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.

Ramucirumab-related Oral Pyogenic Granuloma: A Report of Two Cases.

Pyogenic granuloma (PG) is a granulomatous elevated lesion that occurs on the skin and mucous membranes. We herein report two cases of intra-oral PG that developed during the administration of ramucirumab for gastric cancer. Case 1 involved a 55-year-old man with a 6-mm tumor on the right tongue, and case 2 involved a 67-year-old man with a 5-mm tumor on the upper lip. The imbalance in angiogenesis caused by ramucirumab and the deterioration in the local oral environment were suggested to have caused the PG. Medical and dental collaboration is essential during the administration of ramucirumab.

Metachronous bilateral breast metastases of a lung neuroendocrine tumor: A case report.

Breast metastases of primary lung neuroendocrine tumors are rarely reported. The current report presents the case of a 41-year old female with no history of smoking who initially underwent surgery for a breast fibroadenoma, during which a neuroendocrine tumor of the right lung was detected via chest X-ray. The patient underwent surgery for the tumor and developed right breast nodules after adjuvant chemotherapy. Histological and immunohistochemical examinations of biopsies from these nodules indicated breast metastasis of the primary lung neuroendocrine tumor. The patient underwent mastectomy of the right breast but subsequently developed metastases in the left breast, for which local radiotherapy was administered. The observed metachronous bilateral breast metastases indicated that the contralateral breast should be considered during an investigation of metastasis.

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.

[USEFULNESS OF VIVID (VISUALIZATION OF VARIOUS INTEGRATION WITH DIFFUSION) ON COGNITIVE FUSION PROSTATE BIOPSY].

(Purpose) We created an image reconstructing multiparametric MRI system called VIVID (Visualization of Various Integration with Diffusion) and examined the efficacy of VIVID in detecting prostate cancer. (Methods and materials) The subjects were 80 patients who underwent one target biopsy with reference to MRI images in addition to 8-20 biopsies. (Results) The significant cancer detection rate was 61%, the significant cancer detection rate of PI-RADS 4 or 5 was 55%, and the significant cancer detection rate of VIVID score 4 or 5 was 55%. Three cases with PI-RADS 4 at TZ lesion with positive T2WI only were evaluated as having VIVID scores 1 or 2. Cancer was not detected with target biopsy from the site. (Conclusion) Our finding suggest that VIVID correctly excludes TZ lesions with only T2WI positively in multiparametric MRI.

Renal primitive neuroectodermal tumor with elevated plasma adrenocorticotropic hormone levels: A case report.

INTRODUCTION: Primitive neuroectodermal tumors are small round-cell tumors - Ewing sarcoma family, frequently occurring in the extremities, but rarely in the kidney. CASE PRESENTATION: A 58-year-old woman presented with whole-body edema and weakness of lower limb muscles. Computed tomography revealed a left renal tumor, and the plasma adrenocorticotropic hormone level was elevated. The tumor was surgically removed without complications, her plasma adrenocorticotropic hormone reverted to normal levels, and symptoms disappeared after surgery. Histopathological examination revealed a primitive neuroectodermal tumor arising in her kidney. The patient was alive without metastasis 3 years after the surgery. CONCLUSION: We report the first case of renal primitive neuroectodermal tumor accompanying elevated plasma adrenocorticotropic hormone levels which are thought to be produced and secreted in an ectopic fashion.

Decreasing expression of glucose-regulated protein GRP78/BiP as a significant prognostic predictor in patients with advanced laryngeal squamous cell carcinoma.

