Masayuki Toishi

Tumor Size and Computed Tomography Attenuation of Pulmonary Pure Ground-Glass Nodules Are Useful for Predicting Pathological Invasiveness

Objectives Pulmonary ground-glass nodules (GGNs) are occasionally diagnosed as invasive adenocarcinomas. This study aimed to evaluate the clinicopathological features of patients with pulmonary GGNs to identify factors predictive of pathological invasion. Methods We retrospectively evaluated 101 pulmonary GGNs resected between July 2006 and November 2013 and pathologically classified them as adenocarcinoma in situ (AIS; n = 47), minimally invasive adenocarcinoma (MIA; n = 30), or invasive adenocarcinoma (I-ADC; n = 24). The age, sex, smoking history, tumor size, and computed tomography (CT) attenuation of the 3 groups were compared. Receiver operating characteristic (ROC) curve analyses were performed to identify factors that could predict the presence of pathologically invasive adenocarcinomas. Results Tumor size was significantly larger in the MIA and I-ADC groups than in the AIS group. CT attenuation was significantly greater in the I-ADC group than in the AIS and MIA groups. In ROC curve analyses, the sensitivity and specificity of tumor size (cutoff, 11 mm) were 95.8% and 46.8%, respectively, and those for CT attenuation (cutoff, −680 HU) were 95.8% and 35.1%, respectively; the areas under the curve (AUC) were 0.75 and 0.77, respectively. A combination of tumor size and CT attenuation (cutoffs of 11 mm and −680 HU for tumor size and CT attenuation, respectively) yielded in a sensitivity and specificity of 91.7% and 71.4%, respectively, with an AUC of 0.82. Conclusions Tumor size and CT attenuation were predictive factors of pathological invasiveness for pulmonary GGNs. Use of a combination of tumor size and CT attenuation facilitated more accurate prediction of invasive adenocarcinoma than the use of these factors independently.

Computed tomography attenuation predicts the growth of pure ground-glass nodules.

OBJECTIVES Cases of lung cancer with pure ground-glass nodules (GGNs) have been detected with increasing frequency since the advent of computed tomography (CT), and growth is sometimes noted during follow-up. The objective of this study was to evaluate the potential predictive factors for pure GGN growth. MATERIALS AND METHODS We retrospectively examined 124 cases involving pure GGNs. Patients were monitored for > 2 years using high-resolution CT. After a median follow-up period of 57.0 months, GGNs showed growth in 64 of the 124 cases. We compared the patient characteristics and tumor properties of cases with and without growth. The predictive value of the mean CT attenuation for GGN growth was evaluated using receiver operating characteristic curve analysis. RESULTS Univariate analysis revealed significant differences between mean CT attenuation values in patients with and without growth (-602.9 ± 90.7 Hounsfield units [HU] vs -705.7 ± 77.7HU, P < 0.0001). The final incidence of growth was estimated to be significantly higher for lesions with a mean CT attenuation value of ≥ -670HU (n = 62; 93.2%) than for lesions with values of < -670HU (n = 62; 31.6%; P < 0.0001). The sensitivity and specificity for predicting tumor growth using this cutoff value were 78.1% and 80.0%, respectively (area under the curve, 0.81). CONCLUSION The mean CT attenuation value could be useful in predicting the growth of GGNs.

Usefulness of vessel-sealing devices for ≤7 mm diameter vessels: a randomized controlled trial for human thoracoscopic lobectomy in primary lung cancer

