Efficacy of adjuvant EGFR inhibitors and impact of clinical factors in resected EGFR-mutated non-small-cell lung cancer: a meta-analysis.

Background: The role of adjuvant EGFR tyrosine kinase inhibitors (TKIs) in resected EGFR-mutated non-small-cell lung cancer (NSCLC) remains unclear. Materials & methods: We evaluated pooled hazard ratio and 95% CI for disease-free survival, overall survival and prespecified subgroups. Results: Seven prospective studies with 1288 patients were included in the meta-analysis. Adjuvant EGFR TKIs significantly improved disease-free survival in EGFR-mutated resected NSCLC (HR: 0.41; 95% CI: 0.24-0.70) and in all subgroups. However, the overall survival benefit was not significant (HR: 0.65; 95% CI: 0.36-1.17). The benefit of adjuvant TKIs may be associated with TKI regimens, treatment duration, pathological stage and EGFR mutation type. Conclusion: Adjuvant EGFR TKIs significantly improved disease-free survival and nonsignificantly improved overall survival in resected EGFR-mutated NSCLC.

For lung cancer patients who undergo radical surgery and whose tumors have EGFR mutation (a specific gene alteration in the tumor tissue), the optimal treatment following surgery is unclear. We summarized the available studies to compare the efficacy of anti-EGFR targeted therapies (EGFR inhibitors) with chemotherapy in patients after surgery. We found patients who received EGFR inhibitors after surgery had longer survival without disease recurrence, and a tendency toward longer overall survival than patients who received chemotherapy or no further therapy. The different treatment regimes, treatment duration, tumor stage and EGFR mutation type may impact the efficacy of EGFR inhibitors in these patients after undergoing surgery.

Genes associated with increased brain metastasis risk in non-small cell lung cancer: Comprehensive genomic profiling of 61 resected brain metastases versus primary non-small cell lung cancer (Guangdong Association Study of Thoracic Oncology 1036).

BACKGROUND: Patients with brain metastases (BMs) have a poor prognosis and limited therapeutic options. Lung cancer is the most common primary malignancy giving rise to BMs; thus, understanding the molecular mechanisms behind increased BM risk is essential for identifying therapeutic targets and developing effective interventions. METHODS: Sixty-one patients who underwent surgical resection of primary non-small cell lung cancer (NSCLC) and BMs were retrospectively studied. Comprehensive genomic profiling of primary NSCLC and matched BMs was performed with next-generation sequencing targeting 416 cancer-relevant genes. RESULTS: Mutations of major drivers, including EGFR, KRAS, TP53, and ALK, were highly concordant between primary NSCLC and matched BMs (>80%), whereas discordance suggested the unique genomic evolution and oncogenic mechanisms of NSCLC BMs. BMs also demonstrated higher levels of copy number variations in comparison with primary NSCLC. Furthermore, the alterations of genes encoding CDK4/CCND1, CDKN2A/2B, and PI3K signaling pathways were enriched in BMs, and this suggested their correlation with increased metastatic risk. Indeed, patients with activated PI3K signaling in their primary NSCLC had significantly shorter BM-free survival (hazard ratio, 8.49; P = .0005). In addition, mutated TP53 or an activated WNT pathway via CTNNB1, APC, and AXIN2 mutations trended toward shorter BM-free intervals but not significantly so. CONCLUSIONS: These findings yield detailed insights into the genomic complexity and heterogeneity of primary NSCLC and matched BMs. This study highlights the significant correlation of PI3K signaling with increased metastatic risk in patients with NSCLC and identifies genomic alterations enriched in NSCLC BMs that could serve as prognostic markers and potential therapeutic targets for treating patients with NSCLC BMs.

Overexpression of MUC13, a Poor Prognostic Predictor, Promotes Cell Growth by Activating Wnt Signaling in Hepatocellular Carcinoma.