BACKGROUND: The immunoglobulin heavy chain binding protein (BiP)/glucose-regulated protein 78 (GRP78) is important in the endoplasmic reticulum stress, and is highly expressed in various human cancers. The clinical and pathological features of GRP78/BiP are unclear in patients with advanced laryngeal squamous cell carcinoma (SCC). The purpose of this study was to investigate the clinicopathological significance of GRP78/BiP as a prognostic marker for laryngeal SCC. METHODS: A total of 59 patients with advanced laryngeal SCC (stage III/IV) were analyzed, and tumor specimens were stained by immunohistochemistry for GRP78/BiP and Ki-67. Microvessel density was determined by immunohistochemical staining for CD34 and p53. RESULTS: Expression of GRP78/BiP was confirmed in 87% of cases. Decreased expression of GRP78/BiP was highly associated with positive expression of p53. Decreased GRP78/BiP expression was identified on multivariate analysis as an independent factor of decreased progression-free survival (PFS). CONCLUSION: GRP78/BiP was found to be commonly expressed in laryngeal SCC, whereas its downregulation was found to serve a significant prognostic role for predicting poor survival in patients with laryngeal SCC with advanced disease. GRP78/BiP may be a potentially attractive target for the treatment of various human neoplasms. © 2016 Wiley Periodicals, Inc. Head Neck 38: First-1544, 2016.

Tumor-infiltrating CD45RO(+) memory cells are associated with a favorable prognosis breast cancer.

BACKGROUND: CD45RO is a marker for memory lymphocytes. Whether CD45RO(+) tumor-infiltrating lymphocytes (TILs) prevent breast cancer recurrence is unclear. METHODS: In the present study, we evaluated CD45RO expression in TILs as a predictor of prognosis in 98 patients with breast cancer who underwent radical surgery without neoadjuvant chemotherapy. Patients were classified as CD45RO(+)/TILs(High) or CD45RO(+)/TILs(Low) based on median immunohistochemistry levels. RESULTS: CD45RO(+)/TILs(High) were associated with smaller tumor size. The CD45RO(+)/TILs(High) group also had significantly fewer metastatic lymph nodes (P = 0.0082) and fewer peritumoral lymphatic invasions (P = 0.0284). The CD45RO(+)/TILs(High) group enjoyed longer recurrence-free survival (P = 0.0453) but not cancer-specific survival (P = 0.0640) in univariate analysis. CONCLUSIONS: These results suggested that CD45RO(+) effector cells may both help eradicate local tumors and prevent metastases to the lymphatic systems in breast cancer patients. High ratio of CD45RO expressing TILs was associated with recurrence-free survival improvement and a trend toward cancer-specific survival improvement in breast cancer patients.

Impact of vascular invasion of a primary tumor as a strong risk factor for disease recurrence in patients with node-positive breast cancer.

The presence of lymph node metastasis is considered to be the most significant indicator of prognosis. However, in some cases with node-positive breast cancer, cancer cell dissemination is localized to the lymphatic systems. It is, therefore, important to develop selection criteria for strong adjuvant therapy in patients with node-positive breast cancer. This study was undertaken to evaluate the presence of vascular invasion that may reflect systemic disease as a predictor of disease recurrence in node-positive breast cancer. We retrospectively evaluated the cases of 134 consecutive female patients with breast cancer with lymph node metastasis who underwent radical breast operations. We examined the relationship between recurrence and clinicopathological factors, particularly vascular invasion. The presence of vascular invasion was found to be significant in a univariate analysis. The presence of vascular invasion was the independent risk factor in a multivariate analysis. Among the 66 patients without vascular invasion, four (6.1%) had disease recurrence. On the other hand, among the 68 patients with vascular invasion, 15 (22.1%) had a recurrence. It is interesting to note that despite the presence of lymph node metastasis, the group without vascular invasion had few patients with distant metastases. Our results suggest that the presence of vascular invasion could be an indicator of high biological aggressiveness and may be a strong prognostic factor for node-positive breast cancer.

Expression of Amino Acid Transporters (LAT1 and ASCT2) in Patients with Stage III/IV Laryngeal Squamous Cell Carcinoma.

