Decreased SATB2 expression is associated with metastasis and poor prognosis in human clear cell renal cell carcinoma

In this study, we investigate the expression and role of special AT-rich sequence-binding protein-2 (SATB2) in clear cell renal cell carcinoma (ccRCC) tissue, and to evaluate the clinical and prognostic significance of SATB2 protein in patients with ccRCC. The expression of SATB2 and SATB1 was examined in ccRCC tissue by Western blotting, real-time PCR and immunohistochemical staining. The association between clinicopathological features and SATB2 level was investigated. The correlation of SATB2 expression with overall survival was also analyzed. The expression of SATB2 protein in tumor tissues was much lower than that in paired normal tissues. The overall survival of the patients with high SATB2 expression was significantly higher than that of the low SATB2 expression group. Low or negative SATB2 expression was significantly correlated with AJCC staging and Furman grade in ccRCC. In contrast, the expression of SATB1 was significantly higher in adjacent tumor tissue than that in normal and tumor tissues. This study provides the first evidence of the expression and clinical significance of SATB2 in ccRCC. Our data suggest that SATB2 functions as a tumor suppressor in the development and progression of ccRCC, and is thereby implicated as a valuable prognostic marker for ccRCC patients.     

The tumour stromal features are associated with resistance to 5‐FU‐based chemoradiotherapy and a poor prognosis in patients with oral squamous cell carcinoma

It has been increasingly recognized that the tumour microenvironment is a critical factor involved in cancer progression. However, little is known about the clinical value of the stromal features in oral squamous cell carcinoma (OSCC). The purpose of this study was to determine the clinical significance of cancer‐associated fibroblasts (CAFs) and tumour‐associated macrophages (TAMs) in OSCC. OSCC specimens were obtained from 60 patients who underwent surgery following 5‐fluorouracil‐based chemoradiotherapy. Paraffin‐embedded sections obtained from biopsy specimens were immunohistochemically analysed. The associations among CAFs, TAMs and various clinicopathological features were examined, and the effects of CAFs and TAMs on the prognosis were evaluated. In the group with a high level of CAFs, the incidence of advanced pT‐ and pN‐stage cases was significantly higher than that in the group with the low level. A high TAMs tumour expression was significantly correlated with a poor response to preoperative chemoradiotherapy. A Kaplan–Meier analysis revealed that higher numbers of CAFs and TAMs were significantly correlated with a poor prognosis. These findings suggest that TAMs are a potential biomarker for predicting the clinical response to 5‐FU‐based chemoradiotherapy, and the expression status of the CAFs and TAMs may be useful for making treatment decisions to improve the survival of OSCC patients.     

Arteriolitis in renal transplant biopsies is associated with poor graft outcome

AIMS: The Banff 1997 classification of renal allograft pathology identifies arteriolitis as a finding of uncertain significance. We sought to improve our understanding of arteriolitis by correlating its occurrence with histopathological and clinical parameters. METHODS AND RESULTS: Twenty allograft kidney biopsies from 19 patients, showing arteriolitis, were identified. Arterioles were defined as small vessels with: (1) wall thickness of 1-3 myocytes; (2) diameter less than one-third of an adjacent glomerulus; and (3) discontinuous or absent elastica. Arteriolitis was defined as mural infiltration by lymphocytes. Other histological findings were categorized according to the Banff 1997 working formulation. Ten biopsies (50%) showed type IIA rejection, seven (35%) showed type I rejection, and three (15%) showed borderline change. Two patients with borderline change had acute rejection in the next biopsy. None of the seven patients with type I rejection had previous or subsequent type II rejection on biopsy. A total 11/20 biopsies (10/19 patients) showing arteriolitis had type IIA rejection in the index or next biopsy. On follow-up, graft loss due to rejection occurred in 5/19 (26%) patients (median 126 days); all had shown type IIA rejection on a previous biopsy. Chronic allograft nephropathy developed in a further 4/19 (21%) patients (median 157 days), of whom three had shown only type I rejection on biopsy. CONCLUSION: Arteriolitis is associated with acute rejection, often type II rejection, and is associated with poor graft outcome. Other causes of arteriolitis were not encountered in this series.     

