Ken Kodama

Intentional limited resection for selected patients with T1 N0 M0 non-small-cell lung cancer: A single-institution study

OBJECTIVES To comparatively evaluate lobectomy and limited resection for T1 N0 M0 non-small-cell lung cancer, we reviewed case series with concurrent nonrandomized controls. METHODS Limited resection with curative intent was performed for 63 patients with T1 N0 M0 non-small-cell lung cancer over a 10-year period. These 63 patients included 46 patients who underwent a segmentectomy as an intentional limited resection. These patients had good pulmonary function and could tolerate a lobectomy in the management of their disease. The other 17 patients underwent wedge resection or segmentectomy as a compromised limited resection because they had poor pulmonary reserve or other limiting factors and could withstand a thoracotomy but could not tolerate a lobectomy in the management of their disease. RESULTS The 5-year survival was 93% in the intentional resection group. The survival curve for this group was not different from that for 77 patients who underwent the standard operation (lobectomy plus complete mediastinal lymph node dissection) for T1 N0 M0 non-small-cell lung cancer during the same period. The frequency of local/regional recurrence in the intentional resection group was 8.7% (4/46); the recurrence in three patients was situated in the mediastinum. According to multivariate analysis, limited resection was not associated with poor survival. CONCLUSION Segmentectomy with regional lymph node dissection, including the mediastinum, should be considered as an acceptable alternative treatment for selected patients with T1 N0 M0 disease.

Meta-Analysis of Postoperative Adjuvant Chemotherapy With Tegafur-Uracil in Non-Small-Cell Lung Cancer

PURPOSE Recent clinical trials have shown the efficacy of platinum-based adjuvant chemotherapy for completely resected non-small-cell lung cancer (NSCLC). In Japan, many clinical trials of adjuvant chemotherapy with tegafur-uracil (UFT) have been conducted, and some trials showed positive results while others showed negative results. Thus, we performed a meta-analysis to assess the efficacy of postoperative adjuvant chemotherapy with UFT in NSCLC. METHODS Among nine trials of postoperative adjuvant UFT-containing chemotherapy, six trials comparing surgery alone with surgery plus UFT were identified. Of six trials, two were three-arm trials including cisplatin-based chemotherapy followed by UFT, and data from that arm were not included in the meta-analysis. RESULTS Of 2,003 eligible patients, most (98.8%) had squamous cell carcinoma or adenocarcinoma, and most had stage I disease; the tumor classification was T1 in 1,308 (65.3%), T2 in 674 (33.6%), and the nodal status was N0 in 1,923 (96.0%). The two treatment groups did not differ significantly in major prognostic factors. The median duration of follow-up was 6.44 years. The survival rates at 5 and 7 years were significantly higher in the surgery plus UFT group (81.5% and 76.5%, respectively) than in the surgery alone group (77.2% and 69.5%, respectively; P = .011 and .001, respectively). The overall pooled hazard ratio was 0.74, and its 95% CI was 0.61 to 0.88 (P = .001). CONCLUSION This meta-analysis showed that postoperative adjuvant chemotherapy with UFT was associated with improved 5- and 7-year survival in a Japanese patient population composed primarily of stage I adenocarcinoma patients.

Quantitative detection of EGFR mutations in circulating tumor DNA derived from lung adenocarcinomas.

Purpose: Examination of somatic epidermal growth factor receptor (EGFR) mutations is now a diagnostic routine for treatment of cancer using EGFR tyrosine kinase inhibitors (EGFR-TKI). Circulating tumor DNA is a promising target for noninvasive diagnostics. We evaluated its utility by quantitatively detecting activating and resistant mutations, which were measured with BEAMing (beads, emulsion, amplification, and magnetics). Experimental Design: Twenty-three patients with lung cancer with progressive disease after EGFR-TKI treatment and 21 patients who had never been treated with EGFR-TKIs were studied. Their primary tumors were confirmed to have activating mutations. In the plasma DNA of each patient, the activating mutation found in the corresponding primary tumor and the T790M resistance mutation were quantified by BEAMing. Results: In 32 of 44 patients, activating mutations were detected in the plasma DNA [72.7%; 95% confidence interval (CI), 58.0%–83.6%]. The T790M mutation was detected in 10 of 23 patients in the first group (43.5%; 95% CI, 25.6%–53.4%). The ratio of T790M to activating mutations ranged from 13.3% to 94.0%. The peak of the distribution of the mutation allele fraction in the plasma DNA was in the 0.1% to 1% range. Conclusions: The major advantage of BEAMing is its ability to calculate the fraction of T790M-positive alleles from the alleles with activating mutations. This feature enables the detection of increases and decreases in the number of T790M mutations in cancer cells, regardless of normal cell DNA contamination, which may be useful for monitoring disease progression. Circulating tumor DNA could potentially be used as an alternative method for EGFR mutation detection. Clin Cancer Res; 17(24); 7808–15. ©2011 AACR.