The aim of this study is to evaluate the clinicopathological significance of L-type amino acid transporter 1 (LAT1) expression in patients with advanced laryngeal squamous cell carcinoma (LSCC). A total of 73 patients with advanced LSCC were retrospectively reviewed. Tumor sections were stained by immunohistochemistry for LAT1, 4F2hc, system ASC amino acid transporter-2 (ASCT2), cell proliferation by Ki-67, microvessel density (MVD) determined by CD34 and p53. A positive LAT1, 4F2hc and ASCT2 expression (staining more than a quarter) in the primary sites were recognized in 85, 80 and 45 %, respectively, and a high LAT1, 4F2hc and ASCT2 expression (staining more than a half) yielded 48, 31 and 18 %, respectively. High expression of LAT1 was significantly associated with lymph node metastasis, 4F2hc, ASCT2, Ki-67 and p53. The expression of LAT1 was significantly correlated with ASCT2, 4F2hc, cell proliferation, and MVD. By univariate analysis, there was no statistically significant relationship between LAT1 expression and prognosis in advanced LSCC. LAT1, 4F2hc and ASCT2 were highly expressed in patients with advanced laryngeal cancer. Our study suggests that the expression of LAT1 plays a crucial role in the metastasis and tumor progression in advanced LSCC.

Prognostic value of extracapsular invasion of axillary lymph nodes combined with peritumoral vascular invasion in patients with breast cancer.

BACKGROUND: Extracapsular invasion (ECI) of metastatic axillary lymph nodes has been associated with aggressive nodal disease but its prognostic role in breast cancer is unclear. The present study evaluated nodal ECI as a predictor of breast cancer recurrence. METHODS: We evaluated 154 women with histologically proven node-positive breast cancer who were diagnosed with invasive ductal carcinoma, and investigated the relationships between ECI and recurrences and other clinicopathological factors, particularly vascular invasion and the number of lymph node metastases. RESULTS: The presence of ECI at positive nodes was significantly associated with the number of positive nodes, and with disease recurrence and survival in univariate (but not multivariate) analysis. Interestingly, all ECI(+) patients with distant metastases in our series had peritumoral vascular invasion (PVI), which may have reflected systemic disease; ECI with PVI of the primary tumor strongly predicted recurrent disease and shorter survival. CONCLUSION: ECI of axillary metastases combined with PVI indicates high tumor aggressiveness. Patients with ECI and PVI may be considered for stronger adjuvant therapies because of their high risk for distant recurrences.

CD98 as a novel prognostic indicator for patients with stage III/IV hypopharyngeal squamous cell carcinoma.

BACKGROUND: Both L-type amino acid transporter 1 (LAT1) and CD98 are strongly expressed in primary human cancer and play essential roles in tumor growth. We studied the clinicopathological significance of LAT1 and CD98 expression in hypopharyngeal squamous cell carcinoma (SCC). METHODS: A total of 70 patients with stage III/IV disease were retrospectively reviewed. Immunohistochemical staining of tumor sections was used to examine LAT1, CD98, Ki-67, CD34, and p53. RESULTS: High LAT1 and CD98 expression were noted in 60.0% and 47.1%, respectively (p = .174). A statistically significant correlation was recognized between LAT1 and CD98 expression and both expressions were closely associated with tumor cell proliferation. Although LAT1 expression was not significantly associated with poor survival, multivariate analysis revealed high CD98 expression to be an independent prognostic factor for predicting a poor outcome. CONCLUSION: CD98 is a promising prognostic marker for predicting outcomes after surgical treatment in patients with advanced hypopharyngeal SCC.

Extracapsular invasion of sentinel lymph nodes is not associated with disease recurrence in breast cancer.

