Validation of the pink esthetic score/white esthetic score at single tooth-supported prostheses in the esthetic zone: A randomized clinical trial.

OBJECTIVES: To validate the reproducibility and inter/intra-observer variability of the Pink Esthetic Score/White Esthetic Score (PES/WES) of single tooth-supported prostheses in the maxillary esthetic zone (13-23). MATERIALS AND METHODS: Forty-five patients were randomly assigned to one of the three treatment options (15 patients per group) receiving each one a different crown type: Porcelain fused to metal (PFM), monolithic zirconia, and lithium disilicate. Eight observers from each of four different specialties (Prosthodontists, Orthodontists, Periodontists, and Oral Surgeons) were recruited and assessed twice and four weeks apart (i.e., T1 and T2) 45 photographs of the single tooth-supported prosthesis using PES/WES and compared them with contralateral teeth. RESULTS: According to the ANOVA and post hoc tests, the zirconia crown type obtained the highest mean score by all observers, with a mean value of 16.70 ± 2.94. The prosthodontists and oral surgeons assigned the lowest mean score to PFM crowns, 13.03 ± 3.47 and 13.80 ± 3.17, respectively. Notably, the prosthodontists awarded the highest scores, specifically 17.50 ± 2.81 for the zirconia crowns. Intraobserver agreement was calculated utilizing the paired t-test. Pairwise comparisons between observers of different specialties revealed significant intraobserver agreement. Interclass correlation coefficient (ICC) scores were statistically significant among four specialties. No difference was detected concerning the interobserver agreement. CONCLUSIONS: The PES/WES index remains consistent across various observers from different specializations, yielding uniform results in the overall esthetic evaluation. Consequently, in light of the presented preliminary positive results, its use might also be considered for the esthetic assessment of single-tooth-supported prostheses. CLINICAL SIGNIFICANCE: The PES/WES index may be employed clinically to evaluate single tooth-supported prostheses as it emerged as a reproducible esthetic scoring system.

Assessment of reproducibility and influence of different dental specialties on functional implant prosthodontic score: A prospective clinical study analyzing single-unit implant crowns.

AIM: Implant therapy in partially edentulous patients has become the most adapted and predictable treatment modality. The success rate of implants has been measured in terms of esthetic, biological, and technical factors such as radiographic bone loss, prosthetic complications, and stability. Despite the existence of several indices for the esthetic assessment of implant crowns, a need for functional evaluation of the implant crown with an objective and reproducible score has arisen. The study aims to validate the reproducibility of the functional implant prosthodontic score (FIPS) and the influence exerted by different dental specialties while evaluating posterior single-unit implant crowns. STUDY SETTING AND DESIGN: This was a prospective clinical study. MATERIALS AND METHODS: Fifteen patients with cement-retained single-implant crowns in the posterior region of the jaws were included. Eight examiners, two prosthodontists, two periodontists, two oral surgeons, and two orthodontists evaluated 15 photographs of single-unit implant crowns during the 1-year follow-up examination. The examiners assessed the photographs for FIPS, which includes five parameters for objectively evaluating the single-unit implant crowns. Assessments were performed twice at a gap of 4 weeks. STATISTICAL ANALYSIS USED: Pearson's correlation with a 95% confidence interval was calculated for the intra-examiner and the Kruskal-Wallis test for inter-examiner reproducibility. RESULTS: The mean total FIPS scores for all included examiners were 7.133 for time T1 and 7.074 for time T2, showing a strong Pearson correlation coefficient for intra-examiner reproducibility. No significant difference was analyzed among different specialties with statistically significant values of the Kruskal-Wallis test. CONCLUSION: Intra- and inter-examiner analysis showed very consistent results during the reproducibility assessment of FIPS. The results validated the use of FIPS as a long-term predictive functional evaluation tool for the single-implant crowns in posterior sites irrespective of the effect of different dental specialties. It could be used for risk estimation and prognosis for long-term survival and performance of implant crowns.

