I am a physician-scientist and currently a resident in Pathology (Anatomic Pathology only program) at the Department of Pathology of the Stanford University School of Medicine/Stanford Healthcare with a particular clinical interest in Breast Pathology and Molecular Genetic Pathology and a research interest in the development of new quantitative approaches to pathology to accurately predict the development of cancer, correctly classify tumors by prognosis and predict response to cancer therapy, leveraging biomedical informatics and computational pathology tools to inquire large datasets of clinical and genomics data, mostly focusing on breast cancer.
Honors & Awards
Arthur Purdy Stout Stipend Award, Arthur Purdy Stout Society of Surgical Pathologists (2018)
Charles B. Carrington Memorial Prize, Department of Pathology, Stanford University School of Medicine (2017)
Trainee Mentored Award in Precision Health, Department of Pathology, Stanford University School of Medicine (2017)
Junior Career and Development Award, Harvard Medical School - Portugal Program (2013)
Residency, Stanford University School of Medicine / Stanford Healthcare, Residency in Pathology
Postdoctoral Fellowship, Harvard Medical School / Beth Israel Deaconess Medical Center, Bioinformatics (2016)
Postdoctoral Fellowship, Harvard Medical School/Dana-Farber Cancer Institute, Oncology (2015)
Graduate Certificate Program, Harvard Medical School - Portugal Program, Clinical Scholars Research Certificate Training Program 2 (Clinical Research) (2013)
Graduate Certificate Program, Harvard Medical School - Portugal Program, Clinical Scholars Research Certificate Training Program 1 (Clinical Research) (2012)
PhD, University of Porto, Faculty of Medicine, Oncology and Molecular Medicine (2017)
MD/MSc, University of Porto, Faculty of Medicine (2009)
- EZH2 protein expression in normal breast epithelium and risk of breast cancer: results from the Nurses' Health Studies BREAST CANCER RESEARCH 2017; 19
Enhancer of zeste homolog 2 (EZH2) is a polycomb-group protein that is involved in stem cell renewal and carcinogenesis. In breast cancer, increased EZH2 expression is associated with aggressiveness and has been suggested to identify normal breast epithelium at increased risk of breast cancer development. However, the association between EZH2 expression in benign breast tissue and breast cancer risk has not previously been evaluated in a large prospective cohort.We examined the association between EZH2 protein expression and subsequent breast cancer risk using logistic regression in a nested case-control study of benign breast disease (BBD) and breast cancer within the Nurses' Health Studies. EZH2 immunohistochemical expression in normal breast epithelium and stroma was evaluated by computational image analysis and its association with breast cancer risk was analyzed after adjusting for matching factors between cases and controls, the concomitant BBD diagnosis, and the Ki67 proliferation index.Women with a breast biopsy in which more than 20% of normal epithelial cells expressed EZH2 had a significantly increased risk of developing breast cancer (odds ratio (OR) 2.95, 95% confidence interval (CI) 1.11-7.84) compared to women with less than 10% EZH2 epithelial expression. The risk of developing breast cancer increased for each 5% increase in EZH2 expression (OR 1.22, 95% CI 1.02-1.46, p value 0.026). Additionally, women with high EZH2 expression and low estrogen receptor (ER) expression had a 4-fold higher risk of breast cancer compared to women with low EZH2 and low ER expression (OR 4.02, 95% CI 1.29-12.59).These results provide further evidence that EZH2 expression in the normal breast epithelium is independently associated with breast cancer risk and might be used to assist in risk stratification for women with benign breast biopsies.
