence-free survival of patients with elevated COX-2 expression was significantly worse than that of patients not showing COX-2 expression. CONCLUSIONS The expression of COX-2 in primary tumors is as strongly correlated with a worse clinical outcome as is increased FDG uptake in cases of lung adenocarcinoma. These findings indicate that the SUVmax of primary tumors might reflect the biological malignant potential in lung adenocarcinomas.

Unknown primary large cell neuroendocrine carcinoma (LCNEC) in the mediastinum

Unknown primary large cell neuroendocrine carcinoma (LCNEC) in the mediastinum is extremely rare. In this report, we present a case of a 53-year-old man with superior vena cava (SVC) syndrome who developed LCNEC in the middle mediastinum. His chief complaint was facial edema. Chest X-ray revealed an abnormal shadow in the right upper mediastinum. Computed tomography (CT) scan of the chest revealed a 67-mm mass in the middle mediastinum. Tumor invasion caused constriction of the SVC. The patient underwent induction chemoradiotherapy with vinorelbin and cisplatin and concurrent radiation therapy. After induction therapy, the tumor size decreased remarkably and was resected completely. The pathological diagnosis was LCNEC.

Recent results regarding the clinical impact of smoking history on postoperative complications in lung cancer patients

Cigarette smoking is a well-known risk factor for perioperative surgery-related complications; however, steady progress in perioperative management has been made year by year. This study investigated the influence of cigarette smoking on postoperative complications in patients with lung cancer over the last three years in our institution. Clinical records of 194 patients who had undergone a pulmonary resection for lung cancer were retrospectively reviewed. The clinico-pathological findings and postoperative complications were compared among patients with smoking history. Smokers, including a higher number of men, had more preoperative respiratory complications, a lower FEV(1)/FVC, larger tumors, and included more squamous cell carcinoma in comparison to non-smokers. A univariate analysis revealed that sex, age and smoking history were independent risk factors in the postoperative complications; however, a multivariate analysis revealed that those factors including smoking history were not independent. In a subgroup of smokers subclassified by their smoking status or smoking index, there were no significant differences in postoperative complications. Over the recent three years of this study, smoking history was not a significant risk factor in postoperative complications. Especially in smokers, smoking status or smoking index was not a significant risk factor in postoperative complications, too.

A case report of intrapulmonary schwannoma

A 38-year-old man without any symptoms was admitted to our institution because of an abnormal shadow found incidentally on a chest X-ray. Chest computed tomography showed a round mass in the lingular segment of the left upper lobe. Lingular segmentectomy was performed, and the histopathological diagnosis was intrapulmonary schwannoma. Immunohistochemical staining revealed a positive result for S-100 protein and negative results for CD34 and desmin. We report this case of intrapulmonary schwannoma, which is extremely rare.

Case of pleural metastasis of prostate cancer

The most frequent sites of prostate cancer metastases are the bone and lung. Pleural metastasis of prostate cancer is clinically rare. We report a case with solitary pleural thickening arising from the metastasis of prostate cancer. A 71‐year‐old man was referred to our hospital for further examination of pleural thickening detected during a chest computed tomography (CT) examination. A video‐assisted pleural biopsy was performed. The pathological findings showed that the tumor cells had spread from the parietal pleura to adipose tissue around the costal muscles. The tumor cells were positive for prostate‐specific antigen (PSA) and negative for calretinin, cytokeratin (Ck5/6) and D2‐40. These findings suggested that the pleural lesion was a metastasis of the prostate cancer.

Lung cancer with sarcoid reaction in the lymph nodes following chemoradiotherapy.

This report describes a case of lung cancer with sarcoid reaction following chemoradiotherapy, showing false-positive accumulation of 18F-fluorodeoxyglucose on positron-emission tomography in a 55-year-old man. Treatment-related sarcoid reaction should be considered when the accumulation of 18F-fluorodeoxyglucose shows rapid extension in the course of treatment.