Zirconia-ceramic versus metal-ceramic implant-supported multiunit fixed dental prostheses: A systematic review and meta-analysis.

Implant-supported prostheses could serve as a reliable restorative option for partial edentulism. Various restorative materials have been utilized in fabricating these prostheses, impacting both esthetics and peri-implant health. The present systematic review aimed to assess the survival rate and mechanical complications of zirconia ceramic compared to metal-ceramic implant-supported multiunit fixed dental prostheses (FDPs). We conducted searches in online databases such as MEDLINE (PubMed), Scopus, and Cochrane up until December 2022. A risk-of-bias assessment was done for all the included studies. Data extraction was performed based on the following parameters: author, year, study design, number of implants, abutment material, age range, observation period, incidence of mechanical complications, and survival rate. This systematic review included six studies (four randomized controlled trials and two retrospective studies). The meta-analysis significantly favored metal-ceramic restorations regarding mechanical complications with a risk ratio (RR) value of 1.64 and P = 0.001. Meta-analysis showed no difference in metal-ceramic FDPs in prostheses survival rate (P = 0.63; RR: 1.27, 95% confidence interval: 0.52-3.37; heterogeneity: P = 0.65; I2: 0%). While metal-ceramic multiunit implant-supported prostheses exhibited fewer mechanical complications compared to zirconia-ceramic prostheses, there was no significant difference in terms of prosthesis survival rate between the two. Hence, both treatments appear to be viable options for long-term implant-supported prostheses.

Accuracy of Intraoral Scanner for Recording Completely Edentulous Arches-A Systematic Review.

Scanning edentulous arches during complete denture fabrication is a crucial step; however, the quality of the resulting digital scan is still questionable. The purpose of this study is to systematically review studies (both clinical and in vitro) and determine whether intraoral scanners have clinically acceptable accuracy when recording completely edentulous arches for the fabrication of removable complete dentures. An electronic search in medical databases like PubMed, Scopus, and Web of Science (WOS), using a combination of relevant keywords, retrieved 334 articles. After full-text evaluation, twelve articles fulfilled the inclusion criteria for this review (eight clinical studies and four in vitro studies). A quality analysis of the included studies was carried out using the QUADAS-2 tool. The accuracy values varied between different intraoral scanners. Different regions of the edentulous arches showed differences in trueness and precision values in both in vitro and clinical studies. Peripheral borders, the inner seal, and poorly traceable structures like the soft palate showed maximum discrepancies. The accuracy of intraoral scanners in recording clear anatomic landmarks like hard tissues with attached mucosa was comparable to conventional edentulous arch impressions. However, higher discrepancies were recorded when digitizing mobile and poorly traceable structures. Intraoral scanners can be used to digitize denture-bearing areas, but the interpretation of the peripheral border and the soft palate should be carefully carried out.

Accuracy of single-unit ceramic crown fabrication after digital versus conventional impressions: A systematic review and meta-analysis.

In the present era when interest in digital dentistry is increasing, the published literature is still confusing about whether digital impression provides similar accuracy as provided by a conventional impression for the fabrication of a single-unit ceramic crown. The aim of the study was to systematically review the in vivo studies comparing marginal, axial, and occlusal fit of single-unit ceramic crowns fabricated after digital impressions with the ones fabricated after conventional impressions. The PubMed, Scopus, and Cochrane online databases were searched for studies comparing the digital impression technique with the conventional technique for single-unit ceramic crowns. Data extraction was done for the year of publication, type of study, country, number of patients, impression system (intraoral scanner [IOS] or conventional impression), marginal fit, axial fit, and occlusal fit. Ten studies were included for meta-analysis regarding the discrepancy in marginal fit, axial fit, and occlusal fit. The digital impression proved to be better than the conventional impression. The mean difference for marginal fit was 6.54 µm (heterogeneity P < 0.00001, I2 = 93%), for axial fit 24.69 µm (heterogeneity P = 0.34, I2 = 11%), and for occlusal fit 6.99 µm (heterogeneity P = 0.03, I2 = 59%). The results of meta-analyses suggest that there is no significant difference between the impression systems (marginally favoring digital impression). The digital impression technique provided better marginal and internal fit of single-unit ceramic crowns than the conventional impression technique. The digital workflow using IOS provided a clinically acceptable marginal fit for single-unit crowns.

