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1.
Pediatr Dev Pathol ; 26(6): 572-582, 2023.
Article in English | MEDLINE | ID: mdl-37962547

ABSTRACT

Unique dental conditions in children include odontogenic cysts and tumors, hereditary dental diseases, developmental anomalies, and lesions associated with the eruption of the primary or permanent teeth. Many of these conditions have long lasting effects on the adult dentition in terms of affecting esthetics, function, and overall quality of life. Inherited dental syndromes affect the dental hard tissues specifically the enamel, dentin, and/or cementum in a generalized manner, involving both primary and permanent teeth. These conditions manifest in altered quality or quantity of the hard tissues, leading to fragility, tooth loss and dental diseases such as caries, periapical pathology, and periodontal disease. This category includes amelogenesis imperfecta, dentinogenesis imperfecta, dentin dysplasia, hypophosphatasia, and hypophosphatemia. Developmental defects such as regional odontodysplasia are defined by involvement of the primary and permanent dentition in a localized manner, identified in early childhood. This review will elaborate on the histologic findings in these selected dental conditions with a discussion on clinical and radiographic findings, as well as molecular features wherever appropriate.


Subject(s)
Amelogenesis Imperfecta , Tooth , Adult , Humans , Child, Preschool , Child , Quality of Life , Tooth/pathology , Amelogenesis Imperfecta/pathology , Syndrome
3.
Transl Oncol ; 12(3): 561-575, 2019 Mar.
Article in English | MEDLINE | ID: mdl-30658316

ABSTRACT

Recent studies provide compelling evidence to suggest that the tight junction protein claudin 1, aberrantly expressed in several cancer types, plays an important role in cancer progression. Dysregulation of claudin 1 has been shown to induce epithelial mesenchymal transition (EMT). Furthermore, activation of the ERK signaling pathway by protein kinase C (PKC) was shown to be necessary for EMT induction. Whether PKC is involved in regulating breast cancer progression has not been addressed. The PKC activator 12-O-tetradecanoylphorbol 13-acetate (TPA) was used to investigate the effect of PKC activity on claudin 1 transcription and protein levels, subcellular distribution, and alterations in EMT markers in human breast cancer (HBC) cell lines. As well, tissue microarray analysis (TMA) of a large cohort of invasive HBC biopsies was conducted to investigate correlations between claudin 1 and PKC isomers. TPA upregulated claudin 1 levels in all HBC cell lines analyzed. In particular, a high induction of claudin 1 protein was observed in the MCF7 cell line. TPA treatment also led to an accumulation of claudin 1 in the cytoplasm. Additionally, we demonstrated that the upregulation of claudin 1 was through the ERK signaling pathway. In patient biopsies, we identified a significant positive correlation between claudin 1, PKCα, and PKCε in ER+ tumors. A similar correlation between claudin 1 and PKCε was identified in ER- tumors, and high PKCε was associated with shorter disease-free survival. Collectively, these studies demonstrate that claudin 1 and the ERK signaling pathway are important players in HBC progression.

4.
Horm Cancer ; 9(4): 288-294, 2018 08.
Article in English | MEDLINE | ID: mdl-29915882

ABSTRACT

Lung cancer is the most common cause of cancer-related deaths worldwide with non-small cell lung cancer (NSCLC) making up most of these cases. Males have poorer overall survival compared to women following a lung cancer diagnosis. Many studies have focused on the effects of estrogen to explain higher survival rates among women, but few have looked at the effects of androgens. We describe the expression of the androgen receptor (AR) and Ki67 in lung cancer specimens in the Manitoba Tumor Bank (MTB) and correlate these factors with patient outcome. Using the MTB, we performed immunohistochemistry on lung cancer tissue to determine expression of the AR and Ki67. These were then correlated with patient outcome. Of the 136 cases, 55% were female and 55% were adenocarcinoma. AR expression was not independently associated with outcome. Ki67 was associated with a significantly higher hazard ratio for death and recurrence (HR 2.19, 95% CI 1.30-3.70; HR 1.92, 95% CI 1.07-3.46, respectively). AR expression modified the effect of Ki67 on outcome, such that when both were expressed, there was no association with recurrence or survival (HR 2.39, 95% CI 1.31-4.36 for AR- Ki67+ vs HR 1.54, 95% CI 0.44-5.37 for AR+ Ki67+). Ki67 was associated with poorer outcomes alone. AR status alone was not associated with outcome. Although the mechanism remains unclear, AR status seems to negate the association of a high Ki67 and poor outcome.


