Rodrigo Natal - Academia.edu (original) (raw)

Papers by Rodrigo Natal

Cancer Research

Objective: To assess the association of MRI BPE and pathological response in women diagnosed with... more Objective: To assess the association of MRI BPE and pathological response in women diagnosed with stage II/III breast cancer submitted to NAC. Methods: This observational and cross-sectional retrospective study was performed in consecutive women who underwent NAC and had MRI exams before and after chemotherapy. The MRI was done before and after 2 weeks of completing NAC. BPE was classified according to ACR-BIRADS 5th edition. The type of BPE before NAC, its changes and the relationship to total pathologic complete response (TpCR) were evaluated. Data were paired with patient age, size on MRI before and after NAC, features of clinical response according to the RECIST criteria, tumor grade and immunohistochemical (IHC) subtypes. MRI assessment included amount of fibroglandular tissue, symmetry of BPE and measurement of tumor at the longest diameter. All images were blinded reviewed by a radiologist. We used for the changes of the BPE the Bowker symmetry test or the McNemar test and to...

Cancer Research

Background: Delays in diagnosis and treatment is associated with recurrence. Access to medical ca... more Background: Delays in diagnosis and treatment is associated with recurrence. Access to medical care in public health systems (PHS) may vary across Southwest Brazil and Houston, Texas. Objective: To evaluate disparities in breast cancer (BC) diagnosis and treatment between public services in southwest Brazil and at a public safety net hospital in Houston, Texas. Methods: Women diagnosed with BC stages I-III between 2009 to 2011, and treated at thefour hospitals in Brazil and two health centers in US were included. All statistical analyses was performed in R studio, and p<0.05 was considered significant. Results: 967 women from PHS were included: 778 from Brazil and 189 from US. Recurrence rates were not significantly different (15.9% vs. 9.5%, p=0.233) Table 1. Clinical and demographic characteristics of the patientsCharacteristicsBrazil (%), n=778US (%), n=189pDiscovery of BC By patient443 (56.9)87 (46) Routine exam82 (10.5)5 (2.7) Screening mammography207 (26.6)63 (33.4) Other...

The FASEB Journal, Apr 1, 2016

IntroductionOverall survival of women with high-grade serous ovarian cancer (HGSOC) is highly rel... more IntroductionOverall survival of women with high-grade serous ovarian cancer (HGSOC) is highly related with platinum resistance. Parameters of collagen can be used as potential new prognostic biomar...

Surgical and Experimental Pathology, 2021

Extracellular matrix (ECM) represents more than a mere intercellular cement. It is physiologicall... more Extracellular matrix (ECM) represents more than a mere intercellular cement. It is physiologically active in cell communication, adhesion and proliferation. Collagen is the most abundant protein, making up to 90% of ECM, and 30% of total protein weight in humans. Second-harmonic generation (SHG) microscopy represents an important tool to study collagen organization of ECM in freshly unfixed tissues and paraffin-embedded tissue samples. This manuscript aims to review some of the applications of SHG microscopy in Oncologic Pathology, mainly in the study of ECM of epithelial tumors. It is shown how collagen parameters measured by this technique can aid in the differential diagnosis and in prognostic stratification. There is a tendency to associate higher amount, lower organization and higher linearity of collagen fibers with tumor progression and metastasizing. These represent complex processes, in which matrix remodeling plays a central role, together with cancer cell genetic modifica...

Cancer Research, 2018

Background: Access to medical care vary across the world and is related to different health syste... more Background: Access to medical care vary across the world and is related to different health systems with an impact in recurrence.Objective: To evaluate disparities in breast cancer(BC) diagnosis and treatment between public and private services in southwest Brazil and at two public safety net hospitals in Houston, Texas.Methods: Women diagnosed with BC stages I-III between 2009 to 2011, and treated at the four hospitals in Brazil and two health centers in US were included. All statistical analyses were performed in R studio software, and p<0.05 was considered significant.Results: 1245 women were included: 967 from public health system (PHS) (20.3% from Houston, Texas) and 274 from private system(PS). Recurrence rate was higher in PHS (14.6% vs. 2.6%, p<0.001) Table 1. Clinical and demographic characteristics of the patientsCharacteristicsPublic (%), n=967Private (%), n=274pDiscovery of BC By patient530 (54.8)92 (33.5) Routine exam87 (9)109 (39.8) Screening mammography270 (27...