View details for DOI 10.1186/s13058-017-0817-6
View details for Web of Science ID 000396919900001
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- Prostate cancer-associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4. Nature medicine 2017
The bromodomain and extraterminal (BET) family of proteins comprises four members-BRD2, BRD3, BRD4 and the testis-specific isoform BRDT-that largely function as transcriptional coactivators and play critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion. BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia, or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer. Pathologically, BET proteins are frequently overexpressed and are clinically linked to various types of human cancer; they are therefore being pursued as attractive therapeutic targets for selective inhibition in patients with cancer. To this end, a number of bromodomain inhibitors, including JQ1 and I-BET, have been developed and have shown promising outcomes in early clinical trials. Although resistance to BET inhibitors has been documented in preclinical models, the molecular mechanisms underlying acquired resistance are largely unknown. Here we report that cullin-3(SPOP) earmarks BET proteins, including BRD2, BRD3 and BRD4, for ubiquitination-mediated degradation. Pathologically, prostate cancer-associated SPOP mutants fail to interact with and promote the degradation of BET proteins, leading to their elevated abundance in SPOP-mutant prostate cancer. As a result, prostate cancer cell lines and organoids derived from individuals harboring SPOP mutations are more resistant to BET-inhibitor-induced cell growth arrest and apoptosis. Therefore, our results elucidate the tumor-suppressor role of SPOP in prostate cancer in which it acts as a negative regulator of BET protein stability and also provide a molecular mechanism for resistance to BET inhibitors in individuals with prostate cancer bearing SPOP mutations.
View details for DOI 10.1038/nm.4378
View details for PubMedID 28805820
- Immune Escape in Breast Cancer During In Situ to Invasive Carcinoma Transition. Cancer discovery Red Flat M 11 Wish Softwalk US Black Women's 2017
To investigate immune escape during breast tumor progression, we analyzed the composition of leukocytes in normal breast tissues, ductal carcinoma in situ (DCIS), and invasive ductal carcinomas (IDC). We found significant tissue and tumor subtype-specific differences in multiple cell types including T cells and neutrophils. Gene expression profiling of CD45+CD3+ T cells demonstrated a decrease in CD8+ signatures in IDCs. Immunofluorescence analysis showed fewer activated GZMB+CD8+ T cells in IDC than in DCIS, including in matched DCIS recurrent IDC. TCR clonotype diversity was significantly higher in DCIS than in IDCs. Immune checkpoint protein TIGIT expressing T cells were more frequent in DCIS whereas high PD-L1 expression and amplification of CD274 (encoding PD-L1) was only detected in triple negative IDCs. Co-amplification of 17q12 chemokine cluster with ERBB2 subdivided HER2+ breast tumors into immunologically and clinically distinct subtypes. Our results show co-evolution of cancer cells and the immune microenvironment during tumor progression.
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- Diagnostic Assessment of Deep Learning Algorithms for Detection of Lymph Node Metastases in Women With Breast Cancer. JAMA 2017; Red Softwalk Wish Black M US Women's 11 Flat US M Red Wish Flat 11 Softwalk Black Women's 318 (22): 2199–2210
Red Women's Black Softwalk Wish Flat 11 US M Application of deep learning algorithms to whole-slide pathology images can potentially improve diagnostic accuracy and efficiency.Assess the performance of automated deep learning algorithms at detecting metastases in hematoxylin and eosin-stained tissue sections of lymph nodes of women with breast cancer and compare it with pathologists' diagnoses in a diagnostic setting.Researcher challenge competition (CAMELYON16) to develop automated solutions for detecting lymph node metastases (November 2015-November 2016). A training data set of whole-slide images from 2 centers in the Netherlands with (n = 110) and without (n = 160) nodal metastases verified by immunohistochemical staining were provided to challenge participants to build algorithms. Algorithm performance was evaluated in an independent test set of 129 whole-slide images (49 with and 80 without metastases). The same test set of corresponding glass slides was also evaluated by a panel of 11 pathologists with time constraint (WTC) from the Netherlands to ascertain likelihood of nodal metastases for each slide in a flexible 2-hour session, simulating routine pathology workflow, and by 1 pathologist without time constraint (WOTC).Deep learning algorithms submitted as part of a challenge competition or pathologist interpretation.The presence of specific metastatic foci and the absence vs presence of lymph node metastasis in a slide or image using receiver operating characteristic curve analysis. The 11 pathologists participating in the simulation exercise rated their diagnostic confidence as definitely normal, probably normal, equivocal, probably tumor, or definitely tumor.The area under the receiver operating characteristic curve (AUC) for the algorithms ranged from 0.556 to 0.994. The top-performing algorithm achieved a lesion-level, true-positive fraction comparable with that of the pathologist WOTC (72.4% [95% CI, 64.3%-80.4%]) at a mean of 0.0125 false-positives per normal whole-slide image. For the whole-slide image classification task, the best algorithm (AUC, 0.994 [95% CI, 0.983-0.999]) performed significantly better than the pathologists WTC in a diagnostic simulation (mean AUC, 0.810 [range, 0.738-0.884]; P < .001). The top 5 algorithms had a mean AUC that was comparable with the pathologist interpreting the slides in the absence of time constraints (mean AUC, 0.960 [range, 0.923-0.994] for the top 5 algorithms vs 0.966 [95% CI, 0.927-0.998] for the pathologist WOTC).In the setting of a challenge competition, some deep learning algorithms achieved better diagnostic performance than a panel of 11 pathologists participating in a simulation exercise designed to mimic routine pathology workflow; algorithm performance was comparable with an expert pathologist interpreting whole-slide images without time constraints. Whether this approach has clinical utility will require evaluation in a clinical setting.