Subject(s)
Carcinoma, Non-Small-Cell Lung/pathology , Ki-67 Antigen/biosynthesis , Lung Neoplasms/pathology , Receptors, Androgen/biosynthesis , Aged , Biomarkers, Tumor/analysis , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/mortality , Disease-Free Survival , Female , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/mortality , Male , Middle Aged , Prognosis
5.
Head Neck ; 40(6): 1263-1270, 2018 06.
Article in English | MEDLINE | ID: mdl-29451953

ABSTRACT

BACKGROUND: The purpose of this study was to use quantitative tissue phenotype (QTP) to assess the surgical margins to examine if a fluorescence visualization-guided surgical approach produces a shift in the surgical field by sparing normal tissue while catching high-risk tissue. METHODS: Using our QTP to calculate the degree of nuclear chromatin abnormalities, Nuclear Phenotypic Score (NPS), we analyzed 1290 biopsy specimens taken from surgical samples of 248 patients enrolled in the Efficacy of Optically-guided Surgery in the Management of Early-staged Oral Cancer (COOLS) trial. Multiple margin specimens were collected from each surgical specimen according to the presence of fluorescence visualization alterations and the distance to the surgical margins. RESULTS: The NPS in fluorescence visualization-altered (fluorescence visualization-positive) samples was significantly higher than that in fluorescence visualization-retained (fluorescence visualization-negative) samples. There was a constant trend of decreasing NPS of margin samples from non-adjacent-fluorescence visualization margins to adjacent-fluorescence visualization margins. CONCLUSION: Our results suggested that using fluorescence visualization to guide surgery has the potential to spare more normal tissue at surgical margins.


Subject(s)
Margins of Excision , Mouth Neoplasms/pathology , Mouth Neoplasms/surgery , Adult , Aged , Aged, 80 and over , Canada , Female , Fluorescence , Humans , Male , Middle Aged , Mouth Neoplasms/diagnostic imaging , Neoplasm Staging , Phenotype , Young Adult
6.
IDCases ; 8: 14-16, 2017.
Article in English | MEDLINE | ID: mdl-28271044

ABSTRACT

The global re-emergence of syphilis is an exigent public health issue requiring both clinicians and public health practitioners to become familiar with the myriad manifestations of this great imitator. This report describes a case of an originally undiagnosed chronic oral syphilitic chancre, subsequently confirmed by both PCR and immunohistochemistry.

7.
PLoS One ; 11(9): e0163387, 2016.
Article in English | MEDLINE | ID: mdl-27649506

ABSTRACT

BACKGROUND: The claudin 1 tight junction protein, solely responsible for the barrier function of epithelial cells, is frequently down regulated in invasive human breast cancer. The underlying mechanism is largely unknown, and no obvious mutations in the claudin 1 gene (CLDN1) have been identified to date in breast cancer. Since many genes have been shown to undergo deregulation through splicing and mis-splicing events in cancer, the current study was undertaken to investigate the occurrence of transcript variants for CLDN1 in human invasive breast cancer. METHODS: RT-PCR analysis of CLDN1 transcripts was conducted on RNA isolated from 12 human invasive breast tumors. The PCR products from each tumor were resolved by agarose gel electrophoresis, cloned and sequenced. Genomic DNA was also isolated from each of the 12 tumors and amplified using PCR CLDN1 specific primers. Sanger sequencing and single nucleotide polymorphism (SNP) analyses were conducted. RESULTS: A number of CLDN1 transcript variants were identified in these breast tumors. All variants were shorter than the classical CLDN1 transcript. Sequence analysis of the PCR products revealed several splice variants, primarily in exon 1 of CLDN1; resulting in truncated proteins. One variant, V1, resulted in a premature stop codon and thus likely led to nonsense mediated decay. Interestingly, another transcript variant, V2, was not detected in normal breast tissue samples. Further, sequence analysis of the tumor genomic DNA revealed SNPs in 3 of the 4 coding exons, including a rare missense SNP (rs140846629) in exon 2 which represents an Ala124Thr substitution. To our knowledge this is the first report of CLDN1 transcript variants in human invasive breast cancer. These studies suggest that alternate splicing may also be a mechanism by which claudin 1 is down regulated at both the mRNA and protein levels in invasive breast cancer and may provide novel insights into how CLDN1 is reduced or silenced in human breast cancer.


