Positron emission tomography (PET) with [18F]2-fluoro-2-deoxy-D-glucose (FDG) may show negative results for bronchioloalveolar lung carcinoma. We investigated the correlation of Glut-1 glucose transporter expression with [18F]FDG uptake in non-small cell lung cancer. Thirty-two patients with 34 non-small cell lung cancers (7 bronchioloalveolar carcinomas, 23 non-bronchioloalveolar adenocarcinomas, 3 squamous cell carcinomas, and 1 adenosquamous cell carcinoma) were studied. Final diagnoses were established by histology (via thoracotomy) in all patients. [18F]FDG PET was performed 40 min after i.v. injection of 185 MBq [18F]FDG. For semi-quantitative analysis of [18F]FDG uptake, standardized uptake values (SUVs) were calculated. Glut-1 expression was studied in terms of the immunohistochemistry of paraffin sections using anti-Glut-1 antibody to determine the intensity (0-3) of Glut-1 immunoreactivity and percentage of the Glut-1-positive area. Of seven bronchioloalveolar carcinomas, six (85.7%) were negative for the expression of Glut-1, while only one (4.3%) of 23 non-bronchioloalveolar adenocarcinomas was negative (P < 0.0001). The percentages of Glut-1-positive area, as well as the SUVs, were significantly lower in bronchioloalveolar carcinomas (n = 7) (2.86% +/- 7.56% and 1.25 +/- 0.75, respectively) than in non-bronchioloalveolar adenocarcinomas (n = 23) (54.83% +/- 25.64%, P < 0.0001, and 3.94 +/- 1.93, P = 0.001, respectively). The degree of cell differentiation correlated with the percentage of Glut-1-positive area and SUVs in adenocarcinoma of the lung. Correlations between SUVs and the intensity of Glut-1 immunoreactivity were also significant (intensities 0 and 1, n = 11, SUV 1.47 +/- 0.63; intensities 2 and 3, n=23, SUV 4.78 +/- 2.13; P < 0.0001). The percentage of Glut-1-positive area correlated significantly with SUVs (n = 34, r = 0.658, P < 0.01). Overexpression of Glut-1 correlated with high [18F]FDG uptake. These findings suggest that Glut-1 expression is related to [18F]FDG uptake in non-small cell lung cancer. Glut-1 expression, as well as [18F]FDG uptake, correlated with the degree of cell differentiation in adenocarcinomas, and both Glut-1 expression and [18F]FDG uptake were significantly lower in bronchioloalveolar carcinomas than in non-bronchioloalveolar carcinomas.

Recent studies have established that amplification of the MET proto-oncogene can cause resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) cell lines with EGFR-activating mutations. The role of non-amplified MET in EGFR-dependent signaling before TKI resistance, however, is not well understood. Using NSCLC cell lines and transgenic models, we demonstrate here that EGFR activation by either mutation or ligand binding increases MET gene expression and protein levels. Our analysis of 202 NSCLC patient specimens was consistent with these observations: levels of MET were significantly higher in NSCLC with EGFR mutations than in NSCLC with wild-type EGFR. EGFR regulation of MET levels in cell lines occurred through the hypoxia-inducible factor (HIF)-1α pathway in a hypoxia-independent manner. This regulation was lost, however, after MET gene amplification or overexpression of a constitutively active form of HIF-1α. EGFR- and hypoxia-induced invasiveness of NSCLC cells, but not cell survival, were found to be MET dependent. These findings establish that, absent MET amplification, EGFR signaling can regulate MET levels through HIF-1α and that MET is a key downstream mediator of EGFR-induced invasiveness in EGFR-dependent NSCLC cells.

To evaluate the impact of Retzius-sparing robot-assisted radical prostatectomy (posterior approach) on early recovery of urinary continence (UC) compared to the conventional approach (anterior approach) for the treatment of clinically localized prostate cancer (PCa). Methods A total of 110 consecutive patients with clinically localized PCa were prospectively randomized in a 1:1 ratio to an anterior group (n = 55) or a posterior group (n = 55). The primary outcome was immediate UC, defined as freedom from any pad use within 1 week after removal of the urinary catheter. The UC rate following surgery was also calculated with Kaplan-Meier curves, and the log-rank test was used for statistical comparison. Intra-operative outcomes, pathological data and oncological outcomes, including positive surgical margin (PSM) status and biochemical recurrence-free survival (BCRFS), were also compared between the two groups. The comparison of the two approaches was also analysed in subgroups after risk stratification. Results Of the patients who underwent the posterior approach, 69.1% achieved immediate UC compared with 30.9% in the anterior group (relative risk 2.24, 95% confidence interval [CI] 1.48-3.51; P = 0.000). The relative Kaplan-Meier curves for UC during the 12-month follow-up revealed statistically better recovery in the posterior group when compared with the anterior group (hazard ratio [HR] 1.51, 95% CI 1.01-2.24; log-rank P = 0.007). No statistically significant differences were observed between the groups regarding complications (P = 0.399), PSM status (P = 0.225) or BCRFS (HR 4.80, 95% CI 0.97-23.78; log-rank P = 0.111). In sub-analyses, no significant difference between the two approaches with regard to UC recovery in patients with high-risk PCa was observed (HR 1.26, 95% CI 0.63-2.51; log-rank P = 0.415). Conclusions The Retzius-sparing approach significantly improved early recovery of UC compared to the conventional approach. Further prospective studies are needed to confirm the benefits of the Retzius-sparing approach for clinically localized PCa, especially for high-risk cases.