Stromal microenvironment namely angiogenesis, tumor-infiltrating lymphocytes, and matrix metalloproteinase in invasive breast carcinoma: Do they have a prognostic role?

Background: The role of stromal microenvironment in growth, invasiveness, and metastatic potential of breast carcinoma (BC) is being recognized increasingly, both to predict prognosis and as potential therapeutic targets. The present study aimed to evaluate the correlation of angiogenesis, tumor-associated lymphocytes, and stromal CD10 expression with clinicopathologic parameters. Materials and Methods: This study included 100 consecutive cases of invasive BC undergoing modified radical mastectomy. Relevant clinical details, pathological grade, lymph nodal status, and clinical stage were noted. Paraffin-embedded sections were subjected to immunohistochemistry for CD34, CD20, CD45RO, and CD10. Microvessel density (MVD), tumor-associated lymphocytes, and stromal CD10 expression were estimated from these sections. Statistical analysis was done using nonparametric tests to correlate the clinic-pathologic features with each of these parameters. Results: MVD was found to be significantly higher in Grade III, node-positive cases, and higher stage breast cancers (P < 0.05). The number of T-lymphocytes was higher in node-positive cases, while B-lymphocytes were lower in number in higher grade tumors. CD10 expression showed a significant positive association with tumor grade, nodal status, and stage (P < 0.05 for each). Conclusion: This study demonstrates that changes in stromal microenvironment of BC such as MVD, tumor-associated lymphocytes, and stromal CD10 expression correlate with the clinicopathological parameters and hence may be exploited as prognostic markers or therapeutic targets, based on further larger studies.

Rehabilitation using implants in free fibula flap of a patient with ameloblastoma: Case report with 4-year follow-up.

Ameloblastoma is a locally invasive odontogenic tumor of the jaw. It can advance to large size resulting in facial deformity, loose teeth, and in severe cases pathologic fracture of the jaws. As ameloblastoma shows local invasiveness and tendency for recurrence, radical surgery which includes marginal resection or segmental resection are preferred. This clinical report describes the prosthetic rehabilitation of a patient affected by extensive mandibular ameloblastoma. Enbloc resection of the tumor and reconstruction by fibula-free flap was done. After initial healing for about 18 months, five endosseous implants were placed and implant-supported fixed hybrid prosthesis using computer-aided design and computer-aided manufacturing milled titanium framework was fabricated. Surgical and prosthodontic challenges are discussed. Osseointegrated implants provide a new perspective of treatment to enhance the quality of life of patients resected for oral tumors.

Prediction of recurrence free survival for esophageal cancer patients using a protein signature based risk model.

BACKGROUND: Biomarkers to predict the risk of disease recurrence in Esophageal squamous cell carcinoma (ESCC) patients are urgently needed to improve treatment. We developed proteins expression-based risk model to predict recurrence free survival for ESCC patients. METHODS: Alterations in Wnt pathway components expression and subcellular localization were analyzed by immunohistochemistry in 80 ESCCs, 61 esophageal dysplastic and 47 normal tissues; correlated with clinicopathological parameters and clinical outcome over 86 months by survival analysis. Significant prognostic factors were identified by multivariable Cox regression analysis. RESULTS: Biomarker signature score based on cytoplasmic ß-catenin, nuclear c-Myc, nuclear DVL and membrane α-catenin was associated with recurrence free survival [Hazard ratio = 1.11 (95% CI = 1.05, 1.17), p < 0.001, C-index = 0.68] and added significant prognostic value over clinical parameters (p < 0.001). The inclusion of Slug further improved prognostic utility (p < 0.001, C-index = 0.71). Biomarker Signature Scoreslug improved risk classification abilities for clinical outcomes at 3 years, accurately predicting recurrence in 79% patients in 1 year and 97% in 3 years in high risk group; 73% patients within low risk group did not have recurrence in 1 year, with AUC of 0.76. CONCLUSIONS: Our comprehensive risk model predictive for recurrence allowed us to determine the robustness of our biomarker panel in stratification of ESCC patients at high or low risk of disease recurrence; high risk patients are stratified for more rigorous personalized treatment while the low risk patients may be spared from harmful side effects of toxic therapy.