Scientific Reports, 2020

The extracellular matrix plays an important role in cellular balance, and collagen fibers are its... more The extracellular matrix plays an important role in cellular balance, and collagen fibers are its most important component. Over the last few years, second harmonic generation (SHG) microscopy has been used for the analysis of collagen fibers in several types of gynaecological cancers, such as breast and ovarian cancer. The value of collagen parameters obtained with this technique to gain insights on the physiopathology and on the prognostic evaluation of cancer has been advocated. Herein, we have characterized the collagen fibers in squamous cell carcinoma (VSCC) and preneoplastic lesions using the SHG microscopy. Collagen parameters, quantity, organization, and uniformity, of VSCC, adjacent skin of VSCC or preneoplastic lesions were compared with values obtained in normal tissue of healthy control. There was an evident decrease in the values of collagen fiber parameters in the VSCC. Increased quantity and uniformity of tumor associated collagen fibers were associated with the pres...

Blood, 2014

Introduction: Follicular lymphoma (FL) is the second most prevalent non-Hodgkin lymphoma worldwid... more Introduction: Follicular lymphoma (FL) is the second most prevalent non-Hodgkin lymphoma worldwide, and is characterized by an indolent course and frequent relapses. Better understanding of FL has shown that angiogenesis (AG) has an important role in its progression to a more aggressive form. The most important mediator of AG is the vascular endothelial growth factor (VEGF), which is encoded by a polymorphic gene. It is already known that allele C of the VEGF 2578C/A polymorphism (rs699947) is related to higher serum concentration of VEGF compared to the A allele. The roles of this genetic polymorphism in clinical manifestations and outcome of FL are still unknown, and therefore these were the aims of the present study. Methods: Our analysis included 86 consecutive FL patients seen at diagnosis at the university hospital. The patients were treated with 6 to 8 cicles of R-CHOP. The clinical data of these patients were obtained from medical records. Genomic DNA was extracted from peri...

Blood, 2015

Introduction: Second-Harmonic Generation microscopy (SHG) has provided progresses in extracellula... more Introduction: Second-Harmonic Generation microscopy (SHG) has provided progresses in extracellular matrix research, mainly regarding automated analysis of collagen fibers. Nodular sclerosis-classical Hodgkin lymphoma (NS) often has a rich collagen deposition, which remains poorly explored in its biological significance and potential prognostic role. The aim of this study was to characterize the collagen component of NS using SHG, and to investigate its clinical value. Methods: Hematoxylin and eosin stained slides from 53 consecutive samples of paraffin embedded NS tissue were analyzed by SHG imaging in an Inverted Zeiss LSM 780-NLO. HIV-positive individuals were excluded. For comparative purposes, 11 reactive lymph nodes (RL) were also randomly selected. In each slide, 3 capsular areas and 3 sclerotic regions (perinodular septa - PS - in NS and fibrotic foci around germinal centers in RL) were chosen. Collagen near blood vessels was not considered. We evaluated quantity, uniformity ...

