Expression of vascular endothelial growth factor and vascular endothelial growth factor receptors 1 and 2 in invasive breast carcinoma: prognostic significance and relationship with markers for aggressiveness

Dhakal H P, Naume B, Synnestvedt M, Borgen E, Kaaresen R, Schlichting E, Wiedswang G, Bassarova A, Holm R, Giercksky K‐E & Nesland J M
(2012) Histopathology  61, 350–364 Expression of vascular endothelial growth factor and vascular endothelial growth factor receptors 1 and 2 in invasive breast carcinoma: prognostic significance and relationship with markers for aggressiveness Aims: Vascular endothelial growth factor (VEGF), VEGF receptor 1 (VEGFR‐1) and VEGF receptor 2 (VEGFR‐2) play a role in breast cancer growth and angiogenesis. We examined the expression and relationship with clinical outcome and other prognostic factors. Methods and results: Tumour sections from 468 breast cancer patients were immunostained for VEGF, VEGFR‐1, and VEGFR‐2, and their relationships with tumour vascularity, disseminated tumour cells (DTCs) in bone marrow and other clinicopathological parameters were evaluated. VEGF, VEGFR‐1 and VEGFR‐2 immunoreactivities were observed in invasive breast carcinoma cells. VEGF expression was significantly associated with VEGFR‐1 and VEGFR‐2 expression (P < 0.001). High‐level cytoplasmic expression of VEGFR‐1 was associated with significantly reduced distant disease‐free survival (DDFS) (P = 0.017, log‐rank) and breast cancer‐specific survival (BCSS) (P = 0.005, log‐rank) for all patients, and for node‐negative patients without systemic treatment (DDFS, P = 0.03, log‐rank; BCSS, P = 0.009, log‐rank). VEGFR‐1 expression was significantly associated with histopathological markers of aggressiveness (P < 0.05). Significantly reduced survival was observed in DTC‐positive patients as compared with DTC‐negative patients in the combined moderate/high VEGFR‐1 group (P < 0.001 for DDFS and BCSS), and the same was true for DDFS in the moderate VEGFR‐2 group (P = 0.006). Conclusions: High‐level expression of VEGFR‐1 indicates reduced survival. Higher‐level expression of VEGFR‐1 or VEGFR‐2 in primary breast carcinomas combined with the presence of DTC selects a prognostically unfavourable patient group.     

Prognostic role of CD44 cell adhesion molecule expression in primary and metastatic renal cell carcinoma: a clinicopathologic study of 125 cases

Possible prognostic utility of CD44 in renal cell carcinoma (RCC) prompted a comparison of its expression in primary and metastatic RCC. A total of 164 paraffin-embedded tissues of primary RCC and metastatic RCCs from 125 patients were immunostained with CD44 (standard form) antibody. It consisted of 86 primary RCCs (50 with subsequent metastasis [MET+] and 36 with no known metastasis [MET−]) during follow up and 78 metastatic RCCs (39 metastatic RCCs only and 39 with matched RCC primary from RCC MET + category). Immunoreactivity for CD44 was scored semiquantitatively as 0, 1, or 2 (0, <5%; 1, 5–50%; 2, ≥50%). Expression of CD44 was significantly higher in metastatic RCCs compared to primary RCCs (p = 0.036). CD44 immunoreactivity in the primary RCC (MET− and MET+) correlated with progression-free survival (p = 0.027). In metastatic RCCs, CD44 immunoreactivity also correlated with survival after detection of first metastasis (p = 0.011). In multivariate analysis, stage (p = 0.0001) and CD44 immunoreactivity (p = 0.03) in primary RCC were independent predictors of progression-free survival. Our study suggests that CD44 status in RCC provides useful prognostic information both in primary and metastatic RCCs and may have applicability in stratifying patients for therapeutic decisions.     

