Expression Analysis of p53, Ki-67 and bcl-2 in Pre-Malignant Lesions of the Cervix

Objectives: The present study has tried to analyze the individual and combined expression of the three markers—p53, Ki-67 and bel-2-in HPV associated pre-malignant lesions of the cervix. Methods: Thirty-four cases of high-grade lesions, 21 low-grade cases and 18 normal cases were histologically assessed. HPV-DNA presence and the viral types were determined through PCR and RFLP, respectively. Marker expression was performed by immuno-histochemistry.Results: With regards to viral types, HPV with high oncogenic potential represented the majority, with just one case reporting the low oncogenic potential for viral infection (HPV 6). HPV was the most frequent and could be associated with the high-grade lesion group, however, no significant associations were found between the viral ones and the marker expression. When the expression location, beyond the basal layer, was taken into account, the three markers proved to be good indicators of the lesion grade. The markers’ combined expression: p53(-), Ki-67(+), bcl-2(-) and p53(-), Ki-67(+), bcl-2(-) was statistically significant when associated with the lesion grade.Conclusions: The results suggest that the p53, Ki-67 and bel-2 markers can contribute to differentiate the lesion grades, whether in its isolate form or in combined form.

Quantitative redox imaging biomarkers for studying tissue metabolic state and its heterogeneity

NAD+/NADH redox state has been implicated in many diseases such as cancer and diabetes aswell as in the regulation of embryonic development and aging,To fluorimetrically sssthemitochondrial redox state,Dr.Chance and co-workers measured the fluorescence of NADH andoxidized flavoproteins(Fp)including favin-adenine-dinucleotide(FAD)and demonstrated theirratio(i.e.the redox ratio)is a sensitive indicator of the mitochondrial redox states.,The Chanceredox sca mer was built to simult aneously measure NADH and Fp in tisue at submilimeter scalein 3D using the freeze-trap protocol.This paper summarizes our recent research experience,development and new applications of the redox scanning technique in collaboration with Dr.Chance beginning in 2005.Dr.Chance initiated or actively involved in many of the projectsduring the last several years of his life.We advanced the redox scanning technigue by measuringthe nominal concentrations(in reference to the frozen solution standards)of the endogenousfuorescent analy tes,i.e.,[NADH]and[rp]to quantify the redox ratios in various biologicaltissues.The advancement has enabled us to identify an array of the redox indices as quantitativeimaging,biomarkers(including[NADH],[Fp],[Fp]/[NADH]+[Fp],[NADH]/[Fp],and theirstandard deviations)for studying some important biological questions on cancer and normaltsue metabolism.We found that the redox indices were asociated or changed with(NADH)tumorigenesis(cancer versus non-cancer of human breast tisue biopsies);(2)tumor metastaticpotential;(3)tumor glucose uptake;(4)tumor p53 stat us;(5)PI3K pathway activation in pre-malignant tissue;(6)therapeutic ffects on tumors;(7)embryonic stem cell diferentiation;(8)the heart under fasting,Together,our work demonstrated that the tisue redox indices obtainedfrom the redox scanning technique may provide usefil information about tisue met abolism and physiology status in normal and diseased tissues.The Chance redox scanner and other redoximaging techniques may have wide-ranging potential applications in many fields,such as cancer,diabetes,developmental process,mitochondrial diseases,neurodegenerative diseases,and aging.

Transvaginal Color Doppler in the Assessment of Cervical Carcinoma and Pre-Cancer: Evidence from a Case Control Study Using Colour Doppler Ultrasonography Pulsatility Index of Uterine Vasculature