Scientific Reports, 2019

one of the promising tools to evaluate collagen in the extracellular matrix is the second-harmoni... more one of the promising tools to evaluate collagen in the extracellular matrix is the second-harmonic generation microscopy (sHG). this approach may shed light on the biological behavior of cancers and their taxonomy, but has not yet been applied to characterize collagen fibers in cases diagnosed as invasive breast carcinoma (BC) of histological special types (IBC-ST). Tissue sections from 99 patients with IBC-ST and 21 of invasive breast carcinoma of no special type (IBC-NST) were submitted to evaluation of collagen parameters by sHG. tissue microarray was performed to evaluate immunohistochemical-based molecular subtype. In intratumoral areas, fsHG and bsHG (forward-sHG and backward-sHG) collagen parameters achieved their lowest values in mucinous, papillary and medullary carcinomas, whereas the highest values were found in classic invasive lobular and tubular carcinomas. Unsupervised hierarchical cluster analysis and minimal spanning tree using intratumoral collagen parameters allowed the identification of three main groups of breast cancer: group A (classic invasive lobular and tubular carcinomas); group B (IBC-Nst, metaplastic, invasive apocrine and micropapillary carcinomas); and group C (medullary, mucinous and papillary carcinomas). Our findings provide further characterization of the tumor microenvironment of IBC-st. this understanding may add information to build more consistent tumor categorization and to refine prognostication. Invasive breast carcinoma is considered a combination of heterogeneous diseases, encompassing multiple entities with distinct biological and clinical features. The most common subtype of breast carcinoma is invasive ductal carcinoma of no special type (IBC-NST), formerly known as invasive ductal carcinoma, which accounts for around 50% to 80% of all breast cancers 1-3. The remaining tumor subtypes are collectively referred to as invasive carcinoma with histological special types (IBC-ST), and account for approximately 25% of invasive breast carcinomas 1-4. Although pathologists have been aware of the diversity of breast cancers and have endeavored to devise approaches to classify the disease into meaningful groups 3,5-9 , this concept has only been brought to the forefront of breast cancer research after the publication of high-throughput microarray-based discovery studies that unraveled the existence of multiple molecular subtypes 10-13 .

Clinical Cancer Research, 2018

Introduction: High-grade serous ovarian carcinoma (HGSOC) is a heterogeneous disease with high mo... more Introduction: High-grade serous ovarian carcinoma (HGSOC) is a heterogeneous disease with high mortality. Initially most women respond to platinum chemotherapy, but rapidly many become resistant to the drug and progress to relapse and death. Better knowledge of the pathways responsible for the mechanisms of invasion and metastasis in women with HGSOC may help in the identification of prognostic biomarkers and in the development of new target therapies. The epithelial-mesenchymal transition (EMT) is an important cellular process related to invasion and metastasis. Some protein components such as the receptor tyrosine kinase, discoidin domain receptor 2 (DDR2), acting on the signal-regulated kinase 1/2 (ERK1/2) extracellular pathway, and the transcriptional co-activator yes-associated protein (YAP), acting in Hippo, are associated with EMT. In such pathways, microRNAs, such as miR-182, miR-96, and miR-9 are described as post-transcriptional regulators. Objective: To evaluate the expre...

Tumor Biology, 2019

The objective of this study is to evaluate the relationship between discoidin domain receptor 2 (... more The objective of this study is to evaluate the relationship between discoidin domain receptor 2 (DDR2) and miR-182 expression with response to platinum-based chemotherapy and survival in women with high-grade serous ovarian cancer (HGSOC). We evaluated 78 women with HGSOC stages I-IV, diagnosed between 1996 and 2013, and followed up until 2016. DDR2 expression was assessed using immunohistochemistry on tissue microarray slides. The microRNAs were evaluated by qRT-PCR. DDR2 expression was high in 11 (14.1%) women. PFS was significantly lower in women with FIGO stage I/II – versus III/IV, post-surgery residual disease and high expression of DDR2. Women with postsurgery residual disease, FIGO stage I/II – versus III/IV and DDR2 expression had worse OS, but only post-surgery residual disease remained an independent prognostic factor for worse OS in multivariable analysis. miR-182 expression levels were significantly lower in patients harboring tumors with higher expression of DDR2 (p &l...

Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 2018

Second-harmonic generation microscopy represents an important tool to evaluate extracellular matr... more Second-harmonic generation microscopy represents an important tool to evaluate extracellular matrix collagen structure, which undergoes changes during cancer progression. Thus, it is potentially relevant to assess breast cancer development. We propose the use of second-harmonic generation images of tumor stroma selected on hematoxylin and eosin-stained slides to evaluate the prognostic value of collagen fibers analyses in peri and intratumoral areas in patients diagnosed with invasive ductal breast carcinoma. Quantitative analyses of collagen parameters were performed using ImageJ software. These parameters presented significantly higher values in peri than in intratumoral areas. Higher intratumoral collagen uniformity was associated with high pathological stages and with the presence of axillary lymph node metastasis. In patients with immunohistochemistry-based luminal subtype, higher intratumoral collagen uniformity and quantity were independently associated with poorer relapse-fr...

Oncotarget, Jan 23, 2018

To evaluate the diagnostic and prognostic value of the immunohistochemical expression of WT1, p53... more To evaluate the diagnostic and prognostic value of the immunohistochemical expression of WT1, p53 and p16 in low- (LGSOCs) and high-grade serous ovarian carcinomas (HGSOCs). HGSOC had a significantly higher proportion of advanced stage disease, higher CA125 levels, higher proportion of post-surgery residual disease and higher recurrence or disease progression. WT1 was expressed in 71.4% of LGSOCs and in 57.1% of HGSOCs ( = 0.32). Focal and/or complete absence of p53 expression with negative p16 expression was found in 90.5% of LGSOCs, in contrast to the 88.1% of HGSOCs with diffuse or complete absence of p53 expression with positive p16 expression (<0.001). The IHC p53/p16 index and the morphological classification were closely matched ( = 0.68). In the univariate analysis, FIGO stage, post-surgery residual disease and histological grade were significantly associated with progression-free survival (PFS) and overall survival (OS). The IHC p53/p16 index was associated only with PFS...

International journal of gynecological cancer : official journal of the International Gynecological Cancer Society, 2018

The purpose of this study was to compare the immunohistochemical expression of BRCA1, Ki67, and β... more The purpose of this study was to compare the immunohistochemical expression of BRCA1, Ki67, and β-catenin in women with low-grade (LGSOC) and high-grade serous ovarian carcinomas (HGSOC) and their relationship with clinicopathological features, response to platinum-based chemotherapy, and survival. For this study, 21 LGSOC and 85 HGSOC stage I to IV cases, diagnosed and treated from 1996 to 2013 and followed-up until December 2016, were included. BRCA1, Ki67, and β-catenin expression was assessed using tissue microarray-based immunohistochemistry. Women with HGSOC were significantly more likely to have advanced-stage disease (P < 0.001), higher CA125 levels (P < 0.001), postsurgery residual disease (P < 0.01), and higher rates of disease progression and recurrence (P = 0.001). The percentage of women with HGSOC whose tumors expressed Ki67 was significantly higher compared with women with LGSOC (P < 0.001). The expression of BRCA1 and β-catenin did not differ between LGSO...

Acta histochemica, 2017

Mucinous breast carcinoma is characterized by the production of variable amounts of mucin. Some s... more Mucinous breast carcinoma is characterized by the production of variable amounts of mucin. Some studies have addressed immunohistochemical characterization of mucinous breast carcinoma using a limited set of antibodies. However, the purpose of the present study was to investigate a larger panel of markers not widely used in daily practice and to determine their pathological implications. Forty patients diagnosed with mucinous breast carcinoma were enrolled. An immunohistochemical study was performed on whole sections of paraffin embedded tissue, using antibodies for the following markers: estrogen receptor alpha and beta, progesterone receptor, androgen receptor, HER2, EGFR, Ki-67, E-cadherin, β-catenin, p53, chromogranin, synaptophysin, GCDFP15, mammaglobin, and CDX2. The pure mucinous type was more prevalent in older patients and more frequently expressed GCDFP15. Capella type B presented more frequently with a high Ki-67 index and neuroendocrine differentiation. Although there wa...