View details for DOI 10.1001/jama.2017.14585
View details for PubMedID 29234806
- Softwalk Black M 11 US Women's Flat Wish Red Precision Cancer Diagnostics: Tracking Genomic Evolution in Clinical Trials PLOS MEDICINE 2016; 13 (12)
In a Perspective, Francisco Beca and Andrew Beck discuss Charles Swanton and colleagues' accompanying Research Article on somatic mutations in patients with inflammatory breast cancer treated in a Phase II clinical trial.
View details for DOI 10.1371/journal.pmed.1002177
View details for Web of Science ID 000392142400004
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- The clinicopathologic and genomic features of fibrotic foci in breast cancer - results from the TCGA cohort NATURE PUBLISHING GROUP. 2018: 50
- Molecular Cytology Applications in Metastases Molecular Applications in Cytology Springer Nature Switzerland AG. 2018; 1: 247–259
- Aspirin Suppresses Growth in PI3K-Mutant Breast Cancer by Activating AMPK and Inhibiting mTORC1 Signaling CANCER RESEARCH 2017; 77 (3): 790-801
Despite the high incidence of oncogenic mutations in PIK3CA, the gene encoding the catalytic subunit of PI3K, PI3K inhibitors have yielded little clinical benefit for breast cancer patients. Recent epidemiologic studies have suggested a therapeutic benefit from aspirin intake in cancers harboring oncogenic PIK3CA Here, we show that mutant PIK3CA-expressing breast cancer cells have greater sensitivity to aspirin-mediated growth suppression than their wild-type counterparts. Aspirin decreased viability and anchorage-independent growth of mutant PIK3CA breast cancer cells independently of its effects on COX-2 and NF-κB. We ascribed the effects of aspirin to AMP-activated protein kinase (AMPK) activation, mTORC1 inhibition, and autophagy induction. In vivo, oncogenic PIK3CA-driven mouse mammary tumors treated daily with aspirin resulted in decreased tumor growth kinetics, whereas combination therapy of aspirin and a PI3K inhibitor further attenuated tumor growth. Our study supports the evaluation of aspirin and PI3K pathway inhibitors as a combination therapy for targeting breast cancer. Cancer Res; 77(3); 790-801. ©2016 AACR.