c-Myc expression is related with cell proliferation and associated with poor clinical outcome in human gastric cancer

We underwent protein assay for Myc expression in 76 human gastric cancer tissues using immunohistochemistry. Expression of Myc protein was analyzed according to proliferative indices measured by flow cytometry. Levels of Myc protein expression was evaluated by correlating with biologic and clinical parameters. In 36 (47.4%) of 76 primary gastric cancers, overexpression of Myc was observed. We could observe expression of Myc protein in a significant portion of early gastric cancer (42.9%). Expression of Myc protein was demonstrated to be more frequent in poorly differentiated cancer cells (p=0.043). However, expression of Myc protein had little influence over progress or extent of the disease. Expression of Myc protein was significantly correlated with increased proliferative activity (p=0.032) and patients with high levels of Myc expression had poor disease-free survival. In a certain proportion of human gastric cancer, Myc protein may function as a regulator of cancer cell growth and expression of Myc may represent an aggressive phenotype of gastric cancer.     

CtBP2 overexpression is associated with tumorigenesis and poor clinical outcome of prostate cancer

Introduction

The aim of the study was to evaluate the expression of CtBP2 in prostate cancer and to determine its relationship with clinicopathologic parameters.

Material and methods

The expression of CtBP2 in 119 prostate cancer tissues and 41 normal tissues was examined by qPCR and Western blot analysis, and the results were correlated with clinicopathologic parameters.

Results

CtBP2 expression in prostate cancer tissues was higher than that in normal samples. CtBP2 overexpression was closely correlated with serum prostatic specific antigen (PSA) (p = 0.018), advanced tumor stage (T3) (p = 0.025), higher Gleason scores (p = 0.019), positive extraprostatic extension (p = 0.012), positive vascular invasion (p = 0.011) and perineural invasion (p = 0.035). However, no significant association was found between CtBP2 abnormal expression and other parameters, including age (p = 0.776), positive lymph node (p = 0.872) and positive surgical margin (p = 0.37). Moreover, CtBP2 overexpression was significantly associated with poor clinical outcome of prostate cancer (p = 0.0168).

Conclusions

CtBP2 is overexpressed in prostate cancer, and its increased expression is closely associated with tumor progression and the outcome of prostate cancer.     

Clinical and cytogenetic features of a population‐based consecutive series of 285 pediatric T‐cell acute lymphoblastic leukemias: Rare T‐cell receptor gene rearrangements are associated with poor outcome

Clinical characteristics and cytogenetic aberrations were ascertained and reviewed in a population‐based consecutive series of 285 pediatric T‐cell acute lymphoblastic leukemias (T‐ALLs) diagnosed between 1992 and 2006 in the Nordic countries. Informative karyotypic results were obtained in 249 (87%) cases, of which 119 (48%) were cytogenetically abnormal. Most (62%) of the aberrant T‐ALLs were pseudodiploid. Structural changes were more common than numerical ones; 86% displayed at least one structural abnormality and 41% at least one numerical anomaly. The most frequent abnormalities were T‐cell receptor (TCR) gene rearrangements (20%) [TCR;11p13 (10%), TCR;10q24 (3%), TCR;other (8%)], del(9p) (17%), +8 (14%), del(6q) (12%), and 11q23 rearrangements (6%). The TCR;other group comprised the rare rearrangements t(X;14)(p11;q11), t(X;7)(q22;q34), t(1;14)(p32;q11), ins(14;5)(q11;q?q?), inv(7)(p15q34), t(8;14)(q24;q11), t(7;11)(q34;p15), and t(12;14)(p13;q11). The clinical characteristics of this Nordic patient cohort agreed well with previous larger series, with a median age of 9.0 years, male predominance (male/female ratio 3.1), median white blood cell (WBC) count of 66.5 × 10⁹/l, and a high incidence of mediastinal mass and central nervous system involvement (59% and 9.5%, respectively). These features did not differ significantly among the various genetic subgroups. 5‐year event‐free survival (EFS) and overall survival for all patients were 0.61 (±0.03) and 0.67 (±0.03), respectively. In a multivariate analysis, two factors affected negatively the EFS, namely a WBC count of ≥200 × 10⁹/l (P < 0.001) and the presence of rare TCR rearrangements (P = 0.001). In conclusion, in this large series of childhood T‐ALLs from the Nordic countries, the cytogenetic findings were not associated with risk of therapy failure with the exception of the TCR;other group. However, further prospective and collaborative investigations of this genetically heterogeneous entity are needed to confirm these results. © 2009 Wiley‐Liss, Inc.     