Retaining and Regaining Esthetics in the Anterior Maxillary Region Using the Socket-Shield Technique.

With the advancement in the implant in dentistry, improvement in the implant designs and placement protocol has enhanced the esthetics outcomes in the anterior zone. Yet the preservation of the peri-implant soft tissue and providing an appropriate emergence profile to the implant crown prosthesis, the tissue grafting procedures are necessary to overcome the ridge contour change. However through the socket-shield technique, the bone resorption process is preserved, and the contour of the buccal gingiva is maintained, thereby preventing its collapse and achieving good aesthetic results. This case report describes the placement of an implant in the upper anterior region and rehabilitation with a cement-retained crown prosthesis using the socket-shield technique and the patient being followed up for 6 months with good results.

Additive Effect of Platelet Rich Fibrin with Coronally Advanced Flap Procedure in Root Coverage of Miller's Class I and II Recession Defects-A PRISMA Compliant Systematic Review and Meta-Analysis.

AIM: This systematic review and meta-analysis aims to assess the additive effect of leukocyte and platelet-rich fibrin (L-PRF) on coronally advanced flap (CAF) procedures in root coverage of Miller's class I and II gingival recession defects. Review methodology: A comprehensive search in MEDLINE (PubMed), Scopus and CENTRAL (the Cochrane Central Register of Controlled Trials), along with an additional hand search, provided eight randomized clinical trials to be included in this review. A total of 167 patients with 470 gingival recession defects were analyzed. A meta-analysis was carried out to assess the change in gingival thickness (GT), width of keratinized gingiva (WKG), root coverage percentage (%RC), clinical attachment level (CAL) and recession depth (RD) at all follow-ups between CAF alone and CAF + L-PRF groups for all included studies. A subgroup analysis was carried out based on recession type (single/multiple). RESULTS: Overall, a significant improvement in GT, CAL and RD was found when treated with CAF + L-PRF. There was a trend for a positive effect in terms of an increase in WKG when using L-PRF, especially in the treatment of single recession, though significance was not achieved (p = 0.08 overall). The results of heterogeneity among the subgroups were varied and were found to be greater than 91.3% for GT and 32.8% for WKG. CONCLUSION: L-PRF when used in addition to CAF showed favorable results for the treatment of class I and II gingival recession defects.

Reproducibility and validity of anterior implant esthetic indices: A review.

BACKGROUND: The purpose of this review was to narrate about the reproducibility and validity of different indices evaluating esthetic aspects in anterior single implant-supported restorations. MATERIALS AND METHODS: An electronic search of Medline, Scopus, Embase, Cochrane Central, and Web of Science databases was performed using the keywords "dental implants," "anterior esthetics," "esthetic score," and "esthetic index." Besides, a manual search of dental implant journals was carried out. RESULTS: The electronic search revealed 932 titles. After further review, 14 articles fulfilled the eligibility criteria and were included in this review. Because of the heterogeneity of the study designs, interventions, and parameters used for assessment of esthetics, no meta-analysis could be performed. CONCLUSION: Many indices have been proposed for the evaluation of the esthetic aspects of single implant-supported reconstructions in the anterior maxilla. All of them have some advantages and drawbacks that this review pointed out. The evidence level of studies used for the validation of these indices is poor. It is necessary to achieve a consensus on the tools for assessment of the esthetic aspect and perform evidence-based studies to validate an appropriate index.

Evolving Trends in Insurance Coverage of Vascular Surgery Patients in Academic Practice.