Introduction: Transvaginal colour Doppler is a non-invasive ultrasound-based technique that allows an in-vivo assessment of tumor vascularization. Several researches done in the last decade have evaluated the role of this technique in assessing carcinoma of the cervix. However there is a significant paucity of literature linked to pre-malignant lesions of the cervix and its diagnosis based on transvaginal colour doppler and its pulstality index (PI). In this paper we present a case control study conducted to assess the validity of transvaginal colour doppler scan and PI in diagnosing malignant and pre-malignant lesions of the cervix. Methodology: A case control study with a total sample of 57 women was conducted at the Nawaloka Hospital for duration of two years. 19 cases of recently diagnosed patients with cervical carcinoma, using cytobrush and colposcopy guided biopsy, evaluated by a consultant histopathologist, were recruited. Staging was done according to FIGO classification. 40 age-matched patients with histologically confirmed normal cervix were selected as controls and 2 were excluded from the study due to the presence of cervical infection. All cases and controls were subjected to transvaginal colour doppler sonography using a 5 MHz 3D probe using GEvolusion6 US machine. The machine was also set for high pass filter at 100 Hz to eliminate low frequency signals occurring from vessel-wall motion. Cervical colour doppler ultrasonography pattern was captured in each case of malignancy, pre-malignancy and controls, and pulstality index (PI) was assessed by the lead gynecologist accredited with ISUOG standards. The highest PI was assessed and recorded in the descending branch of the uterine artery. Results: Women’s mean age was 55.5 years (range 35 - 78). According to clinical staging, there were 4 females with carcinoma in situ, 4 Females with Stage I a, 3 with Stage I b, 4 with Stage II a and 4 with Stage III a. Histologic examination revealed 13 women with squamous cell carcinoma, 2 women with adenocarcinoma and 4 with carcinoma in situ (CIN III) of the cervix. Mean PI value for the cases were 1.94 (range 1.2 - 3.1) and the mean PI value for the controls were 0.805 (range 0.3 - 1.5). Neovascularization was markedly seen in the patients with invasive cervical carcinoma with a PI ranging between 1.99 and 3.10. Chi square test results showed a very high statistically significant difference of PI values between cases and controls (p value < 0.0001). An ROC analysis revealed the optimal cut-off value of PI at 1.475 with a sensitivity of 89.5% and a specificity of 93.5%. Conclusion: Transvaginal doppler ultrasonography and PI of the descending cervical branch of the uterine artery and its branch vasculature allow a non-invasive assessment of tumor vascularization in cervical carcinoma and pre-malignancy. PI with a cut off value of 1.475, can be reliably used to detect and screen pre-malignancies and malignancies at a relatively early stage with a sensitivity of 89.5% and a specificity of 93.5% enabling further definitive evaluation, in a routine gynecology trans vaginal ultrasound assessment.

Gastro-duodenal disease in Africa: Literature review and clinical data from Accra, Ghana

Gastroduodenal disease(GDD)was initially thought to be uncommon in Africa.Amongst others,lack of access to optimal health infrastructure and suspicion of conventional medicine resulted in the reported prevalence of GDD being significantly lower than that in other areas of the world.Following the increasing availability of flexible upper gastro-intestinal endoscopy,it has now become apparent that GDD,especially peptic ulcer disease(PUD),is prevalent across the continent of Africa.Recognised risk factors for gastric cancer(GCA)include Helicobater pylori(H.pylori),diet,Epstein-Barr virus infection and industrial chemical exposure,while those for PUD are H.pylori,non-steroidal antiinflammatory drug(NSAID)-use,smoking and alcohol consumption.Of these,H.pylori is generally accepted to be causally related to the development of atrophic gastritis(AG),intestinal metaplasia(IM),PUD and distal GCA.Here,we perform a systematic review of the patterns of GDD across Africa obtained with endoscopy,and complement the analysis with new data obtained on premalignant gastric his-topathological lesions in Accra,Ghana which was compared with previous data from Maputo,Mozambique.As there is a general lack of structured cohort studies in Africa,we also considered endoscopy-based hospital or tertiary centre studies of symptomatic individuals.In Africa,there is considerable heterogeneity in the prevalence of PUD with no clear geographical patterns.Furthermore,there are differences in PUD within-country despite universally endemic H.pylori infection.PUD is not uncommon in Africa.Most of the African tertiary-centre studies had higher prevalence of PUD when compared with similar studies in western countries.An additional intriguing observation is a recent,ongoing decline in PUD in some African countries where H.pylori infection is still high.One possible reason for the high,sustained prevalence of PUD may be the significant use of NSAIDs in local or over-the-counter preparations.The prevalence of AG and IM,were similar or modestly higher over rates in western countries but lower than those seen in Asia..In our new data,sampling of 136 patients in Accra detected evidence of pre-malignant lesions(AG and/or IM)in 20 individuals(14.7%).Likewise,the prevalence of pre-malignant lesions,in a sample of 109 patients from Maputo,were 8.3%AG and 8.3%IM.While H.pylori is endemic in Africa,the observed prevalence for GCA is rather low.However,cancer data is drawn from country cancer registries that are not comprehensive due to considerable variation in the availability of efficient local cancer reporting systems,diagnostic health facilities and expertise.Validation of cases and their source as well as specificity of outcome definitions are not explicit in most studies further contributing to uncertainty about the precise incidence rates of GCA on the continent.We conclude that evidence is still lacking to support(or not)the African enigma theory due to inconsistencies in the data that indicate a particularly low incidence of GDD in African countries.