Prognostic value of ground-glass opacity found in small lung adenocarcinoma on high-resolution CT scanning

OBJECTIVE This study was undertaken to investigate the value of the ground-glass opacity (GGO) area found on high-resolution computed tomography (HRCT) scanning as a preoperative prognostic indicator. PATIENTS AND METHODS We studied 104 patients with small-sized lung adenocarcinoma, 20 mm or less in diameter, between 1995 and 1999. Three independent radiologists semi-quantitatively scored the extent of GGO on HRCT as greater than or less than 50%. Three independent pathologists semi-quantitatively scored the extent of the bronchioloalveolar carcinoma (BAC) component of the tumor on histologic examination as greater than or less than 50%. As no relapse occurred in patients with GGO greater than 50%, multivariate analysis of this prognostic factor was not possible. RESULTS Fifty patients were scored as having both BAC and GGO greater than 50%, 36 as both BAC and GGO less than 50%, and 16 as BAC greater than 50% and GGO less than 50%. In only two patients (1.9%), BAC less than 50% was overestimated on HRCT as GGO greater than 50%. The sensitivity and specificity of GGO to BAC were 76 and 95%, respectively. The 3 year-relapse-free survival rates in each group of 52 patients with GGO greater than and less than 50% were 100 and 72%, respectively, after a median follow-up of 24 months. Univariate analysis indicated that both GGO and BAC areas were significantly correlated with cancer relapse (P=0.005 and P=0.002). The multivariate analysis revealed an independent prognostic influence of the BAC area on relapse-free survival (P=0.015, relative risk=0.07). CONCLUSIONS To date there has been no relapse among the 52 patients with GGO greater than 50%. This novel classification based on the semiquantitative analysis of GGO area on HRCT should become an useful independent preoperative indicator when deciding on operative procedure, and to predict the potential of relapse in patients with small adenocarcinoma arising from the peripheral lung.

Prospective study of extended segmentectomy for small lung tumors: the final report

BACKGROUND Minimal resection of small lung tumors is still controversial. This study was conducted to clarify whether this type of operation is acceptable. METHODS From January 1992 to December 1994, 73 patients were registered in a multiinstitutional trial of limited resection for peripheral lung tumors less than 2 cm in diameter. The operative procedure consisted of extended segmentectomy in which the cut line of the lung was beyond the burdened segment, confirming N0 disease by intraoperative lymph node examination of frozen sections. The operation was changed to other procedures if the report was positive. RESULTS All the patients were observed more than 5 years. There were no perioperative deaths and no major complications. A total of 55 patients were finally enrolled in this study. Ten patients died postoperatively, 4 of lung cancer and the remaining 6 died of other diseases, with no signs of recurrence. The 5-year survival rate, excluding these 6 patients, was 91.8%; for all patients including those who died it was 81.8%. A total of 18 patients were not included in this study for various reasons. The decrease in forced vital capacity was 11.3% +/- 9.8% compared with the preoperative value. CONCLUSIONS Extended segmentectomy is an alternative method as a standard operation for patients with small peripheral lung tumors, and the loss of lung function is minimal. However, patient selection must be strict, with intraoperative pathologic examination, and a wide margin to the lesion beyond the burdened segment is mandatory.

Intratumor heterogeneity of epidermal growth factor receptor mutations in lung cancer and its correlation to the response to gefitinib

Somatic mutations introduced into the epidermal growth factor receptor (EGFR) gene in non‐small‐cell lung cancer (NSCLC) are important factors to determine therapeutic responses to gefitinib. The current diagnostic test measures the overall EGFR mutation status of the cancer tissue, and may ignore the presence of non‐mutated, gefitinib‐unresponsive cancer cells. Twenty‐one NSCLC patients with EGFR mutations were recruited for the study. All patients were treated with gefitinib after surgical treatment. Fifty to sixty areas of NSCLC tumors were sampled from each tissue, and their EGFR mutation states were determined by a primer extension assay. This assay discriminates between EGFR mutation‐positive and ‐negative cancer cells within a single tumor tissue. Fifteen tissues consisted only of cells with EGFR mutations, but the remaining six tissues contained both mutated and non‐mutated cells. Time to disease progression and overall survival after gefitinib treatment were significantly shorter in those patients with EGFR heterogeneity (P = 0.009 and P = 0.003, respectively). A considerable proportion of NSCLC contains a heterogeneous population of both EGFR mutated and non‐mutated cancer cells, resulting in a reduced response to gefitinib. The intratumor genetic heterogeneity of a target molecule such as EGFR would be an important factor to consider when treating patients with molecular target agents. (Cancer Sci 2008; 99: 929–935)

Natural history of pure ground-glass opacity after long-term follow-up of more than 2 years