BACKGROUND: Insurance coverage of vascular surgery patients may differ from patients with less chronic surgical pathologies. The goal of this study is to identify trends in insurance status of vascular surgery patients over the last 10 years at a busy academic center. METHODS: All consecutive patient visits for a vascular procedure from 2006 to 2016 were retrospectively reviewed from a prospectively collected institutional database. Data points included insurance status, procedures performed, and date of admission. The insurance status was categorized as Medicare, Medicaid, and uninsured. Samples were divided between 2006-2009 and 2011-2016 for comparison. Unpaired t-test, chi-squared test, and regression analysis were used to determine significant trends over the study period. RESULTS: From 2006 to 2016, 6,007 vascular surgery procedures were performed. Procedure volume increased significantly from 1,309 to 4,698 between the 2 timeframes (P < 0.05), whereas the percentage of Medicaid and Medicare patients trended upward but did not achieve significance. There was a significant decrease in the percentage of uninsured patients between the cohorts (5.65% vs. 2.96%, P < 0.05). In 2012, 10.14% of patients were uninsured compared with 2.56% in 2016 (P < 0.05). CONCLUSIONS: Insurance status affects access to care and subsequent outcomes. In our busy academic center, insurance coverage for vascular surgery has significantly increased over the past decade. The number of Medicaid and Medicare patients has slowly increased, but a significant and continuing decline in uninsured patients was observed. Implementation of the Affordable Care Act during this time period may have played a role in providing coverage for patient needing vascular surgery.

ER maleate is a novel anticancer agent in oral cancer: implications for cancer therapy.

ER maleate [10-(3-Aminopropyl)-3, 4-dimethyl-9(10H)-acridinone maleate] identified in a kinome screen was investigated as a novel anticancer agent for oral squamous cell carcinoma (OSCC). Our aim was to demonstrate its anticancer effects, identify putative molecular targets and determine their clinical relevance and investigate its chemosensitization potential for platinum drugs to aid in OSCC management. Biologic effects of ER maleate were determined using oral cancer cell lines in vitro and oral tumor xenografts in vivo. mRNA profiling, real time PCR and western blot revealed ER maleate modulated the expression of polo-like kinase 1 (PLK1) and spleen tyrosine kinase (Syk). Their clinical significance was determined in oral SCC patients by immunohistochemistry and correlated with prognosis by Kaplan-Meier survival and multivariate Cox regression analyses. ER maleate induced cell apoptosis, inhibited proliferation, colony formation, migration and invasion in oral cancer cells. Imagestream analysis revealed cell cycle arrest in G2/M phase and increased polyploidy, unravelling deregulation of cell division and cell death. Mechanistically, ER maleate decreased expression of PLK1 and Syk, induced cleavage of PARP, caspase9 and caspase3, and increased chemosensitivity to carboplatin; significantly suppressed tumor growth and increased antitumor activity of carboplatin in tumor xenografts. ER maleate treated tumor xenografts showed reduced PLK1 and Syk expression. Clinical investigations revealed overexpression of PLK1 and Syk in oral SCC patients that correlated with disease prognosis. Our in vitro and in vivo findings provide a strong rationale for pre-clinical efficacy of ER maleate as a novel anticancer agent and chemosensitizer of platinum drugs for OSCC.

Nuclear heterogeneous nuclear ribonucleoprotein D is associated with poor prognosis and interactome analysis reveals its novel binding partners in oral cancer.