Recently RNA sequencing revealed high mucin 13 (MUC13) expression in hepatocellular carcinoma (HCC) tissues. To understand the clinicopathologic significance of MUC13 in HCC, quantitative PCR and immunohistochemistry were used to detect its expression in paired tumor tissues and nontumor tissues. The oncoprotein role of MUC13 was determined by in vitro and in vivo assays. Overexpression of MUC13 was detected in 74 of 168 primary HCC cases (44%) and was significantly associated with tumor size (P = 0.027), stage (P = 0.006), encapsulation (P = 0.044), venous invasion (P = 0.024), and poor outcome (P = 0.004). Functional studies demonstrated MUC13 had strong oncogenic activity by promoting cell growth, colony formation, cell migration, and tumor formation in nude mice. The pro-oncogenic effect of MUC13 were effectively inhibited by RNA interference. MUC13 promoted cellular G1/S phase transition by activating Wnt signaling. Mechanistically, MUC13 bound to ß-catenin and increased its phosphorylation at Ser552 and Ser675 sites, which subsequently promoted nuclear translocation of ß-catenin and up-regulation of its downstream target genes Axin2, c-Myc, and CyclinD1. Knockdown of AKT with shRNA in MUC13-overexpressing cells nullified the elevated phosphorylation of ß-catenin by MUC13. In clinical HCC samples, nuclear translocation of ß-catenin was significantly associated with MUC13 overexpression (P = 0.001). Overexpression of MUC13 plays a critical role in the development and progression of HCC by activating Wnt signaling.

Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosis using a nanomedicine strategy for the effective treatment of pancreatic cancer.

The synergetic inhibitory effects on human pancreatic cancer by nanoparticle-mediated siRNA and arsenic therapy were investigated both in vitro and in vivo. Poly(ethylene glycol)-block-poly(L-lysine) were prepared to form siRNA-complexed polyplex and poly(ethylene glycol)-block-poly(DL-lactide) were prepared to form arsenic-encapsulated vesicle, respectively. Down-regulation of the mutant Kras gene by siRNA caused defective abilities of proliferation, clonal formation, migration, and invasion of pancreatic cancer cells, as well as cell cycle arrest at the G0/G1 phase, which substantially enhanced the apoptosis-inducing effect of arsenic administration. Consequently, co-administration of the two nanomedicines encapsulating siRNA or arsenic showed ideal tumor growth inhibition both in vitro and in vivo as a result of synergistic effect of the siRNA-directed Kras oncogene silencing and arsenic-induced cell apoptosis. These results suggest that the combination of mutant Kras gene silencing and arsenic therapy using nanoparticle-mediated delivery strategy is promising for pancreatic cancer treatment. FROM THE CLINICAL EDITOR: Treatment of pancreatic cancer remains a major challenge. These authors demonstrate a method that combines a siRNA-based Kras silencing with arsenic delivery to pancreatic cancer cells using nanoparticles, resulting in enhanced apoptosis induction in the treated cells.

Protein tyrosine kinase 6 is associated with nasopharyngeal carcinoma poor prognosis and metastasis.

BACKGROUND: The aim of this study was to analyze the expression of protein tyrosine kinase 6 (PTK6) in nasopharyngeal carcinoma (NPC) samples, and to identify whether PTK6 can serve as a biomarker for the diagnosis and prognosis of NPC. METHODS: We used quantitative RT-PCR and Western blotting analysis to detect mRNA and protein expression of PTK6 in NPC cell lines and immortalized nasopharyngeal epithelial cell lines. 31 NPC and 16 non-tumorous nasopharyngeal mucosa biopsies were collected to detect the difference in the expression of mRNA level of PTK6 by quantitative RT-PCR. We also collected 178 NPC and 10 normal nasopharyngeal epithelial cases with clinical follow-up data to investigate the expression of PTK6 by immunohistochemistry staining (IHC). PTK6 overexpression on cell growth and colony formation ability were measured by the method of cell proliferation assay and colony formation assay. RESULTS: The expression of PTK6 was higher in most of NPC cell lines at both mRNA and protein levels than in immortalized nasopharyngeal epithelial cell lines (NPECs) induced by Bmi-1 (Bmi-1/NPEC1, and Bmi-1/NPEC2). The mRNA level of PTK6 was high in NPC biopsies compared to non-tumorous nasopharyngeal mucosa biopsies. IHC results showed the expression of PTK6 was significantly correlated to tumor size (P<0.001), clinical stage (P<0.001), and metastasis (P=0.016). The patients with high-expression of PTK6 had a significantly poor prognosis compared to those of low-expression (47.8% versus 80.0%, P<0.001), especially in the patients at the advanced stages (42.2% versus 79.1%, P<0.001). Multivariate analysis indicated that the level of PTK6 expression was an independent prognostic factor for the overall survival of patients with NPC (P <0.001). Overexpression of PTK6 in HNE1 cells enhanced the ability of cell proliferation and colony formation. CONCLUSIONS: Our results suggest that high-expression of PTK6 is an independent factor for NPC patients and it might serve as a potential prognostic biomarker for patients with NPC.