XXIV Congresso de Iniciação Científica da Unicamp, 2016

In melanoma, collagen has been described as a potential new prognostic biomarker. In this way, ou... more In melanoma, collagen has been described as a potential new prognostic biomarker. In this way, our purpose was to evaluate the quantity, uniformity and organization of peri-and intratumoral collagen, and to correlate these parameters with clinicopathological features. For this purpose, a total of 22 specimens of cutaneous melanoma were submitted to second-harmonic generation microscopy and image evaluation. Our results suggest that the collagen fiber parameters, mainly organization, are potential candidates to determine with higher precision the border between neoplasia and nonneoplastic dermis.

Advanced Microscopy Techniques IV; and Neurophotonics II, 2015

Introduction: In breast cancer (BC), desmoplastic reaction, assembled primarily by fibroblasts, i... more Introduction: In breast cancer (BC), desmoplastic reaction, assembled primarily by fibroblasts, is associated with unfavorable prognosis, but the reason of this fact remains still unclear. In this context, nonlinear optics microscopy, including Fluorescence Lifetime Imaging Microscopy (FLIM), has provided advancement in cellular metabolism research. In this paper, our purpose is to differentiate BC cells metabolism with or without contact to desmoplastic reaction. Formalin fixed, paraffin embedded samples were used at different points of hematoxylin stained sections. Methodology: Sections from 14 patients with invasive ductal breast carcinoma were analyzed with FLIM methodology to NAD(P)H and FAD fluorescence lifetime on a Confocal Upright LSM780 NLO device (Carl Zeiss AG, Germany). Quantification of the fluorescence lifetime and fluorescence intensity was evaluated by SPC Image software (Becker &Hickl) and ImageJ (NIH), respectively. Optical redox ratio was calculated by dividing the FAD fluorescence intensity by NAD(P)H fluorescence intensity. Data value for FLIM measurements and fluorescence intensities were calculated using Wilcoxon test; p< 0.05 was considered significant. Results: BC cells in contact with desmoplastic reaction presented a significantly lower NAD(P)H and FAD fluorescence lifetime. Furthermore, optical redox ratio was also lower in these tumor cells. Conclusion: Our results suggest that contact of BC cells with desmoplastic reaction increase their metabolic activity, which might explain the adverse prognosis of cases associated with higher peritumoral desmoplastic reaction.

Cancer Research

Objective: To assess the association of MRI BPE and pathological response in women diagnosed with... more Objective: To assess the association of MRI BPE and pathological response in women diagnosed with stage II/III breast cancer submitted to NAC. Methods: This observational and cross-sectional retrospective study was performed in consecutive women who underwent NAC and had MRI exams before and after chemotherapy. The MRI was done before and after 2 weeks of completing NAC. BPE was classified according to ACR-BIRADS 5th edition. The type of BPE before NAC, its changes and the relationship to total pathologic complete response (TpCR) were evaluated. Data were paired with patient age, size on MRI before and after NAC, features of clinical response according to the RECIST criteria, tumor grade and immunohistochemical (IHC) subtypes. MRI assessment included amount of fibroglandular tissue, symmetry of BPE and measurement of tumor at the longest diameter. All images were blinded reviewed by a radiologist. We used for the changes of the BPE the Bowker symmetry test or the McNemar test and to...

Cancer Research

Background: Delays in diagnosis and treatment is associated with recurrence. Access to medical ca... more Background: Delays in diagnosis and treatment is associated with recurrence. Access to medical care in public health systems (PHS) may vary across Southwest Brazil and Houston, Texas. Objective: To evaluate disparities in breast cancer (BC) diagnosis and treatment between public services in southwest Brazil and at a public safety net hospital in Houston, Texas. Methods: Women diagnosed with BC stages I-III between 2009 to 2011, and treated at thefour hospitals in Brazil and two health centers in US were included. All statistical analyses was performed in R studio, and p<0.05 was considered significant. Results: 967 women from PHS were included: 778 from Brazil and 189 from US. Recurrence rates were not significantly different (15.9% vs. 9.5%, p=0.233) Table 1. Clinical and demographic characteristics of the patientsCharacteristicsBrazil (%), n=778US (%), n=189pDiscovery of BC By patient443 (56.9)87 (46) Routine exam82 (10.5)5 (2.7) Screening mammography207 (26.6)63 (33.4) Other...