BACKGROUND: Post-transcriptional regulation by heterogeneous ribonucleoproteins (hnRNPs) is an important regulatory paradigm in cancer development. Our proteomic analysis revealed hnRNPD overexpression in oral dysplasia as compared with normal mucosa; its role in oral carcinogenesis remains unknown. Here in we determined the hnRNPD associated protein networks and its clinical significance in oral squamous cell carcinoma (OSCC). METHODS: Immunoprecipitation (IP) followed by tandem mass spectrometry was used to identify the binding partners of hnRNPD in oral cancer cell lines. Ingenuity pathway analysis (IPA) was carried out to unravel the protein interaction networks associated with hnRNPD and key interactions were confirmed by co-IP-western blotting. hnRNPD expression was analyzed in 183 OSCCs, 44 oral dysplasia and 106 normal tissues using immunohistochemistry (IHC) and correlated with clinico-pathological parameters and follow up data over a period of 91 months. Kaplan-Meier survival and Cox-multivariate-regression analyses were used to evaluate the prognostic significance of hnRNPD in OSCC. RESULTS: We identified 345 binding partners of hnRNPD in oral cancer cells. IPA unraveled novel protein-protein interaction networks associated with hnRNPD and suggested its involvement in multiple cellular processes: DNA repair, replication, chromatin remodeling, cellular proliferation, RNA splicing and stability, thereby directing the fate of oral cancer cells. Protein-protein interactions of hnRNPD with 14-3-3ζ, hnRNPK and S100A9 were confirmed using co-IP-western blotting. IHC analysis showed significant overexpression of nuclear hnRNPD in oral dysplasia [p = 0.001, Odds ratio (OR) = 5.1, 95% CI = 2.1-11.1) and OSCCs (p = 0.001, OR = 8.1, 95% CI = 4.5-14.4) in comparison with normal mucosa. OSCC patients showing nuclear hnRNPD overexpression had significantly reduced recurrence free survival [p = 0.026, Hazard ratio = 1.95, 95% CI = 1.0-3.5] by Kaplan-Meier survival and Cox-multivariate-regression analyses and has potential to define a high-risk subgroup among OSCC patients with nodal negative disease. CONCLUSIONS: Our findings suggest novel functions of hnRNPD in cellular proliferation and survival, besides RNA splicing and stability in oral cancer. Association of nuclear hnRNPD with poor prognosis in OSCC patients taken together with its associated protein networks in oral cancer warrant future studies designed to explore its potential as a plausible novel target for molecular therapeutics.

Anticancer Activity of Apaziquone in Oral Cancer Cells and Xenograft Model: Implications for Oral Cancer Therapy.

Oral squamous cell carcinoma (OSCC) patients diagnosed in late stages have limited chemotherapeutic options underscoring the great need for development of new anticancer agents for more effective disease management. We aimed to investigate the anticancer potential of Apaziquone, [EOquin, USAN, E09, 3-hydroxy-5- aziridinyl-1-methyl-2(1H-indole-4,7-dione)-prop-ß-en-α-ol], a pro-drug belonging to a class of anti-cancer agents called bioreductive alkylating agents, for OSCC. Apaziquone treatment inhibited cell proliferation and induced apoptosis in OSCC cells in vitro. Apaziquone treated OSCC cells showed increased activation of Caspase 9 and Caspase 3, and Poly (ADP ribose) polymerase (PARP) cleavage suggesting induction of apoptosis by apaziquone in oral cancer cells. Importantly, apaziquone treatment significantly reduced oral tumor xenograft volume in immunocompromised NOD/SCID/Crl mice without causing apparent toxicity to normal tissues. In conclusion, our in vitro and in vivo studies identified and demonstrated the pre-clinical efficacy of Apaziquone, as a potential novel anti-cancer therapeutic candidate for oral cancer management.

Anticancer activity of pyrithione zinc in oral cancer cells identified in small molecule screens and xenograft model: Implications for oral cancer therapy.