Pulmonary Sarcomatoid Carcinoma with ALK Rearrangement: Frequency, Clinical-Pathologic Characteristics, and Response to ALK Inhibitor.

PURPOSE: The incidence of anaplastic lymphoma kinase (ALK) rearrangement in pulmonary sarcomatoid carcinoma (PSC) is controversial. In this study, we aimed to reveal the reliable frequency and the clinical-pathologic characteristics of pulmonary sarcomatoid carcinoma (PSC) with ALK rearrangement in Chinese population, and to provide insight into the translatability of anti-ALK treatment in this treatment-refractory disease. METHODS: Immunohistochemistry (IHC) using a Ventana anti-ALK (D5F3) rabbit monoclonal antibody was performed in 141 PSC specimens collected from multiple medical centers. IHC-positive cases were then confirmed using ALK fluorescent in situ hybridization (FISH). The incidence rates and clinical-pathologic characteristics of ALK-rearranged PSC were then analyzed. Response to ALK inhibitor crizotinib in a patient with ALK-rearranged PSC was evaluated according to the response evaluation criteria for solid tumors (RECIST) version 1.1. RESULTS: Five of 141 (3.5%) of PSCs showed ALK rearrangement-positive by IHC and then were confirmed by FISH. Two were carcinosarcomas and the other three were pulmonary pleomorphic carcinoma (PPC). Strong positive ALK rearrangement was observed in both the epithelioid and sarcomatoid components. The median age of ALK-positive patients was younger than that of ALK-negative patients. PSCs in never-smokers were more likely to harbor ALK rearrangement than those in former or current smokers (P<.05). A 40-year-old woman diagnosed with ALK-rearranged PPC experienced a partial response (-32%) to the ALK inhibitor crizotinib. CONCLUSIONS: The incidence rates of ALK rearrangement in PSC in the Chinese population are similar to those of other subtypes of NSCLC. PSCs in younger never-smokers are more often to harbor ALK rearrangement. ALK inhibitors may serve as an effective treatment for ALK-rearranged PSC.

Establishment of an Adjusted Prognosis Analysis Model for Initially Diagnosed Non-Small-Cell Lung Cancer With Brain Metastases From Sun Yat-Sen University Cancer Center.

