Mitsunori Higuchi

Long-term outcomes after video-assisted thoracic surgery (VATS) lobectomy versus lobectomy via open thoracotomy for clinical stage IA non-small cell lung cancer

BackgroundVideo-assisted thoracic surgery (VATS) lobectomy is a standard treatment for lung cancer. This study retrospectively compared long-term outcomes after VATS lobectomy versus lobectomy via open thoracotomy for clinical stage IA non-small cell lung cancer (NSCLC).MethodsFrom July 2002 to June 2012, 160 patients were diagnosed with clinical stage IA NSCLC and underwent lobectomy. Of these, 114 underwent VATS lobectomy and 46 underwent lobectomy via open thoracotomy.ResultsThe 5-year disease-free survival (DFS) rate was 88.0% in the VATS group and 77.1% in the thoracotomy group for clinical stage IA NSCLC (p = 0.1504), and 91.5% in the VATS group and 93.8% in the thoracotomy group for pathological stage IA NSCLC (p = 0.2662). The 5-year overall survival (OS) rate was 94.1% in the VATS group and 81.8% in the thoracotomy group for clinical stage IA NSCLC (p = 0.0268), and 94.8% in the VATS group and 96.2% in the thoracotomy group for pathological stage IA NSCLC (p = 0.5545). The rate of accurate preoperative staging was 71.9% in the VATS group and 56.5% in the thoracotomy group (p = 0.2611). Inconsistencies between the clinical and pathological stages were mainly related to tumor size, nodal status, and pleural invasion. Local recurrence occurred for one lesion in the VATS group and six lesions (five patients) in the thoracotomy group (p = 0.0495).ConclusionsThe DFS and OS were not inferior after VATS compared with thoracotomy. Local control was significantly better after VATS than after thoracotomy. Preoperative staging lacked sufficient accuracy.

Prognostic Impact of Hypoxia-Inducible miRNA-210 in Patients with Lung Adenocarcinoma

Objective. The aim of this study was to investigate the prognostic value of MicroRNA-210 (miR-210) expression in patients with non-small-cell lung cancer (NSCLC). Methods. We examined the miR-210 expression of samples of 80 patients, who underwent surgical resection at Fukushima Medical University from 2004 to 2007, by using quantitative RT-PCR. The relationship between miR-210 expression and clinicopathological factors as well as histological subtype was statistically analyzed. Results. miR-210 expression showed an inverse correlation with disease-free and overall survival in patients with NSCLC. Significant correlations were found between miR-210 expression and lymph node metastasis, late disease stages, and poor prognosis in patients with adenocarcinoma. Multivariate Cox analysis indicated that miR-210 expression was an independent prognostic factor for disease-free survival in patients with adenocarcinoma. Conclusions. We showed that miR-210 may be a prognostic biomarker for patients with NSCLC, especially for those with lung adenocarcinoma.

Expression of peanut agglutinin-binding carbohydrates correlates with nodal involvement in human lung adenocarcinoma.

The expression of 15 kinds of lectin-binding carbohydrates was examined histochemically in lung adenocarcinoma. The relation between expression of lectin binding carbohydrates and clinicopathologic factors was studied. The expression of peanut agglutinin (PNA) binding carbohydrates showed a high lymph node metastatic rate. Relation between PNA-binding carbohydrate expression and lymphatic vessel invasion was also recognized. Multivariate analysis showed that PNA-binding carbohydrate expression was an independent predictive factor of lymph node metastasis (odds ratio: 2.8) and of lymphatic vessel invasion (odds ratio: 5.2). The expression of PNA-binding carbohydrates would be a significant predictive factor for lymph node metastasis of lung adenocarcinomas.

Prognostic impact of the high-sensitivity modified Glasgow prognostic score in patients with resectable non-small cell lung cancer