Expression of p21WAF1 in Astler-Coller stage B2 colorectal cancer is associated with survival benefit from 5FU-based adjuvant chemotherapy

In several, but not all, previous studies, positive p21^WAF1 expression has been suggested as an indicator of a good prognosis in patients with stage III/IV colorectal cancer. However, it is not known whether the same is true for stage B2 patients. The purpose of this study is to assess the influence of p21^WAF1 expression in tumor cells on disease-free survival (DFS) and overall survival (OS) of Astler–Coller stage B2 and C patients with colorectal cancer who underwent 5-fluorouracil-based adjuvant chemotherapy. Nuclear p21^WAF1 was detected by immunohistochemistry in tissue microarrays from 275 colorectal cancers. The expression of p21^WAF1 was associated with DFS (p = 0.025) and OS (p = 0.008) in the subgroup of stage B2 patients that was treated with adjuvant chemotherapy. In multivariate analysis, it remained the only independent prognostic parameter in relation to DFS and OS (p = 0.035 and p = 0.02, respectively). In the subgroup of 72 stage B2 patients with positive p21^WAF1 expression but not in the subgroup of 61 stage B2 patients with negative p21^WAF1 expression, adjuvant chemotherapy was associated with better DFS (85% 5-year survival versus 65% without chemotherapy, p = 0.03) and OS (96% versus 82%, p = 0.014). In the combined stage B2 and C group of patients treated with adjuvant chemotherapy, positive p21^WAF1 expression was also associated with better DFS and OS (p = 0.03, p = 0.002, respectively). Expression of p21^WAF1 in colorectal tumor cells identifies a subgroup of Astler–Coller stage B2 patients who could benefit significantly from 5FU-based chemotherapy and may improve the selection of patients for adjuvant chemotherapy.     

Alpha-methylacyl-CoA racemase (AMACR) expression in epithelial ovarian cancer

Alpha-methylacyl-CoA racemase (AMACR) is involved in the cellular metabolism of fatty acids. It is a prognostic factor in prostate and colorectal cancer. So far, little is known about its expression and prognostic role in ovarian cancer. We investigated the expression of AMACR in a total of 420 ovarian tumors (388 carcinomas, 32 borderline tumors) by immunohistochemistry on tissue microarrays of two independent patient cohorts. In both cohorts, cytoplasmic AMACR expression was identified in 11.8% (16/136) and 5.4% (13/239), respectively, of the ovarian carcinomas. In contrast, borderline tumors did not show any AMACR expression. AMACR expression was significantly associated with histological subtype, FIGO stage, and grade in one cohort and low estrogen receptor levels in the other cohort. In univariate analysis, AMACR expression was significantly associated with poor overall survival (log rank, p = 0.006) and an independent prognostic factor in a multivariate analysis (HR 3.3; CI 1.3–7.9; p = 0.008) but could not be verified in the second cohort. Unlike in other tumor entities, AMACR expression does not seem to have an unequivocal prognostic impact in ovarian cancer. The prevalence may limit the value of AMACR for the differential diagnosis between metastatic colorectal carcinomas and primary ovarian carcinomas, whereas the association with estrogen receptor expression deserves further studies.     

Prognostic value of procalcitonin in <Emphasis Type="Italic">Legionella</Emphasis> pneumonia

The diagnostic reliability and prognostic implications of procalcitonin (PCT) (ng/ml) on admission in patients with community-acquired pneumonia (CAP) due to Legionella pneumophila are unknown. We retrospectively analysed PCT values in 29 patients with microbiologically proven Legionella-CAP admitted to the University Hospital Basel, Switzerland, between 2002 and 2007 and compared them to other markers of infection, namely, C-reactive protein (CRP) (mg/l) and leukocyte count (10⁹/l), and two prognostic severity assessment scores (PSI and CURB65). Laboratory analysis demonstrated that PCT values on admission were >0.1 in over 93%, >0.25 in over 86%, and >0.5 in over 82% of patients with Legionella-CAP. Patients with adverse medical outcomes (59%, n = 17) including need for ICU admission (55%, n = 16) and/or inhospital mortality (14%, n = 4) had significantly higher median PCT values on admission (4.27 [IQR 2.46–9.48] vs 0.97 [IQR 0.29–2.44], p = 0.01), while the PSI (124 [IQR 81–147] vs 94 [IQR 75–116], p = 0.19), the CURB65 (2 [IQR 1–2] vs 1 [1–3], p = 0.47), CRP values (282 [IQR 218–343], p = 0.28 vs 201 [IQR 147–279], p = 0.28), and leukocyte counts (12 [IQR 10–21] vs 12 [IQR 9–15], p = 0.58) were similar. In receiver operating curves, PCT concentrations on admission had a higher prognostic accuracy to predict adverse outcomes (AUC 0.78 [95%CI 0.61–96]) as compared to the PSI (0.64 [95%CI 0.43–0.86], p = 0.23), the CURB65 (0.58 [95%CI 0.36–0.79], p = 0.21), CRP (0.61 [95%CI 0.39–0.84], p = 0.19), and leukocyte count (0.57 [95%CI 0.35–0.78], p = 0.12). Kaplan-Meier curves demonstrated that patients with initial PCT values above the optimal cut-off of 1.5 had a significantly higher risk of death and/or ICU admission (log rank p = 0.003) during the hospital stay. In patients with CAP due to Legionella, PCT levels on admission might be an interesting predictor for adverse medical outcomes. Jeannine Haeuptle, Roya Zaborsky, and Rico Fiumefreddo contributed equally to this article.     

