Correlations of mRNA Levels among Efflux Transporters, Transcriptional Regulators, and Scaffold Proteins in Non-Small-Cell Lung Cancer.

Multidrug resistance (MDR) due to enhanced drug efflux activity of tumor cells can severely impact the efficacy of antitumor therapies. We recently showed that increased activity of the efflux transporter P-glycoprotein (P-gp) associated with activation of Snail transcriptional regulators may be mediated mainly by moesin in lung cancer cells. Here, we aimed to systematically evaluate the relationships among mRNA expression levels of efflux transporters (P-gp, breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 2 (MRP2)), scaffold proteins (ezrin (Ezr), radixin (Rdx), and moesin (Msn); ERM proteins), and SNAI family members (Snail, Slug, and Smac) in clinical lung cancer and noncancer samples. We found high correlations between relative (cancer/noncancer) mRNA expression levels of Snail and Msn, Msn and P-gp, Slug and MRP2, and Smuc and BCRP. These findings support our previous conclusion that Snail regulates P-gp activity via Msn and further suggest that Slug and Smuc may contribute to the functional regulation of MRP2 and BCRP, respectively, in lung cancer cells. This trial is registered with UMIN000023923.

Evidence for reactivation of human herpesvirus 6 in generalized lymphadenopathy in a patient with drug-induced hypersensitivity syndrome.

The present case provides direct evidence of human herpesvirus 6 reactivation in resected lymph node tissue in a patient with drug-induced hypersensitivity syndrome. This case clearly demonstrates that appropriate pathological evaluation of lymphadenopathy for drug-induced hypersensitivity syndrome, which mimics malignant lymphoma in clinical, radiological, and pathological findings, is required.

Castleman disease and mimickers: Clinicopathological findings of atypical lymphoproliferative disorders associated with autoimmune disease.

Atypical lymphoproliferative disorders (LPDs) related with autoimmune disease (AID) show marked clinicopathological diversity, which are defined as three distinct clinicopathological subtypes such as those resembling Castleman disease (CD), atypical paracortical hyperplasia with lymphoid follicles (APHLF), and atypical lymphoplasmacytic and immunoblastic proliferation (ALPIB). We studied excisional biopsy specimens from 31 patients with atypical LPDs associated with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjögren syndrome (SjS). The lesions in these 31 cases were classified into 6 (19.4%) cases resembling CD, 14 (45.2%) cases of APHLF, and 11 (35.5%) cases of ALPIB. Five cases (83.3%) resembling CD were in the active stage with systemic symptoms and multicentric lymphadenopathy. Thirteen cases (92.9%) of APHLF showed systemic symptoms, multicentric lymphadenopathy and abnormal laboratory findings. Histologic findings for cases resembling CD were rare in patients with RA and SjS. In AID patients, histologic findings for cases resembling CD or APHLF findings correlated with disease activity and multicentric lymphadenopathy. Six cases (54.5%) of ALPIB were in the active phase with systemic symptoms and multicentric lymphadenopathy. ALPIB tended to be unrelated to AID activity, especially in the majority of patients with no abnormal laboratory findings. Atypical LPDs associated with AID is a group of diseases that may be overdiagnosed and overtreated. The diagnosis of atypical LPDs associated with AID requires an understanding of the histological findings as well as a comprehensive assessment of the presence of systemic symptoms, the distribution of lymphadenopathy, and abnormal laboratory findings.

Moesin-Mediated P-Glycoprotein Activation During Snail-Induced Epithelial-Mesenchymal Transition in Lung Cancer Cells.

Epithelial-mesenchymal transition (EMT) plays a role in not only cancer metastasis, but also drug resistance, which is associated with increased levels of efflux transporters such as P-glycoprotein (P-gp). Here, we examined whether P-gp activation during Snail-induced EMT of lung cancer cells is mediated by ezrin, radixin, and moesin (ERM), which regulate transporter localization. HCC827 lung cancer cells overexpressing the transcription factor Snail showed increased Rhodamine123 efflux and increased paclitaxel resistance, reflecting increased P-gp activity. Concomitantly, the expression level of moesin, but not ezrin or radixin, was significantly increased. The increase of P-gp activity was suppressed by knockdown of moesin. Thus, the increase of P-gp activity associated with Snail-induced EMT may be mediated mainly by moesin in HCC827 cells. On the other hand, the Snail mRNA expression level was correlated with the expression level of each ERM in 4 non-small-cell lung cancer cell lines (HCC827, A549, H441, H1975) and in tumor tissues, but not normal tissues, of patients with lung cancer. These results suggest that P-gp activation during EMT is at least partially due to increased expression of moesin. Coadministration of moesin inhibitors with anticancer drugs might block P-gp-mediated drug efflux organ-specifically, improving treatment efficacy and minimizing side effects on other organs.

Nuclear Morphometry of Lung Squamous Cell Carcinomas in Cytologic Study.