The purpose of this study was to evaluate the presence of extracapsular invasion (ECI) in positive sentinel lymph nodes (SLNs) as a predictor of disease recurrence in breast cancer. SLN biopsy was performed on 318 breasts of 316 breast cancer patients, of which 50 (15.7%) had positive SLNs. Six (12.0%) of these 50 cases had disease recurrence. The clinicopathologic features of these cases were reviewed. The ECI at SLNs was not significantly associated with disease recurrence. The recurrence-free interval by Kaplan-Meier curves did not differ significantly among patients with and without ECI at SLNs. On the other hand, metastasis at non-SLNs was observed in 12 cases (24.0%) among the 50 cases with positive SLNs, and in the non-SLN metastasis group there were 7 patients with ECI at non-SLNs. Three of 7 cases with ECI at non-SLNs had disease recurrence and none of those 5 without ECI at non-SLNs had disease recurrence. Our current study suggests that the presence of ECI at metastatic SLNs is not associated with recurrent disease in breast cancer. Our results also imply that patients with ECI at positive non-SLNs have a high risk of disease recurrence.

Impact of the prognostic value of vascular invasion, but not lymphatic invasion, of the primary tumor in patients with breast cancer.

BACKGROUND: The prognostic value of lymphovascular invasion (LVI) in patients with breast cancer is unclear. Lymphatic invasion may mainly represent the selective affinity of breast cancer cells for lymph nodes. This study was undertaken to evaluate the presence of vascular invasion that may reflect systemic disease as a predictor of disease recurrence in breast cancer, separate from lymphatic invasion of the primary tumor. PATIENTS AND METHODS: We retrospectively evaluated the cases of 263 consecutive female patients with primary breast cancer who underwent a radical breast operation. We examined the relationship between recurrence and the prognostic significance of clinico-pathological factors, particularly lymphatic (Iy) and vascular invasion (v). RESULTS: The presence of lymphatic invasion and that of vascular invasion were significant in univariate analysis. The presence of vascular invasion was an independent prognostic factor, but lymphatic invasion lost its prognostic significance in multivariate analysis. Among the 91 patients in the ly-/v- group, 5 (5.5%) had disease recurrence, and among the 73 patients in the ly+/v- group, 5 (6.8%) had disease recurrence. On the other hand, among the 95 patients in the ly+/v+ group, 19 (20.0%) had a recurrence, and among the 3 patients in the ly-/v+ group, one had a recurrence. It is interesting to note that despite the presence of lymphatic invasion, the group without vascular invasion (ly+/v-) had a few patients with distant metastases, a result which is similar to that of the ly-/v- group. CONCLUSION: The presence of vascular invasion, but not lymphatic invasion, could be an indicator of high biological aggressiveness and may be a valid prognostic factor for breast cancer.

Early predictive value of non-response to docetaxel in neoadjuvant chemotherapy in breast cancer using 18F-FDG-PET.

BACKGROUND: The aim of this prospective study of patients with breast cancer was to identify non-responders to docetaxel in neoadjuvant chemotherapy (NCT) using fluorine-18-fluorodeoxyglucose positron-emission tomography ((18)F-FDG-PET). PATIENTS AND METHODS: We analyzed the maximum standardized uptake value (SUVmax) of (18)F-FDG-PET before and after the first course and the reduction rate in tumor size shown by magnetic resonance imaging (MRI) before the first and after the fourth course of docetaxel. RESULTS: None of the eight patients (0%) whose SUVmax decrease was less than 18% revealed a clinical partial response or clinical complete response; Seven out of the sixteen patients (44%) with an SUVmax decrease over 45% achieved a complete response. CONCLUSION: An SUVmax reduction rate less than 18% is observed in patients with breast cancer after the first course of docetaxel in NCT and may be indicator of non-response to docetaxel.

The detection of pCR after PST by contrast-enhanced ultrasonography for breast cancer.