High expression of flotillin-2 is associated with poor clinical survival in cervical carcinoma

Aims: To investigate the expression and clinical significance of flotillin-2 (FLOT2) in cervical cancer (CC). Methods: We examined FLOT2 mRNA levels in 10 pairs of cervical cancer and adjacent normal tissues. Immunohistochemistry was performed to analyze FLOT2 protein expression in 115 archived cervical cancer samples. The association between FLOT2 levels, clinicopathologic factors and prognosis was analyzed statistically as well. Results: The cancer tissues of CC patients had clearly increased expression of FLOT2 at mRNA level as compared to adjacent nontumorous tissues. Survival analysis of CC patients indicated that FLOT2 expression was significantly associated with poor overall and local recurrence-free survival (P = 0.025 and P = 0.028, respectively). Moreover, FLOT2 expression was significantly correlated with clinical stage, tumor differentiation, and lymph nodes metastasis. Multivariate analysis revealed that FLOT2 expression was an independent prognostic factor for overall survival in CC patients. Conclusion: FLOT2 may serve as an oncogene in the development of CC, and may serve as a clinicopathologic biomarker for prognosis in CC patients.     

High expression of Twist is associated with tumor aggressiveness and poor prognosis in patients with renal cell carcinoma

Aims: Twist has been reported to play crucial roles for malignant aggressiveness; however, detailed pathological significance of Twist in renal cell carcinoma (RCC) is not fully understood. The present study was to clarify clinical significance and molecular functions of Twist in patients with RCC. Methods: Twist expression was examined by immunohistochemical techniques in 156 formalin-fixed specimens. Cell proliferation, angiogenesis, and apoptosis were measured as the percentage of Ki-67-positive cells (proliferation index, PI), CD31-stained vessels (microvessel density, MVD), and TUNEL-positive cells (apoptotic index, AI). In addition, semi-quantification of matrix metalloproteinase (MMP)-2 was performed. Macrophages were identified with anti-CD68 antibody, and the tumor associated macrophage (TAM) density was calculated as CD68-positive cells per high-power field. Results: Twist expression was positively associated with grade, pT stage, and metastasis (p<0.001). We also noticed that its expression was considerably higher in cancer cells of sarcomatoid RCC and in those at the edge of the tumors. Twist expression was positively correlated with PI, MVD, MMP2 expression, and TAM density (P<0.001), but not with AI, and MMP-2 expression and TAM density were independently correlate by multi-variate analyses. Kaplan-Meir survival curves showed high Twist expression was a worse predictor for cause-specific survival (P<0.001). Conclusions: Twist plays important roles in tumor growth, progression, and survival in patients with RCC patients. Such pathological mechanisms are significantly associated with increased cancer cell proliferation, angiogenesis, MMP2 expression, and macrophage recruitment. These findings are important information for discussion of treatment and observation strategies in these patients.     