Subject(s)
Breast Neoplasms/genetics , Claudin-1/genetics , DNA, Neoplasm , Polymorphism, Single Nucleotide , Breast/pathology , Breast Neoplasms/pathology , Exons , Female , Gene Expression Regulation, Neoplastic , Humans
8.
Breast Cancer Res ; 16(3): R49, 2014 May 22.
Article in English | MEDLINE | ID: mdl-24887419

ABSTRACT

INTRODUCTION: A phosphorylation score for estrogen receptor-alpha (ERα), called P7 score, was shown previously to be an independent prognostic factor in breast cancer patients treated with tamoxifen. Since mechanistic target of rapamycin (mTOR) activation is implicated in resistance to endocrine therapy in breast cancer we determined whether mechanistic target of rapamycin complex 1 (mTORC1) activation, measured by phosphorylation on S2448 (p-mTOR), was associated with the P7-score and/or clinical outcome in the same cohort. METHODS: mTOR phosphorylation status was determined at S2448 residue in vivo by immunohistochemistry in a cohort of more than 400 well-characterized ERα positive breast tumors. MCF7 cells were treated with estrogen and activation of mTOR pathway was determined by Western blotting. RESULTS: Contrary to earlier reports, p-mTOR expression, measured by immunohistochemistry, was negatively associated with size and nodal status. Additionally, p-S2448 mTOR expression was positively correlated with p-S118- ERα, p-S167-ERα and p-S282-ERα but negatively correlated with p-T311- ERα. Consistent with these, p-S2448 mTOR was negatively associated with P7-score and was significantly associated with overall survival (OS) (hazard ratio (HR) = 0.61, P = 0.028, 95% confidence interval (CI) 0.39 to 0.95, n = 337) and relapse-free survival (HR = 0.58, P = 0.0032, 95% CI 0.41 to 0.83, n = 337) following univariate but not multivariate analysis. Furthermore, we show that estrogen can regulate phosphorylation of mTOR and its down stream target p70S6 kinase. Additionally, recombinant mTOR can phosphorylate ERα in vitro. CONCLUSIONS: These data suggest that in breast tumors where there is intact estrogen regulated signaling, mTOR is regulated by estrogen and therefore associated with an increased likelihood of responsiveness to endocrine therapy.


Subject(s)
Breast Neoplasms/drug therapy , Estrogen Receptor alpha/metabolism , Multiprotein Complexes/metabolism , TOR Serine-Threonine Kinases/metabolism , Tamoxifen/therapeutic use , Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/mortality , Cell Line, Tumor , Disease-Free Survival , Drug Resistance, Neoplasm/genetics , Enzyme Activation , Estrogens/pharmacology , Female , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , MCF-7 Cells , Mechanistic Target of Rapamycin Complex 1 , Middle Aged , Multiprotein Complexes/biosynthesis , Phosphorylation , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , TOR Serine-Threonine Kinases/biosynthesis , Treatment Outcome
9.
Head Neck Pathol ; 8(1): 88-109, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24037641

ABSTRACT

Primary sinonasal tract and nasopharyngeal adenoid cystic carcinomas (STACC) are uncommon tumors that are frequently misclassified, resulting in inappropriate clinical management. Eighty-six cases of STACC included 45 females and 41 males, aged 12-91 years (mean 54.4 years). Patients presented most frequently with obstructive symptoms (n = 54), followed by epistaxis (n = 23), auditory symptoms (n = 12), nerve symptoms (n = 11), nasal discharge (n = 11), and/or visual symptoms (n = 10), present for a mean of 18.2 months. The tumors involved the nasal cavity alone (n = 25), nasopharynx alone (n = 13), maxillary sinus alone (n = 4), or a combination of the nasal cavity and paranasal sinuses (n = 44), with a mean size of 3.7 cm. Patients presented equally between low and high stage disease: stage I and II (n = 42) or stage III and IV (n = 44) disease. Histologically, the tumors were invasive (bone: n = 66; neural: n = 47; lymphovascular: n = 33), composed of a variety of growth patterns, including cribriform (n = 33), tubular (n = 16), and solid (n = 9), although frequently a combination of these patterns was seen within a single tumor. Pleomorphism was mild with an intermediate N:C ratio in cells containing hyperchromatic nuclei. Reduplicated basement membrane and glycosaminoglycan material was commonly seen. Necrosis (n = 16) and atypical mitotic figures (n = 11) were infrequently present. Pleomorphic adenoma was present in 9 cases; de-differentiation was seen in two patients. Immunohistochemical studies showed positive reactions for pan-cytokeratin, CK7, CK5/6, CAM5.2, and EMA, with myoepithelial reactivity with SMA, p63, calponin, S100 protein and SMMHC. CD117, CEA, GFAP and p16 were variably present. CK20 and HR HPV were negative. STACC needs to be considered in the differential diagnosis of most sinonasal malignancies, particularly poorly differentiated carcinoma, olfactory neuroblastoma and pleomorphic adenoma. Surgery (n = 82), often accompanied by radiation therapy (n = 36), was generally employed. A majority of patients developed a recurrence (n = 52) 2-144 months after initial presentation. Overall mean follow-up was 19.4 years (range 0.4-37.5 years): 46 patients died with disease (mean 6.4 years); 5 were alive with disease (mean 5.4 years), and 35 patients were either alive or had died of unrelated causes (mean 16.3 years). ACC of the SNT is uncommon. Recurrences are common. The following parameters, when present, suggest an increased incidence of either recurrence or dying with disease: mixed site of involvement, high stage disease (stage IV), skull base involvement, tumor recurrence, a solid histology, perineural invasion, bone invasion, and lymphovascular invasion.