OBJECTIVES Vessel-sealing devices (VSDs) are widely used for various surgical procedures, including thoracoscopic surgery, but very few reports have compared their safety and usefulness with human thoracoscopic lobectomy procedures not employing VSDs. METHODS Primary lung cancer patients for whom a thoracoscopic lobectomy involving mediastinal lymph node dissection was planned in our department from April 2011 to March 2013 were recruited for the study. Patients were randomly allocated to a control group (n = 14) or a VSD group (n = 44), which comprised three sub-groups, namely EnSeal (n = 17), LigaSure (n = 15) and Harmonic (n = 12). The control group comprised patients undergoing surgery solely with ligation and conventional electrocautery. EnSeal, LigaSure and Harmonic were chosen because they are the three most popular disposable VSDs used in Japan. In the VSD groups, the proximal side of pulmonary artery stumps (≤7 mm diameter) were ligated and then treated with respective devices. Primary end-points were burst pressure of the pulmonary artery stump (measured using resected specimens), operative time, intraoperative blood loss, instances of endostapler use, intraoperative surgeon stress (assessed by visual analogue scale) and postoperative drainage volume and duration. As a secondary objective, the individual VSD groups were also compared with each other. RESULTS The burst pressure of ligation-treated pulmonary artery stumps was higher than that of VSD-treated stumps (P <0.0001). The burst pressure of <5-mm-wide VSD-treated stumps was higher than that of ≥5-mm-wide stumps (P = 0.0421). However, the burst pressure for all groups and all vessel diameters was sufficient to withstand the physiological pulmonary artery pressure. The VSD group demonstrated reduced intraoperative blood loss (P = 0.0241), surgeon stress (P = 0.0002), postoperative drainage volume (P = 0.0358) and shortened postoperative drainage duration (P = 0.0449). Operative time and the instances of endostapler use did not significantly differ. Comparison between each of the VSD groups revealed no significant differences. None of the patients experienced serious perioperative complications or died because of surgery. CONCLUSION VSD is simple and safe to use in thoracoscopic lobectomy involving mediastinal lymph node dissection for primary lung cancer. Furthermore, none of the VSDs used in this study presented any observable differences in quality that could lead to clinical problems.

Experience with pulmonary resection for extensively drug-resistant tuberculosis☆

Extensively drug-resistant tuberculosis is becoming a global threat. It is a relatively new phenomenon, and its optimal management remains undetermined. We report our experience in using pulmonary resection for treating patients with this disease. Records were reviewed of 54 consecutive patients undergoing a pulmonary resection for multidrug-resistant tuberculosis at Fukujuji Hospital between 2000 and 2006. These patients were identified using the definition approved by the World Health Organization Global Task Force on extensively drug-resistant tuberculosis in October 2006. Five (9%) patients (3 men and 2 women) aged 31-60 years met the definition. None of the patients was HIV-positive. Although the best available multidrug regimens were initiated, no patient could achieve sputum conversion. Adjuvant resectional surgery was considered because the patients had localized disease. Procedures performed included pneumonectomy (2) and upper lobectomy (3). There was no operative mortality or morbidity. All patients attained sputum-negative status after the operation, and they were maintained on multidrug regimens for 12-25 months postoperatively. All patients remained free from disease at the time of follow-up. Pulmonary resection under cover of state-of-the-art chemotherapy is safe and effective for patients with localized extensively drug-resistant tuberculosis.

The histological characteristics and clinical outcomes of lung cancer in patients with combined pulmonary fibrosis and emphysema

Combined pulmonary fibrosis and emphysema (CPFE) is an important risk factor for lung cancer (LC), because most patients with CPFE are smokers. However, the histological characteristics of LC in patients with CPFE (LC‐CPFE) remain unclear. We conducted this study to explore the clinicopathological characteristics of LC‐CPFE. We retrospectively reviewed data from 985 patients who underwent resection for primary LC, and compared the clinicopathological characteristics of patients with LC‐CPFE and non‐CPFE LC. We identified 72 cases of LC‐CPFE, which were significantly associated with squamous cell carcinoma (SqCC) histology (n = 46, P < 0.001) and higher tumor grade (n = 44, P < 0.001), compared to non‐CPFE LC. Most LC‐CPFE lesions were contiguous with fibrotic areas around the tumor (n = 59, 81.9%), and this association was independent of tumor location. Furthermore, dysplastic epithelium was identified in the fibrotic area for 31 (52.5%) LC‐CPFE lesions. Moreover, compared to patients with pulmonary fibrosis alone in the non‐CPFE group (n = 31), patients with CPFE were predominantly male (P = 0.008) and smokers (P < 0.001), with LC‐CPFE predominantly exhibiting SqCC histology (P = 0.010) and being contiguous with the tumor‐associated fibrotic areas (P < 0.001). Multivariate analysis revealed that CPFE was an independent predictor of overall survival (hazard ratio: 1.734; 95% confidence interval: 1.060–2.791; P = 0.028). Our results indicate that LC‐CPFE has a distinct histological phenotype, can arise from the dysplastic epithelium in the fibrotic area around the tumor, and is associated with poor survival outcomes.