Expression of pERK and pAKT in human astrocytomas: correlation with IDH1-R132H presence,vascular endothelial growth factor,microvascular characteristics and clinical outcome

Although pERK and pAKT are reportedly activated in various neoplasms, little information is available about their significance in astrocytomas. Paraffin-embedded tissue from 82 patients with diffuse infiltrating astrocytomas (grades II to IV) was investigated for the association of pERK and pAKT activation with clinicopathological features, vascular endothelial growth factor (VEGF), isocitrate dehydrogenase 1 and microvascular parameters. Nuclear pERK labelling index (LI) increased with increasing cytoplasmic pERK LI and nuclear and cytoplasmic pAKT LI (p = 0.0019, p = 0.0260 and p = 0.0012, respectively). Accordingly, cytoplasmic pERK increased with increasing levels of nuclear (p = 0.0001) and marginally with cytoplasmic pAKT LI (p = 0.0526). Nuclear and cytoplasmic pERK LI and nuclear pAKT LI were positively correlated with tumour histological grade (p = 0.0040, p = 0.0238 for pERK and p = 0.0004 for pAKT, respectively). VEGF expression was correlated with nuclear pERK (p = 0.0099) and nuclear pAKT LI (p = 0.0002). Interestingly, pERK cytoplasmic LI increased with microvessel calibre (p = 0.0287), whereas pAKT nuclear LI was marginally related to microvessel density (p = 0.0685). The presence of IDH1-R132H was related only to histological grade and lower microvessel calibre. Multivariate survival analysis in the entire cohort selected cytoplasmic pAKT LI (p = 0.045), histological grade, microvessel calibre (p = 0.028), patients' age, gender and surgical excision as independent predictors of survival. Moreover, in glioblastomas, pERK nuclear LI emerged as a favourable prognosticator in the presence of IDH1-R132H. pERK and pAKT in astrocytomas are interrelated and associated with tumour grade and angiogenesis. Moreover, the importance of cytoplasmic pAKT immunoexpression in patients' prognosis and nuclear pERK immunoexpression in glioblastomas is confirmed.     

Histological grading in a large series of advanced stage ovarian carcinomas by three widely used grading systems: consistent lack of prognostic significance. A translational research subprotocol of a prospective randomized phase III study (AGO-OVAR 3 protocol)

While there is no doubt that histologic grading is applicable in early stage ovarian carcinoma, it is still in controversial discussion concerning advanced stage ovarian carcinoma. It was the aim of this study to assess the three most widely used grading systems for ovarian carcinoma in terms of prognostic significance, concordance rates, and reproducibility in a large number of advanced stage ovarian carcinomas of all types after standardized chemotherapy. Representative hematoxylin and eosin slides from 334 cases of stage IIB–IV ovarian carcinoma (prospective randomized, multi-center, phase III study) were used. The first round was grading of all cases according to FIGO, GOG, and Silverberg by one author. The second round (after 1 year) was 30 randomly selected cases graded by three authors. None of the three grading systems was prognostically significant (FIGO p = 0.38; GOG p = 0.70; Silverberg p = 0.92). The concordance rates between the three systems were as follows: FIGO/GOG 95.5%, κ = 0.929; Silverberg/FIGO 69.9%, κ = 0.533; Silverberg/GOG 66.8%, κ = 0,481. Grading of advanced stage ovarian carcinomas was of no value for estimation of prognosis in this homogeneously treated patient group. Alternative methods should be defined, which might help to separate patients with high risk of tumor progression from others with low risk.     