Subject(s)
Biomarkers, Tumor/analysis , Carcinoma, Adenoid Cystic/pathology , Nasopharyngeal Neoplasms/pathology , Paranasal Sinus Neoplasms/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Carcinoma , Carcinoma, Adenoid Cystic/metabolism , Carcinoma, Adenoid Cystic/mortality , Child , Female , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Male , Middle Aged , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/metabolism , Nasopharyngeal Neoplasms/mortality , Paranasal Sinus Neoplasms/metabolism , Paranasal Sinus Neoplasms/mortality , Young Adult
10.
J Cancer Res Clin Oncol ; 139(10): 1637-47, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23907597

ABSTRACT

BACKGROUND: The steroid receptor RNA activator protein (SRAP) is a newly described protein modulating the activity of multiple transcription factors including the estrogen receptor (ER). We have recently reported the immunodetection by Western blot of multiple SRAP peptides in breast tissue. High expression of these peptides, assessed by tissue micro-array (TMA) analysis, was associated with poor prognosis in patients whose primary tumors were ER positive (ER+). In such studies, it is recognized that intensity as well as specificity of the signal detected directly depends upon the antibody used as well as the position of the epitope recognized. To confirm the potential relevance of SRAP as a new prognostic factor, it is critical to establish whether similar results are obtained with independent antibodies. METHODS: Two commercial anti-SRAP antibodies (742A and 743A), respectively, recognizing the N- and C-terminal extremity of the protein, were first used to analyze by Western blot SRAP expression in protein extracts from frozen breast tumor tissue sections. These antibodies were further used to investigate by immunohistochemistry (IHC) SRAP location in paraffin-embedded breast tumors. Comparative TMA analysis of 170 ER+ tumors was eventually performed in order to establish the potential associations existing between SRAP expression and clinical outcome. RESULTS: Multiple SRAP peptides were differentially detected by Western blot. Both antibodies led to similar nuclear and cytoplasmic staining in breast tissue section. A solid correlation was found (Spearman r = 0.46, P < 0.001) between 742A and 743A IHC scores. Results from both antibodies independently showed that dividing expression levels into lower 25 percentile, 26-75 percentile, and highest 25 percentile demonstrated a hazard ratio (HR) of 1.82 (P = 0.0042) for 742A antibody and 1.35 (P = 0.14) for 743A antibody. When both scores are combined, double high expressor (by 742A and 743A) was associated with a poor prognosis of breast-cancer-specific survival (Mantel-Cox: P = 0.005, HR = 2.24). CONCLUSION: Overall, our data suggest the existence in breast tumor tissue of multiple SRAP-like peptides. Assessing their expression in primary breast tumors can predict clinical outcome in ER+ breast cancer patients.