BACKGROUND: The nuclei of most cancer cells in histopathologic preparations differ from normal nuclei and vary individually in size, shape, and chromatin pattern. Although the cytologic characteristics of squamous cell carcinoma (SCC) of the lung have been described, quantification of the cytologic features has not been established. METHODS: Cytologic investigations were performed on bronchial brushings or washings, or fine-needle aspirates. We analyzed the nuclear area (NA) of 50 tumor cells in 32 patients with SCC of the lung and 50 bronchial epithelial cells in 20 patients with no evidence of malignancy including inflammatory lesions. RESULTS: The NA of tumor cells (102.4 ± 26.2 µm2) was significantly larger than that of bronchial epithelial cells (64.1 ± 16.9 µm2) (P = 0.001). The receiver operating characteristic (ROC) curve analysis showed that an NA cutoff level of 86 µm2 had a sensitivity of 75% and specificity of 88% to detect malignant components. CONCLUSION: We conducted quantitative analyses of NA in SCC using cytologic specimen, NA was a useful parameter for evaluation of differential diagnosis between SCC and non-malignancies even in cytologic specimens.

Effects of a novel method for enteral nutrition infusion involving a viscosity-regulating pectin solution: A multicenter randomized controlled trial.

BACKGROUND & AIMS: The initial complications associated with infusion of enteral nutrition (EN) for clinical and nutritional care are vomiting, aspiration pneumonia, and diarrhea. There are many recommendations to prevent these complications. A novel method involving a viscosity-regulating pectin solution has been demonstrated. In Japan, this method along with the other so-called "semi-solid EN" approaches has been widely used in practice. However, there has been no randomized clinical trial to prove the efficiency and safety of a viscosity-regulating pectin solution in EN management. Therefore, we planned and initiated a multicenter randomized controlled trial to determine the efficiency and safety. METHODS: This study included 34 patients from 7 medical institutions who participated. Institutional review board (IRB) approval was obtained from all participating institutions. Patients who required EN management were enrolled and randomly assigned to the viscosity regulation of enteral feeding (VREF) group and control group. The VREF group (n = 15) was managed with the addition of a viscosity-regulating pectin solution. The control group (n = 12) was managed with conventional EN administration, usually in a gradual step-up method. Daily clinical symptoms of pneumonia, fever, vomiting, and diarrhea; defecation frequency; and stool form were observed in the 2 week trial period. The dose of EN and duration of infusion were also examined. RESULTS: A favorable trend for clinical symptoms was noticed in the VREF group. No significant differences were observed in episodes of pneumonia, fever, vomiting, and diarrhea between the 2 groups. An apparent reduction in infusion duration and hardening of stool form were noted in the VREF group. CONCLUSIONS: The novel method involving a viscosity-regulating pectin solution with EN administration can be clinically performed safely and efficiently, similar to the conventional method. Moreover, there were benefits, such as improvement in stool form, a short time for EN infusion, and a reduction in vomiting episodes, with the use of the novel method. This indicates some potential advantages in the quality of life among patients receiving this novel method.

Immediate cytology improves accuracy and decreases complication rate in real-time computed tomography-guided needle lung biopsy.

Computed tomography-guided percutaneous transthoracic needle biopsy (CTNB) of the lung is a well-established diagnostic technique for the evaluation of thoracic lesions. At our institution, we have performed real-time CTNB using automated biopsy needles since 1998 and we introduced immediate cytology in 2004. We evaluate immediate cytology in CTNB to increase the diagnostic accuracy and to reduce the number of inadequate specimens. We retrospectively reviewed a consecutive series of 270 patients (group A: 98 patients before introduction, group B: 172 patients after introduction) who underwent CTNB between 2002 and 2009. We compared the diagnostic performance and the complication rates between two groups. There were no significant differences between groups A and B in patient and lesion characteristics. The rates of one time biopsy were significantly different: 56.1% (55/98) in group A and 69.2% (119/172) in group B. The rates of diagnostic accuracy in groups A and B were 79.6% (78/98) and 94.8% (163/172), respectively; the sensitivity were 74.0% (57/77) and 94.1% (127/135); the specificity were 100% (21/21) and 97.3% (36/37); the rates of major complications were 14.3% (14/98) and 2.9% (5/172). Group B had significantly higher diagnostic accuracy, sensitivity, and a lower complication rate in comparison with group A. CTNB with immediate cytology can improve diagnostic performance and decrease the complication rate. These improvements may help make CTNB less of a burden for patients.

Diffusion-weighted imaging and positron emission tomography in various cytological subtypes of primary lung adenocarcinoma.

The purpose of the study was to retrospectively characterize diffusion-weighted magnetic resonance imaging (DWI) and positron emission tomography for differentiating among the various cytological subtypes of primary lung adenocarcinomas. The maximum diffusion signal intensities and the maximum standardized uptake value (SUV max) of 31 lesions were analyzed after delineation of regions of interest on the images. Diffusion intensities were 0.934 for Clara type, 0.938 for type II type, 1.473 for nongoblet type, and 1.617 for poorly differentiated adenocarcinoma type based on Shimosato's cytological classification (P=.020). The SUV max values were 4.926, 5.491, 5.709, and 12.132, respectively (P=.044). DWI might reflect some of the cytological characteristics of the tumor cells for differentiating the subtypes of lung adenocarcinomas.