BACKGROUND: The current published prognosis models for brain metastases (BMs) from cancer have not addressed the issue of either newly diagnosed non-small-cell lung cancer (NSCLC) with BMs or the lung cancer genotype. We sought to build an adjusted prognosis analysis (APA) model, a new prognosis model specifically for NSCLC patients with BMs at the initial diagnosis using adjusted prognosis analysis (APA). PATIENTS AND METHODS: The model was derived using data from 1158 consecutive patients, with 837 in the derivation cohort and 321 in the validation cohort. The patients had initially received a diagnosis of BMs from NSCLC at Sun Yat-Sen University Cancer Center from 1994 to 2015. The prognostic factors analyzed included patient characteristics, disease characteristics, and treatments. The APA model was built according to the numerical score derived from the hazard ratio of each independent prognostic variable. The predictive accuracy of the APA model was determined using a concordance index and was compared with current prognosis models. The results were validated using bootstrap resampling and a validation cohort. RESULTS: We established 2 prognostic models (APA 1 and 2) for the whole group of patients and for those with known epidermal growth factor receptor (EGFR) genotype, respectively. Six factors were independently associated with survival time: Karnofsky performance status, age, smoking history (replaced by EGFR mutation in APA 2), local treatment of intracranial metastases, EGFR-tyrosine kinase inhibitor treatment, and chemotherapy. Patients in the derivation cohort were stratified into low- (score, 0-2), moderate- (score, 3-5), and high-risk (score 6-7) groups according to the median survival time (16.6, 10.3, and 5.2 months, respectively; P < .001). The results were further confirmed in the validation cohort. CONCLUSION: Compared with recursive partition analysis and graded prognostic assessment, APA seems to be more suitable for initially diagnosed NSCLC with BMs.

The significance of Brf1 overexpression in human hepatocellular carcinoma.

Brf1 (TFIIB-related factor 1) plays a crucial role in cell transformation and tumorigenesis. However, the significance of Brf1 expression in human HCC (hepatocellular carcinoma) cases remains to be addressed. In this study, biopsies of human HCC, liver tumor samples of mice and cell lines of normal and tumor liver were utilized to determine the alteration of Brf1 expression using cytological and molecular biological approaches. Brf1 expression is increased in human HCC cases, which is correlated with shorter survival times. Levels of Brf1 and Pol III (RNA polymerase III-dependent) gene transcription in HCC patients with alcohol consumption are higher than the cases of non-HCC with or without alcohol intake. Induction of Brf1 and Pol III genes by ethanol in hepatoma cells is higher than in non-tumor cells. Ethanol increases the rate of cell transformation. Repression of Brf1 inhibits alcohol-promoted cell transformation. Alcohol consumption enhances Brf1 expression to promote cell transformation. These studies demonstrate that Brf1 is a new biomarker of HCC.

Derived neutrophil to lymphocyte ratio predicts prognosis for patients with HBV-associated hepatocellular carcinoma following transarterial chemoembolization.

The derived neutrophil to lymphocyte ratio (dNLR) has been proposed as an easily determinable prognostic factor for cancer patients, but the prognostic significance of the dNLR in hepatocellular carcinoma (HCC) has not been investigated. The present study aimed to validate the prognostic power of the NLR and dNLR in HCC patients undergoing transarterial chemoembolization (TACE). The data of 279 consecutive patients who underwent TACE for unresectable HBV-associated HCC between September 2009 and November 2011 at the Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center (Guangzhou, China) were retrieved from a prospective database. The cut-off values for the NLR and dNLR were determined by receiver operating characteristic (ROC) analysis. The association between the NLR and dNLR and the clinicopathological characteristics and overall survival (OS) rates and times of patients was analyzed. The area under the curve (AUC) was calculated to evaluate the discriminatory ability of the NLR and dNLR. The median follow-up period was 446 days, the 1, 2 and 3-year OS rates were 38.8, 18.5 and 11.1% respectively, and the median OS time was 264 days. The cut-off values were determined as 2.6 and 1.8 for the NLR and dNLR, respectively. The NLR and dNLR were each associated with patient age, presence of vascular invasion, tumor size, AST level and ALP level. Multivariate analysis showed that the NLR, dNLR, ALT level and AFP level were independent prognostic factors for OS. An elevated NLR or dNLR was associated with a poor prognosis (P=0.001 and P=0.002, respectively). The prognostic power of NLR [AUC=0.539; 95% confidence interval (CI), 0.423-0.656] and dNLR (AUC=0.522; 95% CI, 0.406-0.638) was similar. Elevated dNLR predicted poor prognosis for patients with HBV-associated HCC undergoing TACE, with similar prognostic power to NLR. The dNLR may be used as an alternative to the NLR, as it is easily available and inexpensive.

Increased APOBEC3B Predicts Worse Outcomes in Lung Cancer: A Comprehensive Retrospective Study.