ObjectivesThis study was intended to analyze effects of miR-199a-3p and Smad1 on proliferation, migration and invasion of prostate cancer (PCa) cells.ResultsMiR-199a-3p was significantly decreased in PCa tissues in comparison to that in adjacent normal tissues (P < 0.05). Over-expressed miR-199a-3p markedly suppressed proliferation and invasion of PCa cells (P < 0.05). MiR-199a-3p was negatively correlated with Smad1 expression, and overexpression of Smad1 could antagonize the effects of miR-199a-3p on PCa cells.Materials and methodsThe PCa tissues and their adjacent normal tissues were collected from 54 PCa patients. Expressions of miR-199a-3p and Smad1 mRNA in tissues and cells were evaluated with real-time quantitative polymerase chain reaction (RT-qPCR), and immunohistochemistry assay was used to detect Smad1 protein expressions. The target relationship between miR-199a-3p and Smad1 was assessed by luciferase reporter assay. The PCa cell lines (i.e. PC-3 cells) were transfected with miR-199a-3p mimics and Smad1-cDNA. MTT and Transwell assays were applied to detect proliferative, migratory and invasive abilities of PCa cells.ConclusionsMiR-199a-3p suppressed proliferation and invasion of PCa cells by targeting Smad1.

BackgroundLatent membrane protein (LMP) 1 and LMP2A encoded by Epstein-Barr virus (EBV) are associated with the development of malignancies, but their expression in extranodal NK/T-cell lymphoma, nasal type (ENKTL) and the relationship with clinical characteristics of this disease remain poorly understood. In the present study, we examined the expression of LMP1 and LMP2A in ENKTL, and investigated the correlations between LMP1 and LMP2A expression with clinicopathological characteristics of ENKTL patients.MethodsParaffin sections of surgically removed samples from 16 ENKTL patients were analyzed by immunohistochemistry and the related clinicopathological data were collected and analyzed.ResultsElevated expression (immunohistochemistry score ≥ 4) of LMP1 and LMP2A was detected in the tumor cells of ENKTL. High LMP1 expression was associated with positive B symptoms (p = 0.012), while high LMP2A expression was related to gender (p = 0.029). The expression of both LMP1 and LMP2A showed significant correlations with patients’ overall survival (p = 0.049, p = 0.036).ConclusionLMP1 and LMP2A may be prognostic indicators of survival in patients with ENKTL.Virtual slideshttp://www.diagnosticpathology.diagnomx.eu/vs/2443352538545899

Erlotinib resistance causes a high degree of lethality in non-small-cell lung cancer (NSCLC) patients. The high expression and activation of several receptor tyrosine kinases, such as JAK/STAT3, c-Met, and EGFR, play important roles in drug resistance. The development of tyrosine kinase inhibitors is urgently required in the clinic. Our previous study found that Gambogenic acid (GNA), a small molecule derived from the traditional Chinese medicine herb gamboge, induced cell death in several NSCLC cell lines through JAK/STAT3 inhibition. In this study, we investigated the mechanism of action of GNA in erlotinib-resistant NSCLC and patient-derived cells. The inhibition of GNA on FGFR signaling pathway was examined using biochemical kinase assays. NSCLC cell lines (HCC827, HCC827-Erlotinib-resistant, and H1650) and primary cells from patients with NSCLC with clinical resistance to erlotinib were treated with GNA, erlotinib, or their combination. Both kinase assays and cell- based assays showed that GNA inhibits the phosphorylation of multiple kinases in FGFR signaling pathway in NSCLC. The combination of GNA and erlotinib significantly attenuates the tumor growth of HCC827 and erlotinib-resistant HCC827 xenografts with low toxicity. Importantly, GNA significantly suppresses tumor growth in a lung patient-derived xenograft (PDX) model with FGFR fusion and low EGFR expression. Our findings provide preclinical evidence for using GNA as an FGFR signaling pathway inhibitor to overcome erlotinib resistance in NSCLC treatment or to enhance erlotinib efficacy when used as a combined administration.

The diagnosis of Xp11.2 translocation renal cell carcinoma (tRCC), which relies on morphology and immunohistochemistry (IHC), is often either missed in the diagnosis or misdiagnosed. To improve the accuracy of diagnosis of Xp11.2 tRCC and ASPL-TFE3 renal cell carcinoma (RCC), we investigated newly designed fluorescence in situ hybridization (FISH) probes (diagnostic accuracy study).Based on the genetic characteristics of Xp11.2 tRCC and the ASPL-TFE3 RCC, a new break-apart TFE3 FISH probe and an ASPL-TFE3 dual-fusion FISH probe were designed and applied to 65 patients with RCC who were <45 years old or showed suspicious microscopic features of Xp11.2 tRCC in our hospital. To test the accuracy of the probes, we further performed reverse transcriptase–polymerase chain reaction (PCR) on 8 cases for which frozen tissues were available.Among the 65 cases diagnosed with RCC, TFE3 IHC was positive in 24 cases. Twenty-two cases were confirmed as Xp11.2 tRCC by break-apart TFE3 FISH, and 6 of these cases were further diagnosed as ASPL-TFE3 RCC by ASPL-TFE3 dual-fusion FISH detection. Importantly, reverse transcriptase–PCR showed concordant results with the results of FISH assay in the 8 available frozen cases.The break-apart and ASPL-TFE3 dual-fusion FISH assay can accurately detect the translocation of the TFE3 gene and ASPL-TFE3 fusion gene and can thus serve as a valid complementary method for diagnosing Xp11.2 tRCC and ASPL-TFE3 RCC.

RCRFA might be an alternative for LPA in selected patients with adrenocortical aldosteronoma. Due to limited sample size, more experience is necessary to validate this procedure.