Oral squamous cell carcinoma (OSCC) patients diagnosed in late stages have limited chemotherapeutic options, underscoring the great need for development of new anticancer agents for more effective disease management. We aimed to identify novel anticancer agents for OSCC using quantitative high throughput assays for screening six chemical libraries consisting of 5170 small molecule inhibitors. In depth characterization resulted in identification of pyrithione zinc (PYZ) as the most effective cytotoxic agent inhibiting cell proliferation and inducing apoptosis in OSCC cells in vitro. Further, treatment with PYZ reduced colony forming, migration and invasion potential of oral cancer cells in a dose-dependent manner. PYZ treatment also led to altered expression of several key components of the major signaling pathways including PI3K/AKT/mTOR and WNT/ß-catenin in OSCC cells. In addition, treatment with PYZ also reduced expression of 14-3-3ζ, 14-3-3σ, cyclin D1, c-Myc and pyruvate kinase M2 (PKM2), proteins identified in our earlier studies to be involved in development and progression of OSCCs. Importantly, PYZ treatment significantly reduced tumor xenograft volume in immunocompromised NOD/SCID/Crl mice without causing apparent toxicity to normal tissues. Taken together, we demonstrate in vitro and in vivo efficacy of PYZ in OSCC. In conclusion, we identified PYZ in HTS assays and demonstrated in vitro and in vivo pre-clinical efficacy of PYZ as a novel anticancer therapeutic candidate in OSCC.

Nuclear Ep-ICD expression is a predictor of poor prognosis in "low risk" prostate adenocarcinomas.

INTRODUCTION: Molecular markers for predicting prostate cancer (PCa) that would have poor prognosis are urgently needed for a more personalized treatment for patients. Regulated intramembrane proteolysis of Epithelial cell adhesion molecule results in shedding of the extracellular domain (EpEx) and release of its intracellular domain (Ep-ICD) which triggers oncogenic signaling and might correlate to tumor aggressiveness. This study aimed to explore the potential of Ep-ICD and EpEx to identify PCa that have poor prognosis. METHODS: Immunohistochemical analysis of Ep-ICD and EpEx was carried out in normal prostate tissues (n = 100), benign prostate hyperplasia (BPH, n = 83), and prostate cancer (n = 249) using domain specific antibodies. The expression of Ep-ICD and EpEx was correlated with clinico- pathological parameters and disease free survival (DFS). RESULTS: Reduced expression of nuclear Ep-ICD and membrane EpEx was observed in PCa in comparison with BPH and normal prostate tissues (p = 0.006, p < 0.001 respectively). For patients who had PCa with Gleason Score less than 7, preserved nuclear Ep-ICD emerged as the most significant marker in multivariate analysis for prolonged DFS, where these patients did not have recurrence during follow up of up to 12 years (p = 0.001). CONCLUSION: Reduced expression of nuclear Ep-ICD was associated with shorter disease free survival in patients with a Gleason Score less than 7 and may be useful in identifying patients likely to have aggressive tumors with poor prognosis. Furthermore, nuclear Ep-ICD can differentiate between normal and prostate cancer tissues for ambiguous cases.

Prognostic significance of cytoplasmic S100A2 overexpression in oral cancer patients.

BACKGROUND: Oral squamous cell carcinoma (OSCC) patients are at high risk of loco-regional recurrence and 5-year survival rates are about 50%. Identification of patients at high risk of recurrence will enable rigorous personalized post-treatment management. Most novel biomarkers have failed translation for clinical use because of their limited successful validation in external patient cohorts. The aim of this study was to determine the prognostic significance of alterations in sub-cellular expression of S100A2, a pro-tumorigenic calcium binding protein, identified as a candidate biomarker in our proteomic analysis in OSCC and validation of its clinical utility in an external cohort. METHODS: In a retrospective study, immunohistochemical analysis of S100A2 was carried out in 235 Indian OSCC (Test set) and 129 normal oral tissues, correlated with clinicopathological parameters and disease outcome over 122 months for OSCC patients following the REMARK criteria. The findings were validated in an external cohort (Validation set 115 Canadian OSCC and 51 normal tissues) and data analyzed using the R package. RESULTS: Significant increase in cytoplasmic and decrease in nuclear S100A2 expression was observed in OSCC in comparison with normal tissues. Cox multivariable regression analysis internally and externally validated cytoplasmic S100A2 association with tumor recurrence. Kaplan Meier analysis of patients stratified to high and low risk groups showed significantly different recurrence free survival (Test set- log rank test, p = 0.005, median survival 16 and 69 months respectively and Validation set - p < 0.00001, median survival 9.4 and 59.9 months respectively); 86% and 81% of patients who had recurrence were correctly stratified into the high risk group. Seventy percent and 81% patients stratified into low risk group did not show cancer recurrence within 1 year in Test and Validation sets. CONCLUSIONS: Our study provided clinical evidence for the potential of cytoplasmic S100A2 overexpression as a predictor of recurrence risk in OSCC patients. A unique translational aspect of our study is validation of S100A2 as prognostic marker in two independent cohorts (Canadian and Indian) suggesting this protein is likely to find widespread utility in clinical practice for identifying oral cancer patients at high risk of disease recurrence.