Lung cancer ranks as the most common and lethal malignancy in America and worldwide. APOBEC3B is a newly identified DNA cytosine deaminase, which is supposed to function as a major source of DNA mutation in many different tumors. In this study, we combine the data of online databases and two hundred and twenty-one primary non-small-cell lung carcinoma (NSCLC) specimens from Sun Yat-sen University Cancer Center to investigate, for the first time, the clinical role of APOBEC3B in lung cancer. We found that the APOBEC3 expression was commonly elevated in NSCLC tissues and overexpression of APOBEC3B was correlated with unfavorable prognosis of the patients with NSCLC. Furthermore, APOBEC3B expression was associated with nodal status, TNM staging and adjuvant chemotherapy of the patients with NSCLC. Further research is warranted.

Consolidation chemotherapy improves progression-free survival in stage III small-cell lung cancer following concurrent chemoradiotherapy: a retrospective study.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) is the standard treatment for limited-stage small-cell lung cancer (LD-SCLC). However, the efficacy of consolidation chemotherapy (CCT) in LD-SCLC remains controversial despite several studies that were performed in the early years of CCT use. The aim of this study was to reevaluate the effectiveness and toxicities associated with CCT. METHODS: This retrospective analysis evaluated 177 patients with stage IIIA and IIIB small-cell lung cancer (SCLC) who underwent CCRT from January 2001 to December 2013 at Sun Yat-Sen University Cancer Center (SYSUCC). Overall survival (OS) and progression-free survival (PFS) were analyzed using Kaplan-Meier methods. Univariate and multivariate analyses were performed to analyze patient prognosis factors. RESULTS: Among the 177 patients, 72 (41%) received CCT and 105 (59%) did not receive CCT. PFS was significantly better for patients in the CCT group compared to that for patients in the non-CCT group (median PFS: 17.0 vs 12.9 months, respectively, P=0.031), whereas the differences in OS were not statistically significant (median OS: 31.6 vs 24.8 months, respectively, P=0.118). The 3- and 5-year OS rates were 33.3% and 20.8% for patients in the CCT group and 27.6% and 6.7% for patients in the non-CCT group, respectively. Multivariate analysis revealed that having a pretreatment carcinoembryonic antigen level <5 ng/mL (P=0.035), having undergone prophylactic cranial irradiation (P<0.001), and having received CCT (P=0.002) could serve as favorable independent prognostic factors for PFS. Multivariate analysis for OS also showed that having undergone PCI (P<0.001) and having received CCT (P=0.006) were independent significant prognostic factors. CONCLUSION: CCT can improve PFS for patients with stage IIIA and IIIB SCLC following CCRT without significantly increasing treatment-related toxicities.

Exposure to metal mixtures and human health impacts in a contaminated area in Nanning, China.

Cadmium and lead have been identified as very toxic metals, which are widely present in the environment due to natural and anthropogenic emissions. Many studies have shown that the food chain is the main pathway of cadmium and lead transfer from the environment to humans. It is well documented that many factors will affect their transfer through food chains. Previous investigations on heavy metals were mostly concentrated on one contaminant in isolation. However, in real environments, exposure to mixtures of metals is ubiquitous such that cadmium pollution is invariably being associated with lead and zinc, etc. This study focuses on the contamination and health effects of the metal mixtures. For this purpose, a dietary survey was taken for 3 groups in Nanning in October 2002. Samples of soils, plants (vegetables), urine and blood of humans were measured for Cd, Fe, Cu, Zn, Ca and Pb, in addition, the urinary indicators of renal dysfunction Albumin (ALB), N-acetyl-beta-D-glucosaminidase (NAG), Beta-2-microglobulin (beta2-MG) and Retinol-binding protein (RBP) in urine were also measured. Results showed that soil contamination with metal mixtures had caused significant renal dysfunction of the local residents living in the contaminated area, and the dose-response curve was somewhat altered by the mixed contamination of Cd and Pb as well as the intake of other minerals. The importance of mixtures of metal contamination and human health are also discussed in this paper.