View details for DOI 10.1158/0008-5472.CAN-16-2400
View details for Web of Science ID 000393194400019
View details for PubMedID 27940576
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- Black 11 Wish Softwalk Women's Flat M US Red Dieulafoy’s Lesion Pathology of the Gastrointestinal Tract edited by Carneiro, F., Chaves, P., Ensari, A. Springer International Publishing. 2017; 1: 177–179
- LINC00520 is induced by Src, STAT3, and PI3K and plays a functional role in breast cancer ONCOTARGET 2016; 7 (50): 81981-81994
Long non-coding RNAs (lncRNAs) have been implicated in normal cellular homeostasis as well as pathophysiological conditions, including cancer. Here we performed global gene expression profiling of mammary epithelial cells transformed by oncogenic v-Src, and identified a large subset of uncharacterized lncRNAs potentially involved in breast cancer development. Specifically, our analysis revealed a novel lncRNA, LINC00520 that is upregulated upon ectopic expression of oncogenic v-Src, in a manner that is dependent on the transcription factor STAT3. Similarly, LINC00520 is also increased in mammary epithelial cells transformed by oncogenic PI3K and its expression is decreased upon knockdown of mutant PIK3CA. Additional expression profiling highlight that LINC00520 is elevated in a subset of human breast carcinomas, with preferential enrichment in the basal-like molecular subtype. ShRNA-mediated depletion of LINC00520 results in decreased cell migration and loss of invasive structures in 3D. RNA sequencing analysis uncovers several genes that are differentially expressed upon ectopic expression of LINC00520, a significant subset of which are also induced in v-Src-transformed MCF10A cells. Together, these findings characterize LINC00520 as a lncRNA that is regulated by oncogenic Src, PIK3CA and STAT3, and which may contribute to the molecular etiology of breast cancer.
View details for DOI 10.18632/oncotarget.11962
View details for Web of Science ID 000391352800005
View details for PubMedID 27626181
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- MicroRNA signatures in cytopathology: Are they ready for prime time? CANCER CYTOPATHOLOGY 2016; 124 (9): 613-615
- Intratumor Heterogeneity in Breast Cancer NOVEL BIOMARKERS IN THE CONTINUUM OF BREAST CANCER 2016; 882: 169-189
Wish 11 Flat M Black US Softwalk Red Women's Abstract
Intratumor heterogeneity is the main obstacle to effective cancer treatment and personalized medicine. Both genetic and epigenetic sources of intratumor heterogeneity are well recognized and several technologies have been developed for their characterization. With the technological advances in recent years, investigators are now elucidating intratumor heterogeneity at the single cell level and in situ. However, translating the accumulated knowledge about intratumor heterogeneity to clinical practice has been slow. We are certain that better understanding of the composition and evolution of tumors during disease progression and treatment will improve cancer diagnosis and the design of therapies. Here we review some of the most important considerations related to intratumor heterogeneity. We discuss both genetic and epigenetic sources of intratumor heterogeneity and review experimental approaches that are commonly used to quantify it. We also discuss the impact of intratumor heterogeneity on cancer diagnosis and treatment and share our perspectives on the future of this field.
View details for Web of Science ID 000376034700008
View details for PubMedID 26987535
- Altered PPP2R2A and Cyclin D1 expression defines a subgroup of aggressive luminal-like breast cancer BMC CANCER 2015; 15
PPP2R2A deletions were recently linked to a subgroup of luminal breast carcinoma (BC) that exhibits poor survival. This subgroup also exhibited amplification of a chromosome region containing the Cyclin D1 coding gene, CCND1. Therefore, we aimed to investigate whether a combination of PPP2R2A (B55α) and Cyclin D1 expression statuses evaluated by immunohistochemistry (IHC) could define a subgroup of luminal BC that exhibits poor survival.First we conducted a retrospective cohort study using sequencing data from The Cancer Genome Atlas initiative to correlate PPP2R2A copy number alteration (CNA) status with its expression level and the corresponding overall survival (OS). Next, also using a retrospective cohort study design, we evaluated the PPP2R2A (B55α) expression levels by IHC in a total of 807 BC patients from two independent cohorts (discovery cohort n = 349 and validation cohort n = 458). Cyclin D1 expression was also evaluated, and the PPP2R2A (B55α)(-/low)/Cyclin D1(high) phenotype was evaluated as a predictor of disease-free survival (DFS) and OS in luminal-like BC patients.Deletions in the PPP2R2A gene strongly correlate with lower mRNA expression and poorer OS. PPP2R2A (B55α)(-/low) carcinomas have significantly shorter DFS and OS. Furthermore, in univariate analysis, the PPP2R2A (B55α)(-/low)/Cyclin D1(high) phenotype is significantly associated with poorer DFS and OS. In a multivariate analysis, the PPP2R2A (B55α)(-/low)/Cyclin D1(high) phenotype is significantly associated with poor DFS, thus defining a group of luminal-like BC with higher risk of relapse.We demonstrate that BCs harboring PPP2R2A deletions are associated with worse OS. Moreover, this is the first study to demonstrate that the combination of altered PPP2R2A (B55α) and high Cyclin D1 expression by IHC defines a subgroup of luminal-like BC patients with a high risk of relapse and death.