BACKGROUND: Primary systemic therapy (PST; such as chemotherapy) has been approved as the standard therapy. Breast-conserving surgery is involved in 60-70% of breast cancer operations, and cancer can spread in the period between the initial treatment and preoperative chemotherapy. To reduce the residual tumor in persistent disease of breast tissue, determining the margin including normal tissue when removing the tumor is very difficult. With the development of the color Doppler method, contrast-enhanced ultrasonography (CEUS) allows visualization of the tumor bloodstream. The availability and efficacy of CEUS for setting the resection margin in breast-conserving surgery were examined and compared with MRI imaging as tools for making decisions for breast-conserving surgery. METHODS: One hundred seventy patients underwent breast cancer operations: 59 were PST(+) and 111 PST(-). Imaging studies, ultrasonography and MRI, to measure the size of the tumor were performed twice, before and after chemotherapy, for PST patients. This was carried out not only to measure the residual tumor size after PST, but also to detect whether pathologically complete response (pCR) had been achieved or not. Fifty-nine patients received CEUS after PST, and we determined the precision of CEUS and conventional US. RESULTS: The sensitivity of CEUS for pCR was 80.0% (95% CI 0.571-0.88), specificity 98.0% (95% CI 0.933-0.996), positive predictive value 88.9% (95% CI 0.635-0.978) and negative predictive value 96.0% (95% CI 0.914-0.976). The difference between the pathological examination and ultrasonography, conventional ultrasonography and CEUS was -4.455 ± 2.02 and 2.582 ± 2.298 cm (95% CI -13.11 to -0.96, p = 0.0235); CEUS was near the diameter of the actual pathological examination. CONCLUSION: Contrast-enhanced ultrasonography is suitable for the preoperative examination, especially after PST, to determine the resection margin before breast-conserving surgery and detects pCR, which can help to avoid surgical procedures in the future.

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.

Clinicopathological significance of decreased galectin-3 expression and the long-term prognosis in patients with breast cancer.

PURPOSE: Galectin-3 expression is modulated in cancer cells, and that finding has led to the recognition of galectin-3 as a diagnostic or prognostic marker for various cancers, including breast cancer. This study investigated the correlation between galectin-3 expression and the clinicopathological features in patients with breast cancer, in order to determine the relevance and role of galectin-3 in breast cancer progression. METHODS: Galectin-3 expression was investigated immunohistochemically in 116 patients with breast cancer, and a statistical analysis was performed. RESULTS: Galectin-3 expression in breast cancer was significantly associated with tumor vascular invasion. However, galectin-3 expression was not associated with Ki-67 expression, which reflects tumor proliferation. Disease-free survival and long-term overall survival were significantly shorter for patients with reduced galectin-3 expression. CONCLUSIONS: This study demonstrated that the galectin-3 expression was associated with tumor vascular invasion and metastasis, suggesting that galectin-3 plays a critical role in tumor progression via an invasive mechanism but not via proliferation in breast cancer. Furthermore, reduced expression of galectin-3 is useful for predicting a long-term poor prognosis in patients with breast cancer.

Accuracy of intraoperative macroscopic diagnosis of sentinel node metastases in breast cancer: is accurate prediction possible?

BACKGROUND: Accurate intraoperative diagnosis of sentinel lymph node (SLN) metastases enables the selection of patients who require axillary lymph node dissection, thus avoiding an additional operation. In this study we investigated the accuracy of intraoperative macroscopic diagnosis of SLN metastases in patients with breast cancer. METHODS: SLNs from 276 breast cancer patients with clinically negative nodes were analyzed by macroscopic examination. The results of intraoperative macroscopic diagnosis were compared with those of frozen section analysis. RESULTS: The sensitivity, specificity, overall accuracy, and false negative rate of SLN biopsy in the assessment of node status were 82.1%, 100%, 96.4%, and 17.9%, respectively, for frozen section analysis, and 57.1%, 95.5%, 87.7%, and 42.9%, respectively, for macroscopic evaluation. Even in patients with node metastasis >7 mm, the false negative rate of macroscopic evaluation was 11.1%. CONCLUSIONS: Our results suggest that macroscopic diagnosis is less effective in predicting lymph node status in breast cancer than frozen section analysis. These findings imply that intraoperative macroscopic evaluation of sentinel nodes is never predictive of the final pathology.