LYVE-1 upregulation and lymphatic invasion correlate with adverse prognostic factors and lymph node metastasis in neuroblastoma

Neuroblastoma (NB) accounts for 15% of all childhood cancer deaths. The majority of patients have widespread lymphatic and/or haematogenous metastases at diagnosis, but lymphangiogenesis has not been well documented. Sixty-seven NBs were immunostained for the lymphatic endothelial marker, LYVE-1, and the lymphatic density (LD) and lymphatic invasion (LI), were counted in LYVE-1-expressing lymphatics. LYVE-1-stained lymphatic vessels and LI were present in 26/67 (39%) and 14/67 (21%) of the NBs, respectively. Central LD (CLD) and LI were higher in NBs from stage 4 (p = 0.012, p = 0.004, respectively), high-risk group (p = 0.030, p = 0.002), NBs with high mitosis karyorrhexis index (MKI) (p = 0.011, p = 0.005), unfavourable histology group (p = 0.040, p = 0.017) and distant lymph node metastasis (LNM) (p < 0.001 for each). Marginal LD (MLD) was higher in patients with LNM (p < 0.001). CLD and MLD correlated with LI (p < 0.001 each). Total LYVE-1 protein levels, quantified by a sensitive enzyme-linked immunosorbent assay (n = 55), were also higher in NBs from patients with stage 4 disease (p = 0.046), high-risk group (p = 0.028), MYCN-amplified NBs (p = 0.034) and LNM (p = 0.038). Kaplan–Meier analysis showed that the presence of CLD was associated with both worse OS at 5 years (77% [95% CI: 62–87%] versus 60% [95% CI: 32–80%], p = 0.062) and EFS (74% [95% CI: 58–85%] versus 43% [95% CI: 15–69%], p = 0.070) and LI with OS (71% [95% CI: 57–81%] versus 56% [95% CI: 26–78%], p = 0.055). Significant upregulation of LYVE-1 and the presence of LI in patients with stage 4 and high-risk disease, MYCN-amplification and LNM suggests that LYVE-1 may have value as predictors of outcome.     

Overexpression of carbonic anhydrase IX (CAIX) is an independent unfavorable prognostic marker in endometrioid ovarian cancer

Carbonic anhydrase IX (CAIX) is a strictly membranous expressed metalloenzyme involved in cell adhesion, pH homeostasis, and cancer progression. This study was designed to assess the role of CAIX in primary ovarian cancer. Two hundred five well-characterized primary ovarian carcinomas were analyzed on a tissue microarray. CAIX expression was determined by immunohistochemistry using a four-step scoring system. Moderate and strong membranous CAIX expression was found in 37 out of 205 (18%) of all assessable ovarian cancer specimens. High levels of CAIX expression were related to mucinous and endometrioid phenotype of ovarian carcinomas (p < 0.05). There was no association between CAIX overexpression and tumor stage, grading, and mitotic count of ovarian carcinomas (p > 0.05). In univariate Cox regression analysis, advanced tumor stage (p < 0.01), high tumor grade (p = 0.017), high mitotic count (p = 0.025), and high CAIX expression levels (p = 0.031) were correlated to shorter overall patient survival. High pT stage (p = 0.036) and CAIX overexpression were connected to poor clinical outcome in endometrioid ovarian carcinomas. Multivariate Cox regression hazard analysis comprising tumor stage, tumor grade, mitotic count, and CAIX expression revealed pT2/3 stage and CAIX overexpression (scores 2 and 3) as independent prognostic markers in ovarian cancer (p < 0.01, each) as well as in the subgroup of endometrioid carcinomas (p < 0.05, each). In conclusion, CAIX is overexpressed in a substantial proportion of mucinous and endometrioid ovarian carcinomas and connected to poor patient outcome. Our data support the potential therapeutic benefit of newly developed targeting antibodies in advanced ovarian cancer.     

Prognostic significance of the Fas-receptor/Fas-ligand system in cervical squamous cell carcinoma

We studied whether Fas-receptor (Fas-R; CD95) expression, single-nucleotide polymorphisms (SNPs) in the Fas promoter region, and/or Fas-ligand (Fas-L) production could determine individual susceptibility to cervical cancer progression. The clinicopathologic features of 38 patients with cervical squamous carcinomas (22 stage I, 8 stage II, and 8 stage III+) were reviewed and related with: (a) Fas-R expression by immunohistochemistry; (b) Fas-R SNPs at -670 and -1377 locations by restriction fragment length polymorphism and DNA sequencing; and (c) Fas-L expression by immunohistochemistry. Overall and disease-free survival curves showed significant differences in relation to stage (p < 0.001). Fas-R was identified in 20 of 38 (52.6%) tumors without statistical differences in survival, stage, or Fas-L overproduction. Fas-R GG genotype was more common than expected in advanced tumors (p = 0.065). The Fas-R-1377A allele and AA genotype were unrelated with survival, stage, or Fas-R expression. Fas-L overproduction was detected in 20 of 38 (52.6%) tumors; it was more frequent in advanced-stage tumors and was inversely related to survival (p = 0.03) and decrease in host inflammatory response (p = 0.01). Fas-R expression by tumor cells seems unrelated to stage or lymphoid infiltrate. Tumor production of Fas-L may represent an attempt to destroy the host’s lymphocytic reaction.     