High expression of EphB6 protein in tongue squamous cell carcinoma is associated with a poor outcome

EphB6 is a member in the receptor tyrosine kinase Eph family in that its kinase domain contains several alterations in conserved amino acids and is catalytically inactive. Although EphB6 is expressed both in a variety of embryonic and adult tissues, biological functions of this receptor are largely unknown. In this study, we examined the expression of EphB6 protein in 54 of tissue specimens of tongue squamous cell carcinoma by using a specific polyclonal anti-EphB6 antibody. The relationship between expression of EphB6 and clinical pathologic parameters was analyzed. The expression level of EphB6 in carcinoma cells from 34 out of 54 (63%) specimens was no alterative compared with normal squamous cells in same patient. The level of EphB6 protein staining was increased in carcinoma cells in 20 out of 54 (37%) specimens compared with normal squamous cells in same patient. The high-expression of EphB6 was significantly associated with age (P=0.021), tumor TNM stage (P=0.026) and lymph node metastasis (P=0.046). Patients with high expressed EphB6 protein had a high mortality (P=0.057). No significant relationship between expression of EphB6 and sex, tumor grade, HPV infection, relapse and smoke was found. We showed that patients with high expression of EphB6 had a significantly poor overall survival (OS) compared to patients with negative or weak expression (P=0.042). Our results indicated that EphB6 protein may be used as a new marker for prognosis for tongue squamous cell carcinoma.     

Expression profiles associated with aggressive behavior in Merkel cell carcinoma.

Primary neuroendocrine carcinoma of the skin, or Merkel cell carcinoma, is the most aggressive cutaneous neoplasm. In spite of its similarities to small cell carcinomas from other locations, Merkel cell carcinoma shows many peculiarities probably related to its epidermal origin and the etiologic role of UV radiation. We have immunohistochemically investigated 43 markers on a tissue microarray in which 31 surgically resected Merkel cell carcinomas were represented. Of these, 15 patients remained free of disease after removal, whereas 16 developed metastases. Immunoreactivity was scored according to staining intensity and the percentage of positive cells. We found statistically significant correlations between metastatic tumor spread and overexpression of matrix metalloproteinase (MMP) 7, MMP10/2, tissue inhibitor of metalloproteinase 3, vascular endothelial growth factor (VEGF), P38, stromal NF-kappaB, and synaptophysin. Also detected were statistically significant correlations between the expression levels of MMP7 and VEGF, MMP7 and P21, MMP7 and P38, MMP10/2 and VEGF, P38 and synaptophysin, P38 and P53, and P21 and stromal NF-kappaB. These findings may be helpful in predicting the clinical course of Merkel cell carcinoma and are potentially useful for the development of targeted therapies.     

Increased expression of metastasis-associated in colon cancer-1 in renal cell carcinoma is associated with poor prognosis

Metastasis-associated in colon cancer-1 (MACC1) expression in tumor specimens is an independent prognostic indicator of metastasis, which has recently gained considerable attention in cancer research, due to its overexpression in several types of carcinoma. However, MACC1 expression patterns and its possible role in renal cell carcinoma remain unknown. This study aimed to investigate MACC1 expression in renal cell carcinoma via immunohistochemical analysis and determine the relationship between MACC1 expression and cancer prognosis. Positive MACC1 expression was found to significantly correlate with distant metastasis and TNM stage (P < 0.05). A Kaplan-Meier survival analysis revealed that patients with higher MACC1 expression had a significantly lower disease-free rate (P < 0.05). These results indicate that MACC1 expression is significantly associated with prognosis in patients with renal cell carcinoma. To the best of our knowledge, this is the first study on the significance of MACC1 as a prognostic marker in renal cell carcinoma. MACC1 expression may be a useful target for the development of new therapeutic approaches, including molecular targeted therapeutic agents, for renal cell carcinoma.     