Nuclear Ep-ICD accumulation predicts aggressive clinical course in early stage breast cancer patients.

BACKGROUND: Regulated intramembrane proteolysis of Epithelial cell adhesion molecule (EpCAM) results in release of its intracellular domain (Ep-ICD) which triggers oncogenic signalling. The clinical significance of Ep-ICD in breast cancer remains to be determined. Herein, we examined the expression of nuclear and cytoplasmic Ep-ICD, and membranous extracellular domain of EpCAM (EpEx) in breast cancer patients, to determine its potential utility in predicting aggressive clinical course of the disease. METHODS: In this retrospective study, 266 breast cancers and 45 normal breast tissues were immunohistochemically analyzed to determine the expression patterns of nuclear and cytoplasmic Ep-ICD and membranous EpEx and correlated with clinicopathological parameters and follow up. Disease-free survival was determined by Kaplan-Meier method and multivariate Cox regression analysis. RESULTS: Nuclear Ep-ICD was more frequently expressed in breast cancers compared to normal tissues. Significant association was observed between increased nuclear Ep-ICD expression and reduced disease-free survival in patients with ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) (p < 0.001). Nuclear Ep-ICD was positive in all the 13 DCIS and 25 IDC patients who had reduced disease-free survival, while none of the nuclear Ep-ICD negative DCIS or IDC patients had recurrence during the follow up period. Notably, majority of IDC patients who had recurrence had early stage tumors. Multivariate Cox regression analysis identified nuclear Ep-ICD as the most significant predictive factor for reduced disease-free survival in IDC patients (p = 0.011, Hazard ratio = 80.18). CONCLUSION: Patients with nuclear Ep-ICD positive breast cancers had poor prognosis. The high recurrence of disease in nuclear Ep-ICD positive patients, especially those with early tumor stage suggests that nuclear Ep-ICD accumulation holds the promise of identifying early stage patients with aggressive disease who are likely to be in need of more rigorous post-operative surveillance and/or treatment.

S100A7 overexpression is a predictive marker for high risk of malignant transformation in oral dysplasia.

Early detection of oral lesions (OLs) at high risk of cancer development is of utmost importance for intervention. There is an urgent unmet clinical need for biomarkers that allow identification of high-risk OLs. Recently, we identified and verified a panel of five candidate protein biomarkers namely S100A7, prothymosin alpha, 14-3-3ζ, 14-3-3σ and heterogeneous nuclear ribonucleoprotein K using proteomics to distinguish OLs with dysplasia and oral cancers from normal oral tissues. The objective of our study was to evaluate the potential of these candidate protein biomarkers for identification of oral dysplastic lesions at high risk of cancer development. Using immunohistochemistry, we analyzed expressions of these five candidate protein biomarkers in 110 patients with biopsy-proven oral dysplasia and known clinical outcome and determined their correlations with p16 expression and HPV 16/18 status. Kaplan-Meier survival analysis showed reduced oral cancer-free survival (OCFS) of 68.6 months (p = 0.007) in patients showing cytoplasmic S100A7 overexpression when compared to patients with weak or no S100A7 immunostaining in cytoplasm (mean OCFS = 122.8 months). Multivariate Cox regression analysis revealed cytoplasmic S100A7 overexpression as the most significant candidate marker associated with cancer development in dysplastic lesions (p = 0.041, hazard ratio = 2.36). In conclusion, our study suggested the potential of S100A7 overexpression in identifying OLs with dysplasia at high risk of cancer development.