KiSS-1 overexpression as an independent prognostic marker in hepatocellular carcinoma: an immunohistochemical study

The KiSS-1 gene has been reported to play an important role as a metastasis suppressor gene in various human malignancies. However, there is little information about its possible role in hepatocellular carcinoma (HCC). In this study, we evaluated the prognostic significance of the expression of KiSS-1 and its receptor AXOR12 in 142 HCC tissue specimens by immunohistochemistry. By using a cutoff level of 50%, immunoreactivity of KiSS-1 and AXOR12 was found in 6 (4%) and 11 (8%) HCCs. The expression of KiSS-1 and AXOR12 in HCC correlated with each other (r = 0.42, p < 0.0001) and with the expression in corresponding, surrounding liver tissue (both r = 0.35, p < 0.0001). Positive AXOR12 immunoreactivity in HCC correlated with advanced pT-stage of tumors and low tumor grading (r = 0.18, p = 0.032; r = −0.18, p = 0.029). High KiSS-1 expression in HCC had a statistically significant influence on diminished disease-free and overall survival in uni- (p = 0.006 and p = 0.002) and multivariate analysis (r = 2.874, p = 0.027 and r = 2.913, p = 0.026). In this study, we report for the first time that elevated KiSS-1 expression level in HCC correlates with worsened clinical outcome, as an independent prognostic marker for the aggressiveness of HCC.     

VEGF-mediated signal transduction in lymphatic endothelial cells

The VEGF family of angiogenic ligands consists of VEGFA, VEGFB, VEGFC, VEGFD and placenta growth factor, PlGF. These growth factors bind in an overlapping pattern to three receptor tyrosine kinases, denoted VEGFR1, VEGFR2 and VEGFR3. Originally, VEGFA (the prototype VEGF) was described as a master regulator of vascular endothelial cell biology in vitro and in vivo, transducing its effect through VEGFR2. VEGFA, VEGFB and PlGF bind to VEGFR1, which is a negative regulator of endothelial cell function at least during embryogenesis. VEGFC and VEGFD were identified as lymphatic endothelial factors, acting via VEGFR3. With time, the very clear distinction between the roles of the VEGF ligands in angiogenesis/lymphangiogenesis has given way for a more complex pattern. It seems that the biology of the different VEGFR2 and VEGFR3 ligands overlaps quite extensively and that both receptor types contribute to angiogenesis as well as lymphangiogenesis. This paradigm shift in our understanding is due to the access to more sophisticated reagents and techniques revealing dynamic and plastic expression of ligands and receptors in different physiological and pathological conditions. Moreover, knowledge on the important role of VEGF coreceptors, the neuropilins, in regulating the responsiveness to VEGF has changed our perception on the mechanism of VEGF signal transduction. This review will primarily focus on the properties of VEGR3, its signal transduction and the resulting biology.     

Relationship Between Eosinophilia and Levels of Chemokines (CCL5 and CCL11) and IL-5 in Bronchoalveolar Lavage Fluid of Patients With Mustard Gas-Induced Pulmonary Fibrosis