View details for DOI 10.1186/s12885-015-1266-1
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View details for PubMedID 25879784
- p-mTOR expression is associated with better prognosis in luminal breast carcinoma JOURNAL OF CLINICAL PATHOLOGY 2014; 67 (11): 961-967
Despite considerable interest in the PI3K/AKT/mTOR pathway in breast carcinomas (BC), published data reports contradictory results regarding the association of phosphorylated mammalian target of Rapamycin (p-mTOR) expression with clinico-pathological features and prognosis in BC. Here, we evaluate the main clinico-pathological associations with p-mTOR expression in BC, with focus on the different molecular subtypes.In this retrospective study, 331 BC patients were included in final analysis. Outcome measures included disease-free survival (DFS) and overall survival (OS) times. Baseline data and outcome measures were compared between immunohistochemical p-mTOR expressing and non-expressing BCs. Subgroup analysis was performed to assess the effect of p-mTOR expression in the outcome for each BC molecular subtype.43.8% of the tumours were positive for p-mTOR, with a significant correlation between p-mTOR expression with smaller (<2 cm) (p=0.021) and lower-grade tumours (p<0.001). Expression of p-mTOR was also associated with longer DFS (HR of 0.32, p<0.001) and OS (HR of 0.20, p<0.001). In a multivariable analysis, the HR remained significant with minimal change (HR=0.26, p=0.002 for OS; HR=0.40, p=0.002 for DFS). In subgroup analysis, luminal p-mTOR-expressing tumours demonstrated longer DFS and OS (HR 0.33, p=0.003; HR 0.20, p=0.003, respectively) independently of size, grade, lymph node status and Her-2 overexpression.p-mTOR expression is associated with smaller, lower-grade and with luminal BC. In multivariable analysis, p-mTOR expression was associated with longer DFS and OS, independently of the size, grade and lymph node status, especially in luminal BCs.
View details for DOI 10.1136/jclinpath-2014-202320
View details for Web of Science ID 000344067700006
View details for PubMedID 25053543
- Genotypes and Prevalence of HPV Single and Multiple Concurrent Infections in Women with HSIL DIAGNOSTIC CYTOPATHOLOGY 2014; 42 (11): 919-923
The contribution of human papillomavirus (HPV) types to the carcinogenesis of cervical cancer has been established for a long time. However, the role of phylogenetically related and rare variants remains uncertain, as well as the influence of concurrent multiple HPV genotypes infection. We aimed at studying the prevalence of several HPV genotypes infecting women with single versus concurrent multiple HPV genotypes infection with a HSIL diagnosis in a cervical cytology. We conducted a cross-sectional study using Thin-Prep(®) liquid-based cervical cytology specimens with the diagnosis of high-grade squamous intraepithelial lesion (HSIL), in which HPV genotype was sequentially tested. Genotypes were determined with a PapilloCheck(®) system, a DNA-Chip for the type-specific identification of 18 high-risk and six low-risk types of HPV. Of the total study population, 176 cases had a diagnosis of HSIL and positive HPV genotyping result, being HPV16 the most prevalent genotype (48.86%; 95%CI: 41.58-56.19) followed by HPV31 (14.20%; 95%CI: 9.75-20.18). Concurrent multiple HPV genotypes were detected in 36.93% (95%CI: 30.15-44.27) of the patients. The prevalence of the 10 most common HPV genotypes detected varied significantly according to the presence of single vs. concurrent multiple HPV genotypes (P = 0.022). Moreover, women with concurrent multiple HPV genotypes were on average 3.53 (95%CI: 0.43-6.64) years younger than women with single genotype infection. Our results suggest that women with multiple genotype HPV infection differ in terms of age and distribution of the most prevalent HPV genotypes. Additionally, we provide further evidence of the predominance of HPV16 in HSIL lesions of the uterine cervix.