Subject(s)
Breast Neoplasms/metabolism , Carcinoma, Ductal, Breast/metabolism , Carrier Proteins/metabolism , Aged , Breast Neoplasms/mortality , Carcinoma, Ductal, Breast/mortality , Carrier Proteins/genetics , Female , Gene Expression , Humans , Kaplan-Meier Estimate , MCF-7 Cells , Multivariate Analysis , Peptide Fragments/metabolism , Prognosis , Proportional Hazards Models , Receptors, Estrogen/metabolism , Tissue Array Analysis
11.
BMC Cancer ; 13: 268, 2013 May 30.
Article in English | MEDLINE | ID: mdl-23721519

ABSTRACT

BACKGROUND: Defects in tight junctions, gate-keepers of the integrity of the epidermal barrier function, are known to contribute to cancer development. As such, enhancing our understanding of how the expression of proteins involved in these junctions is regulated in cancer, remains a priority. Although the expression of one of these proteins, claudin 1, is down regulated in most invasive human breast cancers (HBC), we have recently shown that high levels of claudin 1, characterized tumors belonging to the very aggressive basal-like breast cancer (BLBC) subtype. In these tumors, the claudin 1 protein, usually localized in the cell membrane, is often mislocalized to the cytoplasm. METHODS: To examine the clinical relevance of this observation, we have generated and analyzed an invasive HBC tissue microarray consisting of 151 breast tumor samples; 79 of which presented a basal-like phenotype (i.e. ER-ve, PR-ve HER2-ve, CK5/6 or EGFR+ve). We also interrogated the outcome of claudin 1 knockdown in a human BLBC cell line, BT-20. RESULTS: Immunohistochemical analysis of this patient cohort revealed a significant association between high claudin 1 expression and BLBCs in women 55 years of age and older. Interestingly, no significant association was found between claudin 1 and nodal involvement, tumor grade or tumor size. Regression analysis however, showed a significant positive association between claudin 1 and claudin 4, even though claudin 4 did not significantly correlate with patient age. Claudin 1 knockdown in BT-20 cells resulted in decreased cell migration. It also significantly altered the expression of several genes involved in epithelial-mesenchymal-transition (EMT); in particular, SERPINE 1 (PAI1) and SSP1 (osteopontin), known to inhibit EMT and cancer cell migration. Conversely, genes known to maintain EMT through their interaction, SNAIL2, TCF4 and FOXC2 were significantly down regulated. CONCLUSIONS: The association of high claudin 1 protein levels observed in tumors derived from older women with BLBC, suggests that claudin 1 has the potential to serve as a marker which can identify a specific subgroup of patients within the BLBC subtype and thus, further contribute to the characterization of these ill-defined breast cancers. More importantly, our studies strongly suggest that claudin 1 directly participates in promoting breast cancer progression, possibly through the alteration of expression of EMT genes.


Subject(s)
Biomarkers, Tumor/analysis , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Claudin-1/biosynthesis , Age Factors , Aged , Blotting, Western , Breast Neoplasms/genetics , Cell Line, Tumor , Epithelial-Mesenchymal Transition/genetics , Female , Gene Knockdown Techniques , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Middle Aged , Real-Time Polymerase Chain Reaction , Tissue Array Analysis
12.
Head Neck Pathol ; 7(3): 211-23, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23250819

ABSTRACT

The risk model is a validated outcome predictor for patients with head and neck squamous cell carcinoma (Brandwein-Gensler et al. in Am j surg pathol 20:167-178, 2005; Am J Surg Pathol 34:676-688, 2010). This model may potentially shift treatment paradigms for patients with low-stage cancers, as current protocols dictate that they might receive only primary surgery. Here we test the hypothesis that the Risk Model has added prognostic value for low-stage oral cavity squamous cell carcinoma (OCSCC) patients. 299 patients with Stage I/II OCSCC were characterized according to the risk model (Brandwein-Gensler et al. in Am J Surg Pathol 20:167-178, 2005; Am J Surg Pathol 34:676-688, 2010). Cumulative incidence and competing risk analysis were performed for locoregional recurrence (LRR) and disease-specific survival (DSS). Receiver operating characteristic analyses were performed for worst pattern of invasion (WPOI) and the risk categories. 292 patients were analyzed; 30 T1N0 patients (17%) and 26 T2N0 patients (23%) developed LRR. Disease-specific mortality occurred in 9 T1N0 patients (6%) and 9 T2N0 patients (10%). On multivariable analysis, the risk model was significantly predictive of LRR (p = 0.0012, HR 2.41, 95% CI 1.42, 4.11) and DSS (p = 0.0005, HR 9.16, 95% CI 2.65, 31.66) adjusted for potential confounders. WPOI alone was also significantly predictive for LRR adjusted for potential confounders with a cut-point of either WPOI-4 (p = 0.0029, HR 3.63, 95% CI 1.56, 8.47) or WPOI-5 (p = 0.0008, HR 2.55, 95% CI 1.48, 4.41) and for DSS (cut point WPOI-5, p = 0.0001, HR 6.34, 95% CI 2.50, 16.09). Given a WPOI-5, the probability of developing locoregional recurrence is 42%. Given a high-risk classification for a combination of features other than WPOI-5, the probability of developing locoregional recurrence is 32%. The Risk Model is the first validated model that is significantly predictive for the important niche group of low-stage OCSCC patients.


