Strategies for clinical implementation of TNM-Immunoscore in resected nonsmall-cell lung cancer.

Immunoscore is a prognostic tool defined to quantify in situ immune cell infiltrates and appears highly promising as a supplement to the tumor-node-metastasis (TNM) classification of various tumors. In colorectal cancer, an international task force has initiated prospective multicenter studies aiming to implement TNM-Immunoscore (TNM-I) in a routine clinical setting. In breast cancer, recommendations for the evaluation of tumor-infiltrating lymphocytes (TILs) have been proposed by an international working group. Regardless of promising results, there are potential obstacles related to implementing TNM-I into the clinic. Diverse methods may be needed for different malignancies and even within each cancer entity. Nevertheless, a uniform approach across malignancies would be advantageous. In nonsmall-cell lung cancer (NSCLC), there are several previous reports indicating an apparent prognostic importance of TILs, but studies on TILs in a TNM-I setting are sparse and no general recommendations are made. However, recently published data is promising, evoking a realistic hope of a clinical useful NSCLC TNM-I. This review will focus on the TNM-I potential in NSCLC and propose strategies for clinical implementation of a TNM-I in resected NSCLC.

Co-expression of PDGF-B and VEGFR-3 strongly correlates with lymph node metastasis and poor survival in non-small-cell lung cancer.

BACKGROUND: Platelet-derived growth factors (PDGFs) and vascular endothelial growth factors and their receptors [platelet-derived growth factor receptors (PDGFRs) and vascular endothelial growth factor receptors (VEGFRs)] are related to both angiogenesis and lymphangiogenesis and are important targets in new cancer treatment strategies. We aimed to study the PDGFs/PDGFRs and correlations with lymph node metastasis (LNM) and investigate the prognostic impact of the co-expression of PDGF-B and VEGFR-3 and its correlation with LNM. PATIENTS AND METHODS: Tumor tissue samples from 335 resected patients with stage I-IIIA non-small-cell lung cancer (NSCLC) were obtained and tissue microarrays were constructed from duplicate cores of tumor cells and tumor-related stroma from each specimen. Immunohistochemistry was used to evaluate the expression of the molecular markers PDGF-A, PDGF-B, PDGF-C, PDGF-D, PDGFR-alpha, PDGFR-beta, VEGFR-3 and D2-40. RESULTS: There were 232 N0 and 103 N+ patients (76 N1 and 27 N2). In multivariate analyses, high tumor cell PDGF-A expression (P = 0.017) correlated with LNM. Tumor cell co-expression of VEGFR-3 and PDGF-B correlated with nodal metastasis and was an independent indicator of poor prognosis (hazard ratio 4.8, confidence interval 95% 2.80-8.31, P < 0.001). CONCLUSION: Tumor cell PDGF-A expression correlates with LNM, and the co-expression of PDGF-B and VEGFR-3 is strongly associated with poor survival in NSCLC patients.

Low Expression of miR-424-3p is Highly Correlated with Clinical Failure in Prostate Cancer.

Prostate cancer (PC) is a highly heterogenous disease and one of the leading causes of mortality in developed countries. Recently, studies have shown that expression of immune checkpoint proteins are directly or indirectly repressed by microRNAs (miRs) in many types of cancers. The great advantages of using miRs based therapy is the capacity of these short transcripts to target multiple molecules for the same- or different pathways with synergistic immune inhibition effects. miR-424 has previously been described as a biomarker of poor prognosis in different types of cancers. miR-424 is also found to target both the CTLA-4/CD80- and PD-1/PD-L1 axis. In the present study, the clinical significance of miR-424-3p expression in PC tissue was evaluated. Naïve radical prostatectomy specimens from 535 patients was used for tissue microarray construction. In situ hybridization was used to evaluate the expression of miR-424-3p and immunohistochemistry was used for CTLA-4 protein detection. In univariate- and multivariate analyses, low expression of miR-424-3p was significant associated with clinical failure-free survival, (p = 0.004) and p = 0.018 (HR:0.44, CI95% 0.22-0.87). Low expression of miR-424-3p also associated strongly with aggressive phenotype of PC. This highlight the importance of miR-424-3p as potential target for therapeutic treatment in prostate cancer.

The prognostic impact of NF-kappaB p105, vimentin, E-cadherin and Par6 expression in epithelial and stromal compartment in non-small-cell lung cancer.

Vimentin, nuclear factor-kappaB (NF-kappaB) p105, fascin, E-cadherin, TGF-beta, Par6 and atypical PKC are molecular markers that play an important role in cell differentiation. Herein, we investigate their prognostic impact in primary non-small-cell carcinoma (NSCLC). Tumour tissue samples from 335 resected patients with stage I-IIIA were used. Tissue microarrays were constructed from duplicate cores of both neoplastic cells and stromal cells and were immunohistochemically evaluated. In univariate analyses, high tumour epithelial cell expressions of NF-kappaB p105 (P=0.02) and E-cadherin (P=0.03) were positive prognostic indicators for disease-specific survival (DSS), whereas high tumour epithelial cell expression of vimentin (P=0.001) was a negative prognostic indicator. High expression of NF-kappaB p105 (P=0.001) and Par6 (P=0.0001) in the stromal compartment correlated with a good prognosis. In multivariate analyses, the tumour epithelial cell expression of NF-kappaB p105 (P=0.0001) and vimentin (P=0.005) and the stromal cell expression of NF-kappaB p105 (P=0.007) and Par6 (P=0.0001) were independent prognostic factors for DSS. High expression of NF-kappaB p105 and low expression of vimentin in tumour epithelial cells are independent predictors of better survival in primary NSCLC. In stromal cells, high expressions of NF-kappaB p105 and Par6 are both favourable independent prognostic indicators.