View details for DOI 10.1002/dc.23143
View details for Web of Science ID 000343969900001
View details for PubMedID 24623593
- Tumor Heterogeneity: The Lernaean Hydra of Oncology? ONCOLOGY-NEW YORK 2014; 28 (9): 781-784
- Metastatic breast cancer: mechanisms and opportunities for cytology CYTOPATHOLOGY 2014; 11 Flat Wish Women's US Softwalk Red Black M 25 (4): 225-230
Despite significant advances in diagnosis, surgical techniques, general patient care, and local and systemic adjuvant therapies, metastatic disease remains the most critical condition limiting the survival of patients with breast cancer. Therefore, the development of effective treatment against late-arising metastasis has become the centre of clinical attention and is one of the current challenges in cancer research. A deeper understanding of the metastatic cascade is fundamental, and the need for repetitive tumour assessments for the evaluation of tumour evolution is a relatively new practice in routine medical care. As such, fine needle aspiration cytology (FNAC) is ideally placed to monitor biological changes in metastasis that may affect treatment and response. As FNAC is a minimally invasive method, it can be performed repeatedly with relatively little trauma, and selective ancillary tests can be applied to FNAC specimens, including for tumour whose primary nature is known. Herein, we review how the linear and parallel models explain metastatic dissemination, thus influencing therapeutic and clinical decisions, and how cytology, together with immunocytochemistry and molecular analysis, can be a tool for routine clinical practice and clinical trials aimed at metastatic disease with a special emphasis on breast cancer.
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- Softwalk Flat Black M Red 11 Women's US Wish Tactoid body features in a Schwann cell hamartoma of colonic mucosa INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY 2014; 22 (5): 438-441
Mesenchymal colorectal polyps are uncommon lesions, particularly those of neurogenic origin. We describe a mucosal Schwann cell hamartoma of the colon with tactoid features, so far reported in peripheral nerve sheath tumours, and address its differential diagnosis and clinical implications.A 72-year-old man underwent screening colonoscopy that presented a 5-mm polyp on distal sigmoid. Histologically, it displayed a lesion in the lamina propria comprising oval structures with tactoid features and bland spindle cells, entrapping adjacent crypts. No ganglion cells were seen. Spindle cells expressed only S-100 protein and vimentin.Mucosal Schwann cell hamartoma was recently recognized as distinct from common (submucosal) colorectal Schwannomas and so far not associated to inherited syndromes. Thus, it should be considered in the differential diagnosis of look-alike lesions (eg, ganglioneuroma, neuroma, and neurofibroma) that may occur in the setting of inherited syndromes such as Cowden syndrome, multiple endocrine neoplasia-2B, and type 1 neurofibromatosis.
View details for DOI 10.1177/1066896913501384
View details for Web of Science ID 000340174500009
View details for PubMedID 23994879
- 11 Wish US Black Softwalk Flat Women's Red M Growing Indication for FNA to Study and Analyze Tumor Heterogeneity at Metastatic Sites CANCER CYTOPATHOLOGY 2014; 122 (7): 504-511
In routine practice, suspected metastases in patients with cancer are only occasionally biopsied, primarily because of the cost and invasiveness of the procedure. However, biopsies of metastatic lesions can be valuable, not only in confirming the presence of metastatic disease, but also in revealing unsuspected benign disease or secondary malignancies. In addition, such biopsies also allow the assessment of biomarkers that might differ from those on primary tumor cells, and can thereby facilitate selection of the optimal treatment. Because of the increasing recognition of clonal and phenotypic heterogeneity of tumors, we anticipate that in the near future, biopsying of metastatic lesions will constitute a standard-of-care practice, allowing assessment of molecular differences between the primary tumor and metastatic lesions. In our opinion, fine-needle aspiration is currently the best method for making repeated biopsies to monitor the tumor: it is minimally invasive, safe, and cost effective and can be coupled with modern ancillary techniques. Here we provide an up-to-date review of the clinical implications of tumor heterogeneity in metastatic disease and the ancillary molecular techniques used in cytology; we also discuss the role of modern cytology in contemporary diagnosis and management of metastatic cancer.