Subject(s)
Carcinoma, Squamous Cell/classification , Carcinoma, Squamous Cell/pathology , Mouth Neoplasms/classification , Mouth Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Area Under Curve , Carcinoma, Squamous Cell/mortality , Disease-Free Survival , Female , Humans , Male , Middle Aged , Models, Statistical , Mouth Neoplasms/mortality , Neoplasm Invasiveness , Neoplasm Recurrence, Local/epidemiology , Neoplasm Staging , ROC Curve , Risk , Treatment Outcome
13.
Endocr Relat Cancer ; 17(3): 589-97, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20418363

ABSTRACT

To determine the relationship of the multiple sites of oestrogen receptor alpha (ERalpha) phosphorylation to clinical outcome after tamoxifen therapy, sections from tissue microarrays representing over 300 ER+ breast cancers from patients who were treated with surgery+radiation and then tamoxifen were used for immunohistochemical determination of total ERalpha, p-S104/106-ERalpha, p-S118-ERalpha, p-S167-ERalpha, p-S282-ERalpha, p-S294-ERalpha, p-T311-ERalpha and p-S559-ERalpha. Relationships of phosphorylated ERalpha to overall and relapse-free survival (RFS; breast cancer death or recurrence) were tested using single (univariate) and multiple (multivariate) predictor statistical models. Large tumour size, node positivity, high grade, progesterone receptor (PR) negative status and low levels of p-S282-ERalpha were significantly associated with reduced overall survival (OS). Along with tumour size and node status, a novel phosphorylation score (P(7) score > or = 3), taking into account all seven p-ERalpha sites, was significantly associated with reduced OS in univariate and multivariate analyses (hazard ratio (HR)=2.24, 95% confidence interval (CI) 1.15-4.34, n=335; P=0.018). Along with tumour size, node status, grade and PR status, a high P(7) score (> or = 3) was significantly associated with reduced RFS in univariate and multivariate analyses (HR=1.71, 95% CI 1.03-2.86, n=332; P=0.039). Since ERalpha is the site at which integration of diverse signals occurs to regulate breast cancer growth and survival, the ERalpha phosphorylation score may be a surrogate marker of the balance between oestrogen-dependent and crosstalk-dependent receptor activity, and is potentially a prognostic marker of clinical outcome in a tamoxifen-treated population of patients.


Subject(s)
Breast Neoplasms/metabolism , Estrogen Receptor alpha/metabolism , Phosphorylation/physiology , Tamoxifen/therapeutic use , Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/mortality , Disease-Free Survival , Female , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Middle Aged , Predictive Value of Tests , Receptors, Progesterone/metabolism , Tissue Array Analysis , Treatment Outcome
14.
Am J Surg Pathol ; 34(5): 676-88, 2010 May.
Article in English | MEDLINE | ID: mdl-20414102

ABSTRACT

BACKGROUND: Half of the patients with head and neck squamous cell carcinoma (HNSCC) can be expected to fail therapy, indicating that more aggressive treatment is warranted for this group. We have developed a novel risk model that can become a basis for developing new treatment paradigms. Here we report on the performance of our model in a new multicenter cohort. DESIGN: Eligible patients from 3 institutions (Montefiore Medical Center, University of Manitoba, and New York University Medical Center) were identified and pathology slides from their resection specimens were reviewed by Margaret Brandwein-Gensler; risk category was assigned as previously published. Kaplan-Meier analysis was performed for disease progression and survival. Cox proportional hazards regression was performed, adjusted for potential confounders. A teaching module was also developed; attending pathologists were asked to score coded slides after a lecture and multiheaded microscope teaching session. Agreement was assessed by calculating Cohen unweighted kappa coefficients. RESULT: The validation cohort consisted of 305 patients, from the above institutions, with 311 primary HNSCC of the oral cavity, oropharynx, and larynx. The median follow-up period for all patients was 27 months. Risk category predicts time to disease progression (P=0.0005), locoregional recurrence (P=0.013), and overall survival (P=0.0000) by Kaplan-Meier analysis. High-risk status is significantly associated with decreased time to disease progression, adjusted for clinical confounders (P=0.015, hazard ratio 2.32, 95% confidence interval 1.18-4.58) compared with collapsed intermediate and low-risk groups. We also demonstrate substantial interrater agreement (kappa=0.64), and very good rater agreement when compared with the standard (kappa=0.87). CONCLUSIONS: We demonstrate significant predictive performance of the risk model in a new cohort of patients with primary HNSCC, adjusted for confounders. Our training experience also supports the feasibility of adapting the risk model in clinical practice.