Expression of ETV6/TEL is associated with prognosis in non-small cell lung cancer.

The ETV6/TEL gene is a member of the ETS family of transcription factors that has been mainly studied in hematological diseases. This study provides the first investigation of ETV6 expression in non-small cell lung cancer (NSCLC). In this study, ETV6 expression was immunohistochemically studied in 170 consecutive patients with NSCLC. The association between ETV6 expression and clinicopathological parameters was evaluated. Kaplan-Meier survival analysis and Cox proportional hazards models were used to estimate the effect of ETV6 expression on survival. ETV6 expression was observed in 135 of the 170 (79.4%) patients. ETV6 expression was positive for nuclear staining. From the clinicopathological standpoint, the expression of ETV6 was significantly correlated with age (P=0.014). The overall survival was significantly enhanced in the group with a low expression of ETV6 compared with the group with a high expression of ETV6 (five-year survival rates, 56.53% versus 29.88%; P=0.002), and the same finding was obtained for disease-free survival (five-year survival rates, 52.24% versus 30.47%; P=0.001). Multivariable analysis confirmed that ETV6 expression increased the hazard of death after adjusting for other clinicopathological factors (hazard ratio, 2.002; 95% confidence interval, 1.303-3.074; P=0.002). Our study demonstrated that ETV6 was markedly involved in the development of NSCLC and could serve as a potential prognostic marker for this deadly disease.

Effective suppression of the Kirsten rat sarcoma viral oncogene in pancreatic tumor cells via targeted small interfering RNA delivery using nanoparticles.

OBJECTIVES: The objective of this study was to establish an efficient carrier for small interfering RNA (siRNA) delivery targeting pancreatic tumor cells. METHODS: A copolymer consisting of a single-chain variable fragment targeted to human CD44 variant 6 (scFv(CD44v6)) functional group conjugated to polyethylene glycol-poly-L-lysine was synthesized and assembled into micelles encapsulating the siRNAs. Flow cytometry and Western blot assays were performed to evaluate the transfection efficiency and gene-silencing effect of the siRNAs. Afterward, (4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, Transwell, soft agar colony formation, and enzyme-linked immunosorbent assays were performed to evaluate the biological functions of PANC-1 cells after Kirsten rat sarcoma viral oncogene knockdown. In vivo assays were performed using a BALB/c (nu/nu) mouse model subcutaneously injected with PANC-1 xenografts. Real-time in vivo fluorescence imaging was used to monitor the tumor homing of the nanoparticles. RESULTS: The scFv(CD44v6) enabled more efficient delivery of siRNAs and exhibited enhanced gene silencing compared with nontargeted nanoparticles. Furthermore, targeted delivery of the siRNAs induced a potent inhibitory effect on cell proliferation, colony formation, invasion, and vascular endothelial growth factor production. The animal assays revealed that single-chain variable fragment nanoparticles accumulated in the tumor tissue and enhanced the inhibition of tumor growth in vivo. CONCLUSIONS: The scFv(CD44v6)-conjugated nanocarriers provide a highly efficient and safe platform for systemic gene therapy for pancreatic cancer.

Blood-brain barrier permeability of gefitinib in patients with brain metastases from non-small-cell lung cancer before and during whole brain radiation therapy.

INTRODUCTION: To explore the ability of gefitinib to penetrate blood brain barrier (BBB) during whole brain radiation therapy (WBRT). PATIENTS AND METHODS: Enrolled in this study were eligible patients who were diagnosed with BM from NSCLC. Gefitinib was given at 250 mg/day for 30 days, then concurrently with WBRT (40 Gy/20 F/4 w), followed by maintenance. Serial CSF and blood samples were collected on 30 day after gefitinib administration, and at the time of 10, 20, 30 and 40 Gy following WBRT. CSF and plasma samples of 13 patients without BM who were treated with gefitinib were collected as control. CSF and plasma gefitinib levels were measured by LC-MS/MS. RESULTS: Fifteen BM patients completed gefitinib plus WBRT. The CSF-to-plasma ratio of gefitinib in patients with BM was higher than that in patients without BM (1.34% vs. 0.36%, P < 0.001). The CSF-to-plasma ratio of gefitinib increased with the increased dose of WBRT and reached the peak (1.87 ± 0.72%) at 30 Gy, which was significantly higher than that 1.34 ± 0.49% at 0 Gy (P = 0.01). The median time to progression of brain lesions and the median overall survival were 7.07 and 15.4 months, respectively. CONCLUSION: The BBB permeability of gefitinib increased in accordance with escalated dose of WBRT.