BACKGROUND Pure ground-glass opacity (PGGO) is a new entity that has been clearly defined on high-resolution computed tomography (CT) during the last half decade. It is important to investigate the natural history of PGGO through long-term observation for the management of this new entity. METHODS We investigated 19 patients with PGGO(s) defined on high-resolution computed tomography and retained as PGGO for more than 2 years. The PGGOs of 11 patients were detected at annual mass screening by low-radiation-dose CT (low-dose CT), 7 at follow-up CT after cancer resection, and 1 incidentally on CT. After long-term observation, 10 of 19 patients underwent operation and 9 are currently being followed-up with CT. Their growth characteristics and histologic findings are reported. RESULTS The median follow-up period was 32 months, ranging from 24 to 124 months. The sizes of PGGOs at the time of discovery were 4 to 18 mm in largest diameter (average 8.6 mm). During follow-up, the size of PGGO showed no change in 8 patients, increased slightly (up to 5 mm) in 6 patients, and increased by more than 5 mm in 5 patients. Ten patients had limited resection (segmentectomy or wide wedge resection) with negative surgical margin by intraoperative lavage cytology of the resection margin of the lung. Of them, 5 patients had adenocarcinoma, 3 pulmonary lymphoproliferative disorder, and 1 each atypical adenomatous hyperplasia and focal fibrosis. There was no clear tendency between the degree of size change and histology. In all but 1 of 9 patients with follow-up only, the PGGOs showed either no change or only a slight increase within 5 mm in largest diameter. CONCLUSIONS These data suggest that some PGGOs will never progress to clinical disease and would be included in the category of overdiagnosis bias. However, a prior history of lung cancer should significantly raise the index of suspicion, as 4 of 5 proven cancer cases in this small series fell into that category. Because of the difficulties of preoperative and intraoperative histodiagnosis of PGGO, minimally invasive surgery may be appropriate from the viewpoints of both diagnosis and curability.

Tumor-Secreted Lactic Acid Promotes IL-23/IL-17 Proinflammatory Pathway

IL-23 is a proinflammatory cytokine consisting of a p19 subunit and a p40 subunit that is shared with IL-12. IL-23 is overexpressed in and around tumor tissues, where it induces local inflammation and promotes tumor development. Many tumor cells produce large amounts of lactic acid by altering their glucose metabolism. In this study, we show that lactic acid secreted by tumor cells enhances the transcription of IL-23p19 and IL-23 production in monocytes/macrophages and in tumor-infiltrating immune cells that are stimulated with TLR2 and 4 ligands. DNA elements responsible for this enhancing activity of lactic acid were detected in a 2.7-kb 5′-flanking region of the human IL-23p19 gene. The effect of lactic acid was strictly regulated by extracellular pH. Furthermore, by inducing IL-23 overproduction, lactic acid facilitated the Ag-dependent secretion of proinflammatory cytokine IL-17 but not IFN-γ by TLR ligand-stimulated mouse splenocytes. Interestingly, this effect was observed even in the absence of TLR ligand stimulation. These results suggest that rather than just being a terminal metabolite, lactic acid is a proinflammatory mediator that is secreted by tumor cells to activate the IL-23/IL-17 proinflammatory pathway but not the Th1 pathway. Targeting the lactic acid-induced proinflammatory response may be a useful approach for treating cancer.

Prognostic value of bronchiolo-alveolar carcinoma component of small lung adenocarcinoma

BACKGROUND Bronchiolo-alveolar carcinoma (BAC) is often observed in lung adenocarcinoma, but its clinicopathological and prognostic significance, especially in small peripheral lung adenocarcinoma, remains undetermined. METHODS We assessed 206 consecutive cases of surgically resected small peripheral lung adenocarcinoma (less than 2 cm in diameter) recorded between 1973 and 1997. According to the component area of well differentiated BAC within maximally cut surface specimens of tumor tissue, we semiquantitatively classified the tumors into four types: those in which the BAC component comprised 0% (type I), 1% to 49% (type II), 50% to 99% (type III), and 100% (type IV) of the tumor tissue. RESULTS Forty tumors were classified as type I, 75 as type II, 74 as type III, and 17 as type IV. The tumors with less BAC, especially type I and II, showed a significantly more aggressive nodal involvement and tumor stage, and consequently a worse prognosis, while type IV tumors had no nodal involvement and the most favorable prognosis. The patients with type III showed clinicopathological characteristics somewhere between those of type II and type IV patients. Among stage I patients, however, those with type II had the worst prognosis, while those with type I showed as good a prognosis as the other two groups. CONCLUSIONS This novel classification based on the degree of BAC involvement in small peripheral lung adenocarcinoma may reflect clinicopathological and prognostic characteristics. This classification may prove practical for planning therapeutic strategies, in particular surgical treatment.

Link of a new type of apoptosis-inducing gene ASY/Nogo-B to human cancer.

Although apoptosis plays an essential role in the embryogenesis and homeostasis of multicellular organisms, this mechanism has not yet been fully clarified. We isolated a novel human apoptosis-inducing gene, ASY, which encodes an endoplasmic reticulum-targeting protein without any known apoptosis-related motifs. This gene is identical to the Nogo-B, a splice variant of the Nogo-A which has recently been shown to be an inhibitor of neuronal regeneration in the central nervous system. Ectopic expression of the ASY gene led to extensive apoptosis, particularly in cancer cells. Furthermore, transcription of the ASY gene was suppressed in small cell lung cancer. These results suggest that a new type of apoptosis-inducing gene, namely, ASY, may be involved in the development of certain types of cancer.