Frequency of unemployment among epileptic patients in Tikrit, Iraq.

Epilepsy is a chronic illness that affects all ages and which has long-term complications, such as impairment of employability. We estimated the unemployment rate among 100 epileptic patients attending two public medical clinics in Tikrit. The overall rate of unemployment was 33%. The rate was significantly greater in those whose epilepsy was not controlled and those in whom the age at onset of epilepsy was younger.

The spectrum of child abuse presenting to a university hospital in Riyadh.

BACKGROUND: Child abuse is prevalent worldwide, although it is often underreported. we describe the pattern of child abuse and neglect presenting to the emergency room of our hospital, the sociocultural changes which brought this about, and suggest ways to deal with this emotionally sensitive issue. PATIENTS AND METHODS: Thirteen cases of child abuse and neglect were seen in the emergency room of King Khalid University Hospital over a period of one year from July 1996 to June 1997. There were four cases of non-accidental injury, three of which had serious injury. There were three cases of sexual abuse, four cases of neglect, resulting in the death of one child and severe emaciation in another. There was one suspected case of Munchausen syndrome by proxy, and one case of child labor with neglect. CONCLUSION: Public awareness of the problem of child abuse has increased, and recent media reports reflect the significance accorded to the issue. As more information is obtained on this subject and policies and guidelines are set in place, efforts at reporting and preventing physical and psychological trauma will gather momentum.

Gene expression, function and ischemia tolerance in male and female rat hearts after sub-toxic levels of angiotensin II.

To examine the response to chronic high-dose angiotensin II (Ang II) and a proposed milder response in female hearts with respect to gene expression and ischemic injury. Female and male litter-matched rats were treated with 400 ng kg(-1) min(-1) Ang II for 14 days. Hearts were isolated, subjected to 30-min ischemia and 30-min reperfusion in combination with functional monitoring and thereafter harvested for gene expression, WB and histology. Ang II-treated hearts showed signs of non-hypertrophic remodeling and had significantly higher end diastolic pressure after reperfusion, but no significant gender difference was detected. Ang II increased expression of genes related to heart function (ANF, ß-MCH, Ankrd-1, PKC-α, PKC-δ TNF-α); fibrosis (Col I-α1, Col III-α1, Fn-1, Timp1) and apoptosis (P53, Casp-3) without changing heart weight but with 68% increase in collagen content. High (sub-toxic) dose of Ang II resulted in marked heart remodeling and diastolic dysfunction after ischemia without significant myocyte hypertrophy or ventricular chamber dilatation. Although there were some gender-dependent differences in gene expression, female gender did not protect against the overall response.

Pregnancy protects against antiangiogenic and fibrogenic effects of angiotensin II in rat hearts.

AIM: To investigate the difference between physiological and pathological cardiac remodelling induced, respectively, by pregnancy and angiotensin (Ang) II, and to test the hypothesis that pregnancy protects against Ang II effects. METHODS: Female Wistar rats, pregnant (n = 12) and non-pregnant (n = 12), were implanted with mini-pumps containing saline (sham) or 150 ng kg(-1) min(-1) Ang II. Ten days later echocardiography and blood pressure measurement were performed. Expression of 22 genes was assessed using RT-PCR. Microscopic sections of LV were prepared to determine collagen content (Sirius Red staining), vessel density (ß-actin immunolabelling) and myocytes diameter (Toluidine Blue). RESULTS: Heart weight (HW) was increased in Ang II treated groups compared with their controls. Furthermore, HW of Ang II treated pregnant rats (1.0 ± 0.03 g) was higher than that in non-pregnant sham (0.7 ± 0.02 g), pregnant (0.8 ± 0.01 g) and Ang II treated non-pregnant (0.8 ± 0.02 g) rats. Relative LV wall thickness showed similar pattern. Aortic pressure was significantly increased in Ang II groups. Collagen content was increased in Ang II (4.0 ± 0.5%) compared with sham (1.5 ± 0.1%) but reduced again when treated rats were pregnant (2.8 ± 0.4%). Vessel density was reduced by 47.8% after Ang II treatment in non-pregnant and by only 13.9% in pregnant rats. Gene expression analysis showed increased expression of atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), anykrin repeat domain-containing protein 1 (Ankrd-1), protein kinase C-α and -δ and tumour suppressor gene TP53 (p53) in Ang II treated groups and upregulation of ANF, BNP and Ankrd-1 remained when pregnancy was combined with Ang II. Pregnancy reduced expression of: α-myosin heavy chain, tumour necrosis factor-α, p53, endothelial nitric oxide synthase and inducible nitric oxide synthase. CONCLUSION: Pregnancy seems to counteract the detrimental effects of Ang II on fibrosis and angiogenesis in heart. In addition, pregnancy and Ang II lead to partly opposite changes in the expression of some genes important for heart function.

Frequency of unemployment among epileptic patients in Tikrit, Iraq

Epilepsy is a chronic illness that affects all ages and which has long-term complications, such as impairment of employability. We estimated the unemployment rate among 100 epileptic patients attending two public medical clinics in Tikrit. The overall rate of unemployment was 33%. The rate was significantly greater in those whose epilepsy was not controlled and those in whom the age at onset of epilepsy was younger