Transfer of metals from soil to vegetables in an area near a smelter in Nanning, China.

A field survey was conducted to investigate the metal contamination in soils and vegetables, and to evaluate the possible health risks to local population through foodchain transfer near a smelter in Nanning, southern China. Contamination levels in soils and vegetables with cadmium (Cd), lead (Pb), zinc (Zn) and copper (Cu) were measured, and transfer factors (TF) from soils to vegetable plants and its health risk (risk index, RI) were calculated accordingly. Results showed that both soils and vegetables from villages 1 and 2 (V1 and V2, 1500 m and 500 m from the smelter) were heavily contaminated, compared to a village 50 km from the smelter. Geometric mean of Cd and Pb concentrations in vegetables for V1 and V2, respectively, were 0.15 and 0.24 mg Cd kg(-1) and 0.45 and 0.38 mg Pb kg(-1) (on fresh weight basis). Oral intake of Cd and Pb through vegetables poses high health risk to local residents. Risk indices for V1 and V2, respectively, were 3.87 and 7.42 for Cd, and 1.44 and 13.5 for Pb. The complexity of metal contamination and their health risks are also discussed.

Perineural Invasion and TAMs in Pancreatic Ductal Adenocarcinomas: Review of the Original Pathology Reports Using Immunohistochemical Enhancement and Relationships with Clinicopathological Features.

OBJECTIVES: Tumor-associated macrophages (TAMs) are thought to be involved in the perineural invasion (PNI) process and to be associated with poor prognoses. The associations between TAMs, PNI, and clinicopathological features in pancreatic ductal adenocarcinomas (PDAs) remain to be elucidated. METHODS: Fifty-nine PDA patients who had undergone pancreaticoduodenectomy were retrospectively examined. The PNI statuses and TAMs were reviewed following H&E staining and S-100, CD68, and CD163 immunohistochemical staining. The relationships between PNI, TAMs, and overall survival and various clinical and histopathologic factors were investigated. RESULTS: PNI was identified in 83% (49/59) of the cases, the TAM density of the PNI(+) group was greater than that of the PNI(-) group, and the infiltrating TAMs around the nerves that were invaded by cancer were much more numerous than those around the nerves without cancer cell invasion. The incidences of PNI, lymph node metastasis, high serum CA19-9 level, cancers in the body/tail, and advanced pathological stage were associated with shorter OSs. In the PNI(+) group, lymph node metastasis and high levels of TAM infiltration were associated with worse prognoses. CONCLUSIONS: TAMs might enhance PNI, and the incidence of PNI was associated with poor prognosis. PNI(+) status and high levels of TAM infiltration further worsen the prognosis. Therapies targeting TAMs might represent auxiliary and preventive treatment for PNI in PDA patients.

Oncofetal protein IMP3: a new diagnostic biomarker for laryngeal carcinoma.