OBJECTIVE The present study compared the prognostic value of the Glasgow prognostic score (GPS), modified GPS (mGPS), high-sensitivity mGPS (HS-mGPS), neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), prognostic index (PI), and prognostic nutritional index (PNI) in patients with resectable non-small cell lung cancer (NSCLC). MATERIALS AND METHODS This retrospective study included 327 consecutive patients with resectable NSCLC with a follow.-up period. >5. years. Initially, the HS-mGPS was directly compared with the GPS and mGPS in terms of their ability to predict survival in patients with resectable NSCLC. Second, inflammation.-based scores, including the HS-mGPS, NLR, PLR, PI, and PNI, were analyzed preoperatively using multivariate Cox analysis. Clinical characteristics reflecting cancer progression were also analyzed. RESULTS Elevated GPS (P < 0.001), mGPS (P < 0.001), and HS-mGPS (P < 0.001) levels were associated with reduced overall survival. The HS-mGPS (P < 0.001) was superior to the GPS and mGPS (P = 0.884) as a prognostic marker of postoperative outcomes. On multivariate Cox analysis, age (P = 0.026), p-T status (P < 0.001), p-N status (P < 0.001), lymphatic vessel invasion (P = 0.008), and the HS-mGPS (P = 0.016) were independent prognostic factors for survival. CONCLUSION These results suggest that the HS-mGPS might have a greater prognostic impact than the GPS, mGPS, NLR, PLR, PI, or PNI in patients with resectable NSCLC.

Clinical significance of expanded Foxp3+ Helios- regulatory T cells in patients with non-small cell lung cancer

The functions of different regulatory T cell (Treg) types in cancer progression are unclear. Recently, expression of the transcription factor Helios was proposed as a marker for natural (non-induced) Tregs. The present study investigated the clinical significance of Helios expression in patients with non-small cell lung cancer (NSCLC). We enrolled 64 patients with NSCLC, of whom 45 were treated surgically and 19 received chemotherapy because of advanced/recurrent disease. Their peripheral blood mononuclear cells were examined by flow cytometry. From the 45 surgery patients, we matched 9 patients with recurrent disease with 9 stage-matched patients without recurrence (n=18), compared their specimens immunohistochemically for tumor infiltrating lymphocytes (TILs) and analyzed these data against clinicopathological factors. Helios expression in Foxp3+ Tregs was 47.5±13.3% in peripheral blood and 18.1±13.4% in tumor specimens. Percentage of Helios− Tregs among CD4+ T cells were significantly higher in the cancer patients (2.4%), especially those with stage IA disease (2.6%) than in healthy donors (1.5%; P<0.001). Patients with low levels of Helios expression in Tregs among their TILs had significantly poorer survival (P=0.038). Helios− Tregs may affect immune suppression, even in early stage NSCLC; they could also be a useful prognostic biomarker in patients with NSCLC, and possibly a novel cancer immunotherapy target.

Recent advances in immunotherapy for non-small-cell lung cancer

Despite of recent development in the field of molecular targeted therapies, lung cancer is a leading cause of cancer death in the world. Remarkable progress has been made recently in immunotherapy for patients with non-small-cell lung cancer (NSCLC), with several modalities, concepts, and treatment settings being investigated. In vaccine development, large-scale clinical trials such as those with L-BLP25, belagenpumatucel-L, TG4010, and talactoferrin are already ongoing and some results have been reported. A trial of a vaccine as adjuvant therapy for patients with completely resected NSCLC is also ongoing with one of the major cancer-testis antigens, melanoma-associated antigen (MAGE)-A3. More recently, the effectiveness of multiple peptide vaccines has also been shown. Recently developed unique treatment modalities are the immune checkpoint inhibitors, such as antibodies against PD-1 and PD-L1, which also show promise. However, although therapeutic cancer vaccines are generally thought to be safe, severe adverse events should be monitored carefully when using immune checkpoint inhibitors. Here, we discuss recent advances and future perspectives of immunotherapy for patients with NSCLC.

Epidermal growth factor receptor gene mutation as risk factor for recurrence in patients with surgically resected lung adenocarcinoma: a matched-pair analysis

OBJECTIVES Epidermal growth factor receptor (EGFR) mutation is a robust prognostic factor in patients with lung adenocarcinoma (ADC). However, the role of EGFR mutation status as a recurrence-risk factor remains unknown because the presence of such mutations is associated with other background characteristics. We therefore conducted a matched-pair analysis to compare recurrence-free survival (RFS) in matched cohorts of patients with lung ADC. METHODS We enrolled 379 patients who underwent surgical resection for lung ADC between 2005 and 2012. We determined the EGFR mutation status of each tumour. Matching their age, gender, smoking history and pathological stage (pStage), we compared RFS between matched cohorts with and without EGFR mutation (n = 86 each). RESULTS The median age was 67 years, there were 39 (45%) men, 39 (45%) ex- or current smokers and pStage I: 71 (83%), II: 5 (6%), III: 8 (9%), IV: 2 (2%) in each group. The 3- and 5-year RFS rates in patients with mutant and wild-type EGFR were 85 and 78%, and 74 and 60%, respectively, with significant differences between the groups (P = 0.040). Multivariate analysis identified vascular invasion and lymphatic permeation, but not EGFR mutation status, as independent risk factors for recurrence. CONCLUSIONS EGFR-gene mutation might be a favourable recurrence-risk factor in patients with surgically resected lung ADC, but further studies in larger cohorts are needed to verify this hypothesis.