Objective Therefore, this study was designed to analyze the bronchoalveolar lavage (BAL) fluid concentrations of IL-5, RANTES (CCL5) and eotaxin (CCL11) and also to examine the relationship between the percentage and absolute number of the BAL eosinophils and these measured chemokines in patients with sulfur mustard (SM) gas-induced pulmonary fibrosis (PF). Patients Fifteen veterans with mustard gas-induced PF and 14 normal veterans as control group. Intervention Pulmonary function tests, tests for D_LCO, computed tomography scans of the chest, analyses of BAL fluids for RANTES (CCL5), eotaxin (CCL11), and IL-5 were performed in all cases. Results Eosinophilic alveolitis was the predominant feature (p < 0.0001). There were significant differences in CCL5, CCL11, and IL-5 levels of BAL fluid between patients with PF and controls (p < 0.0001, p < 0.0001, and p = 0.001, respectively). The concentrations of CCL5 and CCL11 showed positive correlations with percentage (r = 0.57 and p = 0.03; r = 0.52 and p = 0.04, respectively) and absolute counts (r = 0.54 and p = 0.04, r = 0.53 and p = 0.04, respectively) of BAL eosinophils. There were significant positive correlations between the concentrations of IL-5 and the proportion and total cell number of eosinophils in BAL (r = 0.67 and p = 0.01; r = 0.59 and p = 0.02, respectively) too. Conclusion A significant correlation between BAL CCL5, CCL11, and IL-5 levels and eosinophils in patients with pulmonary fibrosis due to SM gas inhalation has been demonstrated, suggesting that these C–C chemokines and IL-5 contribute to the recruitment of eosinophils cells in the lung in these victims.     

Mycobacterial infections in adult patients with hematological malignancy

We retrospectively analyzed the clinical and microbiological characteristics of adult patients with hematological malignancy and nontuberculous mycobacteria (NTM) infections from 2001 to 2010. During the study period, 50 patients with hematological malignancy and tuberculosis (TB) were also evaluated. Among 2,846 patients with hematological malignancy, 34 (1.2%) patients had NTM infections. Mycobacterium avium-intracellulare complex (13 patients, 38%) was the most commonly isolated species, followed by M. abscessus (21%), M. fortuitum (18%), and M. kansasii (18%). Twenty-six patients had pulmonary NTM infection and eight patients had disseminated disease. Neutropenia was more frequently encountered among patients with disseminated NTM disease (p = 0.007) at diagnosis than among patients with pulmonary disease only. Twenty-five (74%) patients received adequate initial antibiotic treatment. Five of the 34 patients died within 30 days after diagnosis. Cox regression multivariate analysis showed that chronic kidney disease (p = 0.017) and neutropenia at diagnosis (p = 0.032) were independent prognostic factors of NTM infection in patients with hematological malignancy. Patients with NTM infection had higher absolute neutrophil counts at diagnosis (p = 0.003) and a higher 30-day mortality rate (15% vs. 2%, p = 0.025) than TB patients. Hematological patients with chronic kidney disease and febrile neutropenia who developed NTM infection had significant worse prognosis than patients with TB infection.     

Maspin overexpression correlates with increased expression of vascular endothelial growth factors A, C, and D in human ovarian carcinoma

The vascular endothelial growth factor (VEGF) family, including VEGFA, VEGFC, and VEGFD, plays an essential role in the angiogenesis of both pathologic and nonpathologic conditions. Maspin belongs to the serpin superfamily and has been identified as a tumor suppressor because it inhibits motility, invasion, and angiogenesis. Few studies have compared maspin with VEGF in ovarian carcinoma. Therefore, we investigated the expression and correlation of maspin, VEGFA, VEGFC, and VEGFD with the tumorigenesis of the ovary and clinicopathologic variables.

Using immunohistochemistry, we examined maspin, VEGFA, VEGFC, and VEGFD expression in 60 ovarian carcinoma tissues (35 serous papillary carcinomas, 18 endometrioid carcinomas, and 7 primary ovarian mucinous carcinomas). Staining of cells was scored as +2 if more than 50% of the cells were positive, as +1 if less than 50% of the cells were positive, and as negative if none of the cells stained positive.

Overexpression of maspin, VEGFC, and VEGFD was significantly associated with high tumor grade (P<.001, P=.004, P<.001, respectively), clinical stage (P=.002, .01, and .001, respectively), the presence of ascites (P<.001, P=.03, and P=.001, respectively), and the presence of metastatic lymph nodes (P=.002, P<.001, and P<.001, respectively). Maspin was correlated with VEGFA (P=.01), VEGFC (P<.001), and VEGFD (P<.001). The VEGFA score was positively correlated with high tumor grade (P=.04), lymphovascular space invasion (LVSI) (P<.001), International Federation of Gynecology and Obstetrics (FIGO) stage (P=.009), maspin, VEGFC (P=.003), and VEGFD (P=.003), but it was not correlated with the presence of ascites and metastatic lymph nodes.