A pilot study of radiologic measures of abdominal adiposity:weighty contributors to early pancreatic carcinogenesis worth evaluating?

Objective:Intra-abdominal fat is a risk factor for pancreatic cancer(PC),but little is known about its contribution to PC precursors known as intraductal papillary mucinous neoplasms(IPMNs).Our goal was to evaluate quantitative radiologic measures of abdominal/visceral obesity as possible diagnostic markers of IPMN severity/pathology.Methods:In a cohort of 34 surgically-resected,pathologically-confirmed IPMNs(17 benign;17 malignant) with preoperative abdominal computed tomography(CT) images,we calculated body mass index(BMI) and four radiologic measures of obesity:total abdominal fat(TAF) area,visceral fat area(VFA),subcutaneous fat area(SFA),and visceral to subcutaneous fat ratio(V/S).Measures were compared between groups using Wilcoxon two-sample exact tests and other metrics.Results:Mean BMI for individuals with malignant IPMNs(28.9 kg/m^2) was higher than mean BMI for those with benign IPMNs(25.8 kg/m^2)(P=0.045).Mean VFA was higher for patients with malignant IPMNs(199.3 cm^2) compared to benign IPMNs(120.4cm^2),P=0.092.V/S was significantly higher(P=0.013) for patients with malignant versus benign IPMNs(1.25 vs.0.69 cm^2),especially among females.The accuracy,sensitivity,specificity,and positive and negative predictive value of V/S in predicting malignant IPMN pathology were 74%,71%,76%,75%,and 72%,respectively.Conclusions:Preliminary findings suggest measures of visceral fat from routine medical images may help predict IPMN pathology,acting as potential noninvasive diagnostic adjuncts for management and targets for intervention that may be more biologically-relevant than BMI.Further investigation of gender-specific associations in larger,prospective IPMN cohorts is warranted to validate and expand upon these observations.

Cellular plasticity and metastasis in breast cancer: a pre- and post-malignant problem

As a field we have made tremendous strides in treating breast cancer,with a decline in the past 30 years of overall breast cancer mortality.However,this progress is met with little affect once the disease spreads beyond the primary site.With a 5-year survival rate of 22%,10-year of 13%,for those patients with metastatic breast cancer(mBC),our ability to effectively treat wide spread disease is minimal.A major contributing factor to this ineffectiveness is the complex make-up,or heterogeneity,of the primary site.Within a primary tumor,secreted factors,malignant and pre-malignant epithelial cells,immune cells,stromal fibroblasts and many others all reside alongside each other creating a dynamic environment contributing to metastasis.Furthermore,heterogeneity contributes to our lack of understanding regarding the cells'remarkable ability to undergo epithelial/non-cancer stem cell(CSC)to mesenchymal/CSC(E-M/CSC)plasticity.The enhanced invasion&motility,tumor-initiating potential,and acquired therapeutic resistance which accompanies E-M/CSC plasticity implicates a significant role in metastasis.While most work trying to understand E-M/CSC plasticity has been done on malignant cells,recent evidence is emerging concerning the ability for pre-malignant cells to undergo E-M/CSC plasticity and contribute to the metastatic process.Here we will discuss the importance of E-M/CSC plasticity within malignant and pre-malignant populations of the tumor.Moreover,we will discuss how one may potentially target these populations,ultimately disrupting the metastatic cascade and increasing patient survival for those with mBC.