Cancer‐associated fibroblasts predict poor outcome and promote periostin‐dependent invasion in oesophageal adenocarcinoma

Interactions between cancer cells and cancer‐associated fibroblasts (CAFs) play an important role in tumour development and progression. In this study we investigated the functional role of CAFs in oesophageal adenocarcinoma (EAC). We used immunochemistry to analyse a cohort of 183 EAC patients for CAF markers related to disease mortality. We characterized CAFs and normal oesophageal fibroblasts (NOFs) using western blotting, immunofluorescence and gel contraction. Transwell assays, 3D organotypic culture and xenograft models were used to examine the effects on EAC cell function and to dissect molecular mechanisms regulating invasion. Most EACs (93%) contained CAFs with a myofibroblastic (α‐SMA‐positive) phenotype, which correlated significantly with poor survival [p = 0.016; HR 7. 1 (1.7–29.4)]. Primary CAFs isolated from EACs have a contractile, myofibroblastic phenotype and promote EAC cell invasion in vitro (Transwell assays, p ≤ 0.05; organotypic culture, p < 0.001) and in vivo (p ≤ 0.05). In vitro, this pro‐invasive effect is modulated through the matricellular protein periostin. Periostin is secreted by CAFs and acts as a ligand for EAC cell integrins αvβ3 and αvβ5, promoting activation of the PI3kinase–Akt pathway. In patient samples, periostin expression at the tumour cell–stromal interface correlates with poor overall and disease‐free survival. Our study highlights the importance of the tumour stroma in EAC progression. Paracrine interaction between CAF‐secreted periostin and EAC‐expressed integrins results in PI3 kinase–Akt activation and increased tumour cell invasion. Most EACs contain a myofibroblastic CAF‐rich stroma; this may explain the aggressive, highly infiltrative nature of the disease, and suggests that stromal targeting may produce therapeutic benefit in EAC patients. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Myelodysplastic syndrome/acute myeloid leukemia with t(3;21)(q26.2;q22) is commonly a therapy-related disease associated with poor outcome

The t(3;21)(q26.2;q22) translocation is rare in cases of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). We studied 17 patients with MDS/AML associated with t(3;21) and compared them with 17 patients with MDS associated with inv(3) (q21q26.2)/t(3;3)(q21;q26.2), because these entities share 3q26 locus abnormalities. The t(3;21) group included 9 men and 8 women, with a median age of 62 years (range, 13-81 years). One case was de novo AML and 16 cases were therapy-related, including 12 MDS (blasts, <15%) and 4 AML (blasts, 33%-50%). All patients had multilineage dysplasia, whereas none had thrombocytosis. Additional cytogenetic aberrations were identified in 12 cases, including -7/7q (n = 9) and a complex karyotype (n = 7). All patients died, with 1- and 2-year survival rates of 35% and 6%, respectively. Although multilineage dysplasia and frequent association with -7/7q were similar in both groups, MDS/AML cases associated with t(3;21) have a higher frequency of therapy-related disease and shorter survival times, suggesting that they are distinct from MDS/AML cases associated with inv(3)/t(3;3).     

Proliferative activity of renal cell carcinoma associated with acquired cystic disease of the kidney: comparison with typical renal cell carcinoma

To assess the proliferative activity of renal cell carcinoma (RCC-A) in patients with acquired cystic disease of the kidney (ACDK) after long-term hemodialysis, we analyzed cell cycle, DNA ploidy, and S-phase fraction by flow cytometry (FCM) and proliferating cell nuclear antigen (PCNA) labeling index by immunohistochemistry. The data were compared with those of typical RCC (tRCC). Sixteen (88.9%) of 18 RCC-As showed a diploid pattern. The values of cells at each phase in the cell cycle in RCC-A group (S, 4.36% + 2.16%; G2M, 5.06% + 1.90%; S+G2M, 9.41% + 2.81%; P <.05) were significantly different from those of tRCCs (S, 8.91% + 6.58%; G2M, 8.77% + 5.73%; S+G2M; 17.67% + 7.61%). The PCNA labeling index was statistically significantly lower in the RCC-As (24.01% +/- 13.4%; P <.05) than in tRCCs (42.27% +/- 26.1%). These results indicate that the RCC-As are less proliferative than tRCC and are consistent with the observation that RCC-As are less aggressive neoplasms.