The FASEB Journal, Apr 1, 2016

IntroductionOverall survival of women with high-grade serous ovarian cancer (HGSOC) is highly rel... more IntroductionOverall survival of women with high-grade serous ovarian cancer (HGSOC) is highly related with platinum resistance. Parameters of collagen can be used as potential new prognostic biomar...

Surgical and Experimental Pathology, 2021

Extracellular matrix (ECM) represents more than a mere intercellular cement. It is physiologicall... more Extracellular matrix (ECM) represents more than a mere intercellular cement. It is physiologically active in cell communication, adhesion and proliferation. Collagen is the most abundant protein, making up to 90% of ECM, and 30% of total protein weight in humans. Second-harmonic generation (SHG) microscopy represents an important tool to study collagen organization of ECM in freshly unfixed tissues and paraffin-embedded tissue samples. This manuscript aims to review some of the applications of SHG microscopy in Oncologic Pathology, mainly in the study of ECM of epithelial tumors. It is shown how collagen parameters measured by this technique can aid in the differential diagnosis and in prognostic stratification. There is a tendency to associate higher amount, lower organization and higher linearity of collagen fibers with tumor progression and metastasizing. These represent complex processes, in which matrix remodeling plays a central role, together with cancer cell genetic modifica...

Cancer Research, 2018

Background: Access to medical care vary across the world and is related to different health syste... more Background: Access to medical care vary across the world and is related to different health systems with an impact in recurrence.Objective: To evaluate disparities in breast cancer(BC) diagnosis and treatment between public and private services in southwest Brazil and at two public safety net hospitals in Houston, Texas.Methods: Women diagnosed with BC stages I-III between 2009 to 2011, and treated at the four hospitals in Brazil and two health centers in US were included. All statistical analyses were performed in R studio software, and p<0.05 was considered significant.Results: 1245 women were included: 967 from public health system (PHS) (20.3% from Houston, Texas) and 274 from private system(PS). Recurrence rate was higher in PHS (14.6% vs. 2.6%, p<0.001) Table 1. Clinical and demographic characteristics of the patientsCharacteristicsPublic (%), n=967Private (%), n=274pDiscovery of BC By patient530 (54.8)92 (33.5) Routine exam87 (9)109 (39.8) Screening mammography270 (27...

Scientific Reports, 2020

The extracellular matrix plays an important role in cellular balance, and collagen fibers are its... more The extracellular matrix plays an important role in cellular balance, and collagen fibers are its most important component. Over the last few years, second harmonic generation (SHG) microscopy has been used for the analysis of collagen fibers in several types of gynaecological cancers, such as breast and ovarian cancer. The value of collagen parameters obtained with this technique to gain insights on the physiopathology and on the prognostic evaluation of cancer has been advocated. Herein, we have characterized the collagen fibers in squamous cell carcinoma (VSCC) and preneoplastic lesions using the SHG microscopy. Collagen parameters, quantity, organization, and uniformity, of VSCC, adjacent skin of VSCC or preneoplastic lesions were compared with values obtained in normal tissue of healthy control. There was an evident decrease in the values of collagen fiber parameters in the VSCC. Increased quantity and uniformity of tumor associated collagen fibers were associated with the pres...