Maspin, VEGFC, and VEGFD are expressed in ovarian tumors with a poor prognostic parameters, and seem to play a role in ovarian cancer angiogenesis, progression, and lymph node metastases. Our results indicate that in contrast to most other carcinomas, maspin expression is directly associated with the biological aggressiveness of ovarian carcinoma. These results may offer new insights regarding the role of maspin in ovarian cancer and might also affect the diagnosis and treatment strategies.     

Serum sFas, Leptin, and VEGF in Patients with Ovarian Cancer and Benign Tumors

The initial levels of soluble Fas antigen (sFas), leptin, and vascular endothelium growth factor (VEGF) were measured in the sera of 100 patients with ovarian cancer and benign tumors and in 60 healthy women aged 28–65 years. Serum levels of sFas and VEGF were elevated in the total group of patients with ovarian tumors, while leptin levels were the same as in healthy women. The studied parameters did not depend on the age of patients and healthy women. The levels of sFas and leptin were virtually the same in benign and malignant ovarian tumors, while VEGF concentration was higher in patients with ovarian cancer. The mean serum levels of sFas, VEGF, and leptin in patients with poorly and moderately differentiated serous ovarian cancer were 2-fold higher than in well-differentiated tumors (p<0.05), while serum concentrations of sFas and leptin increased with the disease stage progress in patients with ovarian cancer (p<0.05). According to the data of unifactorial analysis, the increase in serum levels of sFas and VEGF in ovarian cancer patients correlated with short duration of the relapse-free period. Multifactorial analysis showed that the disease stage (p=0.006), presence of ascites (p=0.03), VEGF concentration (p=0.02), and the sFas/leptin coeffi cient (p=0.045) are highly signifi cant independent factors for predicting the relapse-free survival of patients with serous ovarian cancer.     

The efficacy of classical massage on stress perception and cortisol following primary treatment of breast cancer

To investigate the efficacy of classical massage on stress perception and mood disturbances, 34 women diagnosed with primary breast cancer were randomized into an intervention or control group. For a period of 5 weeks, the intervention group (n = 17) received biweekly 30-min classical massages. The control group (n = 17) received no additional treatment to their routine health care. The Perceived Stress Questionnaire (PSQ) and the Berlin Mood Questionnaire (BSF) were used and the patients’ blood was collected at baseline (T1), at the end of the intervention period (T2), and 6 weeks after T2 (T3). Compared with control group, women in the intervention group reported significantly lower mood disturbances, especially for anger (p = 0.048), anxious depression (p = 0.03) at T2, and tiredness at T3 (p = 0.01). No group differences were found in PSQ scales, cortisol and serotonin concentrations at T2 and T3. However, perceived stress and cortisol serum levels (p = 0.03) were significantly reduced after massage therapy (T2) compared with baseline in the intervention group. Further research is needed to validate our findings.     

SMAD4 protein expression and cell proliferation in colorectal adenocarcinomas

The TGFβ signalling pathway is a growth inhibitor system that operates in both normal and tumour cells. Alterations to components of this pathway, including SMAD4, result in resistance to growth inhibition and uncontrolled proliferation. The aim of this study was to analyse the relationships between SMAD4, a key protein in the growth-inhibiting TGFβ pathway; cell proliferation proteins Ki67, p27 and S-phase kinase-associated protein 2 (SKP2); and mismatch repair (MMR) proteins as well as prognostic indicators in colorectal adenocarcinomas. A series of 230 sporadic colorectal adenocarcinomas were studied using tissue microarrays by immunohistochemistry for SMAD4, Ki67, p27, SKP2 and MMR protein (hMLH1, hMSH2 and hMSH6) expression. Protein expression was analysed with respect to pathological prognostic criteria. Loss of SMAD4 nuclear expression (27/230, 12%) correlated with the presence of lymph node metastases, MMR protein expression and the absence of p27 in tumour cells (p = 0.04, p = 0.08 and p = 0.03, respectively). A high Ki67 index did not correlate with SMAD4 expression; however, it did correlate with moderate or poor histological differentiation, SKP2 expression and aberrant or absent MMR protein expression (p = 0.02, p < 0.01 and p < 0.01, respectively). In conclusion, the results of our study suggest that the loss of SMAD4, occurring in 12% of colorectal adenocarcinomas, correlated with the presence of lymph node metastases and absence of p27 expression but not with high cellular proliferation. However, high proliferation correlated with SKP2 and aberrant MMR protein expression. Although the advantage of immunohistochemistry is high throughput, our results allow only an initial evaluation, and subsequent studies, including genetic analyses, are required.