Successfully resected intrathoracic low-grade fibromyxoid sarcoma

A low-grade fibromyxoid sarcoma (LGFMS), an Evans tumor, is highly unusual. It is rarely described as a primary neoplasm in the thoracic cavity. We experienced a case of a 20-year-old woman with a right intrathoracic tumor that was surgically treated. Postoperative pathology of the resected specimen revealed the tumor to be LGFMS based on its histological appearance, immunohistological staining, and evidence of fused in sarcoma (FUS) translocation by fluorescence in situ hybridization. Tumor resection was performed with a free surgical margin, and the resultant chest wall defect was repaired using prosthetic mesh. The patient has been well without any recurrence for 18 months since surgery.

Expression of Notch1 and Numb in small cell lung cancer

Notch signaling in tumorigenesis functions as an oncogene or tumor suppressor according to the type of malignancy. Numb represses intracellular Notch signaling. Previous studies have demonstrated that Notch signaling suppresses the proliferation of small cell lung cancer (SCLC) cell lines. However, in SCLC, the association between Notch1 and Numb expression and clinicopathological factors or prognosis has remained unclear. In this study, we evaluated the expression of Notch1 and Numb in SCLC. We immunohistochemically assessed 125 SCLCs that were surgically resected at 16 institutions participating in either the Hokkaido Lung Cancer Clinical Study Group Trial (HOT) or the Fukushima Investigative Group for Healing Thoracic Malignancy (FIGHT) between 2003 and 2013. Correlations between Notch1 or Numb expression and various clinicopathological features were evaluated. Notch1 expression was associated with ECOG performance status. Numb expression was associated with age, sex, and pathological histology (SCLC or Combined SCLC). Analysis of cellular biological expression did not demonstrate a significant correlation between the expression of Notch1 and of Numb. Multivariate Cox regression analysis showed that high Notch1 expression was an independent favorable prognostic factor for SCLC(hazard ratio = 0.503, P = 0.023). High Notch1 expression, but not Numb expression, is associated with favorable prognosis in SCLC.

Prognostic impact of clinical variables on surgically resected small-cell lung cancer: Results of a retrospective multicenter analysis (FIGHT002A and HOT1301A)

OBJECTIVES Several American and Japanese guidelines recommend surgery for patients with c-stage I small-cell lung cancer (SCLC), whereas the European Society of Medical Oncology (ESMO) guidelines recommend surgery for patients with not only c-stage I but also c-stage II (T2N1) SCLC. In addition, previous studies identified various factors other than clinical stage that are related to survival in these patients. Thus, further validation and examination of the association of clinical stage and other clinical variables with survival are required for establishing practical management of early-stage SCLC. PATIENTS AND METHODS We reviewed the clinical courses of 156 SCLC patients who had undergone surgery at 17 institutions between January 2003 and January 2013. RESULTS Clinical stages (tumor-node-metastasis [TNM] version 7) of the 156 patients were 98 cases in IA, 14 in IB, 16 in IIA, 7 in IIB, 18 in IIIA, and 3 in IIIB. Median overall survival (OS) was 33.3 months (95% confidence interval: 20.9-45.8). Multivariate analysis revealed that OS was longer in patients either at c-stage II and under, with a maximum tumor diameter of <20mm, with preoperative diagnosis, without a history or presence of other types of cancer, or who underwent prophylactic cranial irradiation (PCI). CONCLUSION These results indicate that a history or presence of other types of cancer might be a major decisive factor for surgery. Patients with c-stages I and II (c-T2N1) can be considered for surgery, and PCI may be useful in patients undergoing surgery in a practical setting, partly supporting the ESMO guidelines.(1).