An accurate diagnosis of laryngeal squamous cell carcinoma (LSCC) is essential for patient management. The diagnosis of LSCC, especially in superficial biopsies, can present a diagnostic challenge for pathologists. The ability to diagnose LSCC would be greatly improved by the detection of a tumor-associated antigen. IMP3 is an oncofetal protein associated with aggressive and advanced tumors and is specifically expressed in malignant tumors but not found in benign tissues. The aim of this study was to determine the expression and diagnostic value of IMP3 in LSCC to determine whether it can serve as a diagnostic biomarker. A total of 238 cases (laryngectomy, n = 121; biopsy, n = 117) consisting of 11 laryngeal carcinoma in situ/severe dysplasia and 227 invasive LSCC were examined by immunohistochemistry for IMP3 expression. IMP3 showed strong cytoplasmic staining in 217 (92%) of 238 LSCCs regardless of histologic grade. In addition, 58 (89%) of 65 small biopsies (≤5 mm in greatest dimension) containing a minute amount of carcinoma were positive for IMP3. In contrast to malignant tumors, IMP3 expression was not found in any of the adjacent benign squamous epithelium (0/118 cases; 0%), mild or moderate dysplasia (0/139 cases; 0%), or pseudoepitheliomatous hyperplasia (0/99 cases; 0%). In summary, we are the first to describe that IMP3 is a highly sensitive and specific biomarker for LSCC. The expression of IMP3 in LSCC can be used as a positive biomarker to increase the level of confidence in establishing a definitive diagnosis of a malignancy in laryngeal biopsy.

Reduced expression of ZDHHC2 is associated with lymph node metastasis and poor prognosis in gastric adenocarcinoma.

BACKGROUND: Zinc finger, DHHC-type containing 2 (ZDHHC2), originally named as reduced expression associated with metastasis protein (REAM), has been proposed as a putative tumor/metastasis suppressor gene and is often aberrantly decreased in human cancers. However ZDHHC2 expression pattern and its clinical significance have not yet been investigated in gastric adenocarcinoma. METHODOLOGY/PRINCIPAL FINDINGS: Quantitative Real-Time PCR (qRT-PCR) and immunostaining were performed to detect ZDHHC2 expression in gastric adenocarcinoma, and then the correlation between ZDHHC2 expression and clinicpathologic parameters, and patient survival was analyzed. Compared to the adjacent normal tissues, ZDHHC2 expression was significantly reduced in gastric tumor tissues as shown by qRT-PCR and immunostaining. Low expression of ZDHHC2 was observed in 44.7% (211/472) of gastric adenocarcinoma patients, and was associated significantly with lymph node metastasis (p<0.001) and histological grade (p<0.001). Multivariate Cox regression analysis indicated that ZDHHC2 expression had a significant, independent predictive value for survival of gastric cancer patients (HR = 0.627, p = 0.001). CONCLUSIONS/SIGNIFICANCE: Our data suggest that reduced ZDHHC2 expression is associated with lymph node metastasis and independently predicts an unfavorable prognosis in gastric adenocarcinoma patients.

[Metastatic lymph node ratio and outcome of surgical patients with stage III colorectal cancer].

OBJECTIVE: Evaluate the prognostic value of lymph node ratio (LNR) in patients undergoing resection of stage III colorectal cancer. METHODS: The clinicopathological and follow-up data were collected from 174 surgical patients with stage III colorectal cancer. The 5-year disease-free survival (DFS) and overall survival (OS) were evaluated using Kaplan-Meier method. The impact of LNR and clinicopathological factors on DFS and OS were evaluated using univariate and multivariate analysis. RESULTS: After a median follow-up of 62.5 months, the 5-year DFS and OS of the patients were 51.8% and 56.3%, respectively. The median number of lymph nodes harvested and the median number of positive lymph nodes examined were 10 and 3, respectively. The patients were stratified into 4 groups according to LNR quartiles (LNR1, LNR≤0.125; LNR2, 0.1250.500), whose 5-year DFS and OS were 64.2%, 53.5%, 41.8%, and 25.7% (P<0.05) and 68.1%, 60.8%, 49.2%, and 32.7% (P<0.05), respectively. Multivariate analysis identified age, T stage and LNR as the independent predictors of both DFS and OS. Subgroup analysis showed that LNR had an independent prognostic value on DFS and OS irrespective of the number of lymph nodes harvested. CONCLUSION: LNR is an independent prognostic factor for survival in patients with stage III colorectal cancer and is superior to the pN category in TNM staging.