Subject(s)
Carcinoma, Squamous Cell/pathology , Head and Neck Neoplasms/pathology , Carcinoma, Squamous Cell/classification , Carcinoma, Squamous Cell/mortality , Female , Head and Neck Neoplasms/classification , Head and Neck Neoplasms/mortality , Humans , Kaplan-Meier Estimate , Male , Manitoba/epidemiology , Middle Aged , New York City/epidemiology , Prognosis , Proportional Hazards Models , Reproducibility of Results , Risk Factors , Survival Rate
15.
Breast Cancer Res ; 11(5): R67, 2009.
Article in English | MEDLINE | ID: mdl-19740422

ABSTRACT

INTRODUCTION: The steroid receptor RNA activator is a functional RNA suspected to participate in the mechanisms underlying breast tumor progression. This RNA is also able to encode for a protein, Steroid Receptor RNA Activator Protein (SRAP), whose exact function remains to be determined. Our aim was to assess, in a large breast cancer cohort, whether levels of this protein could be associated with outcome or established clinical parameters. METHODS: Following antibody validation, SRAP expression was assessed by tissue-microarray (TMA) analysis of 372 breast tumors. Clinical follow-up and parameters such as steroid receptor and node status were available for all the corresponding cases. Immunohistochemical scores were independently determined by three investigators and averaged. Statistical analyses were performed using standard univariate and multivariate tests. RESULTS: SRAP levels were significantly (Mann-Whitney rank sum test, P < 0.05) higher in estrogen receptor-alpha positive (ER+, n = 271), in progesterone receptor positive (PR+, n = 257) and in older patients (age > 64 years, n = 182). When considering ER+ tumors, PR+ tumors, or younger patients (< or = 64 years), cases with high SRAP expression had a significantly (Mantel-Cox test, P < 0.05) worse breast cancer specific survival (BCSS) than those with low SRAP levels. SRAP also appeared as a very powerful indicator of poor prognostic for BCSS in the subset of ER+, node negative and young breast cancer patients (Cox regression analysis, n = 60, BCSS Hazard Ratio = 8.61, P < 0.006). CONCLUSIONS: Our data suggest that SRAP levels might provide additional information on potential risk of recurrence and negative outcome in a specific set of patients with otherwise good prognosis when considering only estrogen receptor and nodal status.


Subject(s)
Biomarkers, Tumor/biosynthesis , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , RNA, Untranslated/biosynthesis , Receptors, Estrogen/biosynthesis , Blotting, Western , Breast Neoplasms/pathology , Cell Line, Tumor , Humans , Immunohistochemistry , Lymph Nodes/pathology , Microarray Analysis/methods , RNA, Long Noncoding
16.
J Steroid Biochem Mol Biol ; 114(1-2): 90-5, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19429437

ABSTRACT

Estrogen receptor (ER)alpha activity is regulated by phosphorylation at several sites. Recently several antibodies specific for individual phosphorylated sites within ERalpha have became available. Validation and use of these antibodies suggests that several forms of phosphorylated ERalpha can be detected in multiple ER+ human breast tumor samples, thus providing relevance for investigating the regulation and function of phosphorylated ERalpha in human breast cancer. Generally, the phosphorylated ERalpha isoforms are associated with parameters that suggest that they are markers of an intact estrogen dependent signaling pathway and better clinical outcome with respect to tamoxifen therapy. Profiling of phosphorylated ERalpha may provide better biomarkers of endocrine therapy response over and above those currently available.