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- Primary relapse site pattern in women with triple-negative breast cancer PATHOLOGY RESEARCH AND PRACTICE 2014; 210 (9): 571-575
Despite the remarkable improvements in breast cancer (BC) characterization, accurate prediction of BC clinical behavior is often still difficult to achieve. Some studies have investigated the association between the molecular subtype, namely the basal-like BC and the pattern of relapse, however only few investigated the association between relapse pattern and immunohistochemical defined triple-negative breast cancers (TNBCs). The aim of this study was to evaluate the pattern of relapse in patients with TNBC, namely the primary distant relapse site. One-hundred twenty nine (129) invasive breast carcinomas with follow-up information were classified according to the molecular subtype using immunohistochemistry for ER, PgR and Her2. The association between TNBC and distant relapse primary site was analyzed by logistic regression. Using multivariate logistic regression analysis patients with TNBC displayed only 0.09 (95% CI: 0.00-0.74; p=0.02) the odds of the non-TNBC patients of developing bone primary relapse. Regarding visceral and lymph-node relapse, no differences between in this cohort were found. Though classically regarded as aggressive tumors, TNBCs rarely development primary relapse in bone when compared to non-TNBC, a clinical relevant fact when investigating a metastasis of an occult or non-sampled primary BC.
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View details for PubMedID 24939141
- Improved malignancy prediction by B3 breast lesions subclassification ANNALS OF DIAGNOSTIC PATHOLOGY 2013; 17 (5): 434-436
Softwalk Flat US Women's Wish Red Black M 11 Core-needle biopsy (CNB) of breast lesions can be classified into 5 categories according to lesion type and associated risk of malignancy. B3 category (lesion of uncertain malignant potential) constitutes a challenging problem in clinical decision, with most ending in excisional biopsy. Therefore, the aim of this study was to establish the incidence of malignancy on excision biopsy of B3 lesions and assess if subclassification (in B3a and B3b categories) according to the presence of atypia in otherwise B3 lesions better predicts malignancy on excision. Forty-eight cases with diagnosis of B3 lesion on CNB and matched surgical excision specimen were included to evaluate the positive predictive value (PPV) and odds for malignancy in CNB. All cases were further subclassified into B3a and B3b categories. B3 category lesions had an overall PPV for malignancy of 12.5% and significant low odds of malignancy of 0.14. When subclassified, B3b (lesions with atypia) demonstrated a higher PPV for malignancy (36.36%) with a nonsignificant odds. Inversely, B3a (lesions without atypia) demonstrated a PPV for malignancy of only 5.41% and a significant low odds of malignancy of only 0.06. The described low rate of malignancy in some of B3 lesions additionally reinforces the practice of avoiding surgical excision in selected patients and provides data that additionally support B3 lesion subclassification according to the presence of atypia. Subclassification of B3 category can further refine the current classification of associated risk of malignancy with possible implications in clinical management.