Potential Role of ASC, a Proapoptotic Protein, for Determining the Cisplatin Susceptibility of Lung Cancer Cells

Primary lung cancer is the most frequent cause of cancer-related deaths worldwide. Cisplatin has been used as a key drug in the treatment for patients with lung cancer; however, most of the patients failed to respond to cisplatin within several months, and the mechanisms underlying the cisplatin resistance have not been fully elucidated. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is a key adaptor protein in the formation of inflammasomes. ASC is also involved in apoptotic signaling. Importantly, ASC expression is decreased in lung cancer and various cancers, but its precise function in tumor progression remains unknown. To explore the hitherto unknown role of ASC in lung cancer, we initially searched for lung cancer cell lines with higher expression levels of ASC using Cancer Cell Line Encyclopedia (CCLE) database, thereby identifying the A549 human non-small cell lung cancer cell line. Accordingly, with retroviral shRNA, the expression of ASC was forced to decrease in A549 cells. Stable ASC-knockdown cells, thus established, showed the increased activities of proliferation, motility, and invasion, compared with control cells. Importantly, ASC-knockdown cells also became resistant to cisplatin, but not to other anti-cancer agents, 5-fluorouracil and paclitaxel. Bcl-2 and phospho-Src levels were increased in ASC-knockdown cells. A Bcl-2 inhibitor, ABT-199, induced an apoptotic response in ASC-knockdown cells, and dasatinib, a Src inhibitor, blocked cell invasiveness. Thus, ASC may be involved in tumor suppression and cell death via Bcl-2 and pSrc. Targeting Bcl-2 and Src in ASC-downregulated populations of lung cancer may improve treatment outcome.

Higher Tissue Levels of Thymidylate Synthase Determined by ELISA Are Associated with Poor Prognosis of Patients with Lung Cancer

Thymidylate synthase (TS) is essential in thymidylate biosynthesis and DNA replication. Dihydropyrimidine dehydrogenase (DPD) is a rate-limiting enzyme in pyrimidine catabolism and is important in catabolism of 5-fluorouracil (5-FU). The significance of TS and DPD expressed in lung cancer remains controversial. Here we analyzed the relationship between TS and DPD expression and clinicopathological features of lung cancer. Enzyme-linked immunosorbent assays (ELISAs) were used to measure TS and DPD levels in paired tumor and non-tumor lung tissues obtained from 168 patients (107 adenocarcinomas, 39 squamous cell carcinomas, and 22 others), who had operations at the Shinshu University Hospital from 2004 to 2007 and were followed up for a median of 57.0 months. TS and DPD expression levels were higher in tumor tissues, and TS expression levels were significantly lower in adenocarcinomas than those in other subtypes. In addition, patients with low TS levels survived longer compared with patents with high TS levels. By contrast, DPD expression levels were not correlated with overall patient survival. Importantly, patients with low TS and DPD levels exhibited significantly prolonged survival than those with high TS and DPD. Among the 168 patients, 59 patients were treated with tegafur-uracil (UFT), a DPD-inhibitory fluoropyrimidine, and the UFT-treated patients with high TS and high DPD levels showed worst prognosis. Our study demonstrates a significant correlation between low TS expression levels and long-term prognosis of patients with lung cancer. Thus, ELISA is a clinically useful method to measure TS and DPD expression in lung cancer tissues.

Pulmonary artery reconstruction with a prosthetic conduit in lung cancer.

In radical pulmonary resection for advanced lung cancer, reconstruction of the pulmonary artery (PA) can preserve the lung parenchyma. Reconstruction techniques have gained acceptance because they enable the surgeon to avoid pneumonectomy. Various techniques have been documented, such as direct suturing, end-to-end anastomosis, and a patch or conduit reconstruction. We present two lobectomy cases in which the patients underwent PA reconstruction with prosthetic conduits because they were unfit for other procedures. In both cases, the conduits showed good postoperative patency. When interposition of a conduit is required for PA reconstruction, the use of a prosthetic conduit should be considered in selected cases.