Subject(s)
Breast Neoplasms/metabolism , Estrogen Receptor alpha/metabolism , Protein Isoforms/metabolism , Biopsy , Breast Neoplasms/pathology , Disease-Free Survival , Estrogen Receptor alpha/genetics , Female , Humans , Phosphorylation , Protein Isoforms/genetics , Signal Transduction/physiology
17.
Virchows Arch ; 454(6): 647-56, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19387682

ABSTRACT

In the present study we investigated the protein expression of claudins 1, 3, and 4 and their relationship to clinical variables and outcome in a cohort of ER-ve and ER+ve human invasive breast cancers. Immunohistochemical analysis was performed on tissue microarrays representing a total of 412 tumors and interpretable data was derived from 314, 299, and 306 tumors for claudins 1, 3, and 4, respectively. In the ER+ve subset, 5%, 89%, and 52%, and in the ER-ve subset, 39%, 79%, and 79% of tumors stained positively for claudins 1, 3, and 4, respectively (p < 0.0001, p = 0.026, p < 0.0001). Thus, in the two subsets, a significantly higher number of tumors were positive for claudins 3 and 4, compared to claudin 1. In addition, protein expressions of claudins 1 and 4 were significantly higher in those tumors that displayed characteristics of the basal-like subtype of breast cancers (ER-ve, Her-2-ve, EGFR+ve, CK5/6+ve). This study shows a unique pattern of expression for the different claudins in ER-ve and ER+ve tumors. Our data also suggests that increased expression of claudins 1 and 4 was associated with the basal-like subtype of breast cancers, a subtype generally linked to poor outcome.


Subject(s)
Biomarkers, Tumor/metabolism , Breast Neoplasms/metabolism , Membrane Proteins/metabolism , Receptors, Estrogen/deficiency , Breast Neoplasms/pathology , Claudin-1 , Claudin-3 , Claudin-4 , Female , Humans , Neoplasm Invasiveness , Tissue Array Analysis
18.
Article in English | MEDLINE | ID: mdl-19071037

ABSTRACT

OBJECTIVE: This study looked at the independent impact of intraoperative frozen section assessment of the adequacy of margins of excision on disease control and survival. STUDY DESIGN: The design was a review of outcome of historical cohort of 416 surgically treated oral cancer patients at a comprehensive cancer center. Status of the margins at permanent sections, disease failure at the primary site, and survival data of 229 patients who had frozen sections were compared by univariate and multivariate analysis with 197 patients who did not have frozen sections. RESULTS: Failure at the primary site was independently influenced by age at diagnosis (P < .001), T stage (P = .016), N stage (P = .042), and status of margins on paraffin sections (P = .005). Chance of achieving clear margins on paraffin sections was, however, not significantly improved by the use of frozen sections. On multivariate analysis, the use of frozen sections did not independently have an impact on local failure or survival. CONCLUSIONS: Frozen section assessment of mucosal margins has not improved the disease outcome.


Subject(s)
Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/surgery , Frozen Sections/statistics & numerical data , Mouth Neoplasms/pathology , Mouth Neoplasms/surgery , Age Factors , Carcinoma, Squamous Cell/mortality , Disease-Free Survival , Early Detection of Cancer , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Mouth Mucosa/pathology , Mouth Neoplasms/mortality , Neoplasm Recurrence, Local , Neoplasm Staging , Paraffin Embedding , Proportional Hazards Models , Treatment Outcome
19.
Oral Oncol ; 42(4): 421-9, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16488655

ABSTRACT

Amyloidosis refers to the idiopathic, extracellular deposition of fibrillar proteins, termed amyloid, in tissues. Although amyloidosis is a rare disease, the head and neck region has been reported as a frequent site of amyloid deposits, accounting for approximately 19% of reported amyloid cases in one review. Fifteen cases of head and neck amyloid, excluding the brain, with clinical follow-up were identified in the Surgical Pathology files from 1985 to 2005 at Emory University Hospital. The histopathology, histochemistry, and patient follow-up were reviewed. Nine men and six women with an age range of 18-76 years (mean 55.7 years) were identified. The initial clinical presentation was dependent on the site of amyloid deposits. The clinical types of amyloidosis included localized amyloid deposits in the larynx and tongue, plasma cell dyscrasia associated AL amyloidosis, and hemodialysis-associated amyloidosis. Secondary amyloidosis developed in one patient with carcinoid tumor.


Subject(s)
Amyloidosis/pathology , Laryngeal Diseases/pathology , Pharyngeal Diseases/pathology , Tongue Diseases/pathology , Adolescent , Adult , Aged , Amyloidosis/surgery , Female , Head , Humans , Immunohistochemistry , Laryngeal Diseases/surgery , Lip Diseases/pathology , Lip Diseases/surgery , Male , Middle Aged , Neck , Pharyngeal Diseases/surgery , Tongue Diseases/surgery
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