View details for DOI 10.1016/j.anndiagpath.2013.05.003
View details for Web of Science ID 000324896100009
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- Loss of caveolin-1 and gain of MCT4 expression in the tumor stroma Key events in the progression from an in situ to an invasive breast carcinoma CELL CYCLE 2013; 12 (16)11 Black US Softwalk Red M Wish Flat Women's : 2684-2690
The progression from in situ to invasive breast carcinoma is still an event poorly understood. However, it has been suggested that interactions between the neoplastic cells and the tumor microenvironment may play an important role in this process. Thus, the determination of differential tumor-stromal metabolic interactions could be an important step in invasiveness. The expression of stromal Caveolin-1 (Cav-1) has already been implicated in the progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC). Additionally, stromal Cav-1 expression has been associated with the expression of stromal monocarboxylate transporter 4 (MCT4) in invasive breast cancer. However, the role of stromal MCT4 in invasiveness has never been explored, neither the association between Cav-1 and MCT4 in the transition from breast DCIS to IDC. Therefore, our aim was to investigate in a series of breast cancer samples including matched in situ and invasive components, if there was a relationship between stromal Cav-1 and MCT4 in the progression from in situ to invasive carcinoma. We found loss of stromal Cav-1 in the progression to IDC in 75% of the cases. In contrast, MCT4 stromal expression was acquired in 87% of the IDCs. Interestingly, a concomitant loss of Cav-1 and gain of MCT4 was observed in the stroma of 75% of the cases, when matched in situ and invasive carcinomas were compared. These results suggest that alterations in Cav-1 and MCT4 may thus mark a critical point in the progression from in situ to invasive breast cancer.
View details for DOI 10.4161/cc.25794
View details for Web of Science ID 000326703800028
View details for PubMedID 23907124
- Cancer stem cells markers CD44, CD24 and ALDH1 in breast cancer special histological types JOURNAL OF CLINICAL PATHOLOGY 2013; 66 (3): 187-191
CD44, CD24 and ALDH1 are the most consistently used biomarkers to identify and characterise the breast cancer stem cell (CSC) phenotype. However, most studies performed until now analysed samples of invasive ductal carcinomas of no special type (IDC-NST). Therefore, prevalence and clinical significance of these CSC markers in breast carcinomas of special histological types (SHT) is largely unknown. For that reason, this study aims to determine the distribution of the breast CD44, CD24 and ALDH1 CSC markers among a series of invasive breast carcinomas of SHT, in comparison with a series of IDC-NST.117 invasive SHT breast carcinomas were analysed for the expression of CD44, CD24 and ALDH1, by immuhohistochemistry. The distribution of these CSC markers was evaluated among the distinct histological special types, and the results were compared with a series of 466 IDC-NST.The expression prevalence of the breast CSC markers differed between special types and IDC-NST. Medullary, papillary and tubular carcinomas were enriched in the CSC phenotype CD44(+)/CD24(-/low) (80.0%, 100.0% and 100.0%, respectively, vs 45.3% in IDC-NST). Considering the ALDH1 cytoplasmic tumour expression, only medullary and metaplastic carcinomas displayed significant increase in CD44(+)/CD24(-/low)/ALDH1(+) CSC phenotype frequency (36.4% and 28.6%, respectively, vs 4.8% in IDC-NST).The expression distribution of breast CSC markers is largely dependent on histological type. Interestingly, within the distinct SHT, medullary and metaplastic carcinomas are the two types highly associated with high-grade carcinomas, basal-like and claudin-low molecular subtypes, and to the CSC phenotype CD44(+)/CD24(-/low)/ALDH1(+).
View details for DOI 10.1136/jclinpath-2012-201169
View details for Web of Science ID 000315292200003
View details for PubMedID 23112116
- Oral squamous cell carcinoma in a Crohn's disease patient taking azathioprine: Case report and review of the literature JOURNAL OF CROHNS & COLITIS 2012; 6 (7): 792-795
Thiopurines are widely used for remission maintenance and post-operative recurrence prevention in Crohn's disease. The increased risk of cancer in transplant recipients on azathioprine is well recognized and there are concerns that this may also be true for inflammatory bowel disease patients. We report a case of a 33-year-old Caucasian woman with Crohn's disease treated with azathioprine for 9 years who developed an ulcerated lesion at the right superior retromolar trigone. Biopsy specimen revealed a squamous cell carcinoma.
View details for DOI 10.1016/j.crohns.2012.03.004
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- Training does not affect exhaled nitric oxide in competitive swimmers ALLERGY 2008; 63 (5): 623-624
View details for DOI 10.1111/j.1398-9995.2008.01659.x
View details for PubMedID 18394139