Blood, 2014

Introduction: Follicular lymphoma (FL) is the second most prevalent non-Hodgkin lymphoma worldwid... more Introduction: Follicular lymphoma (FL) is the second most prevalent non-Hodgkin lymphoma worldwide, and is characterized by an indolent course and frequent relapses. Better understanding of FL has shown that angiogenesis (AG) has an important role in its progression to a more aggressive form. The most important mediator of AG is the vascular endothelial growth factor (VEGF), which is encoded by a polymorphic gene. It is already known that allele C of the VEGF 2578C/A polymorphism (rs699947) is related to higher serum concentration of VEGF compared to the A allele. The roles of this genetic polymorphism in clinical manifestations and outcome of FL are still unknown, and therefore these were the aims of the present study. Methods: Our analysis included 86 consecutive FL patients seen at diagnosis at the university hospital. The patients were treated with 6 to 8 cicles of R-CHOP. The clinical data of these patients were obtained from medical records. Genomic DNA was extracted from peri...

Blood, 2015

Introduction: Second-Harmonic Generation microscopy (SHG) has provided progresses in extracellula... more Introduction: Second-Harmonic Generation microscopy (SHG) has provided progresses in extracellular matrix research, mainly regarding automated analysis of collagen fibers. Nodular sclerosis-classical Hodgkin lymphoma (NS) often has a rich collagen deposition, which remains poorly explored in its biological significance and potential prognostic role. The aim of this study was to characterize the collagen component of NS using SHG, and to investigate its clinical value. Methods: Hematoxylin and eosin stained slides from 53 consecutive samples of paraffin embedded NS tissue were analyzed by SHG imaging in an Inverted Zeiss LSM 780-NLO. HIV-positive individuals were excluded. For comparative purposes, 11 reactive lymph nodes (RL) were also randomly selected. In each slide, 3 capsular areas and 3 sclerotic regions (perinodular septa - PS - in NS and fibrotic foci around germinal centers in RL) were chosen. Collagen near blood vessels was not considered. We evaluated quantity, uniformity ...

Scientific Reports, 2019

one of the promising tools to evaluate collagen in the extracellular matrix is the second-harmoni... more one of the promising tools to evaluate collagen in the extracellular matrix is the second-harmonic generation microscopy (sHG). this approach may shed light on the biological behavior of cancers and their taxonomy, but has not yet been applied to characterize collagen fibers in cases diagnosed as invasive breast carcinoma (BC) of histological special types (IBC-ST). Tissue sections from 99 patients with IBC-ST and 21 of invasive breast carcinoma of no special type (IBC-NST) were submitted to evaluation of collagen parameters by sHG. tissue microarray was performed to evaluate immunohistochemical-based molecular subtype. In intratumoral areas, fsHG and bsHG (forward-sHG and backward-sHG) collagen parameters achieved their lowest values in mucinous, papillary and medullary carcinomas, whereas the highest values were found in classic invasive lobular and tubular carcinomas. Unsupervised hierarchical cluster analysis and minimal spanning tree using intratumoral collagen parameters allowed the identification of three main groups of breast cancer: group A (classic invasive lobular and tubular carcinomas); group B (IBC-Nst, metaplastic, invasive apocrine and micropapillary carcinomas); and group C (medullary, mucinous and papillary carcinomas). Our findings provide further characterization of the tumor microenvironment of IBC-st. this understanding may add information to build more consistent tumor categorization and to refine prognostication. Invasive breast carcinoma is considered a combination of heterogeneous diseases, encompassing multiple entities with distinct biological and clinical features. The most common subtype of breast carcinoma is invasive ductal carcinoma of no special type (IBC-NST), formerly known as invasive ductal carcinoma, which accounts for around 50% to 80% of all breast cancers 1-3. The remaining tumor subtypes are collectively referred to as invasive carcinoma with histological special types (IBC-ST), and account for approximately 25% of invasive breast carcinomas 1-4. Although pathologists have been aware of the diversity of breast cancers and have endeavored to devise approaches to classify the disease into meaningful groups 3,5-9 , this concept has only been brought to the forefront of breast cancer research after the publication of high-throughput microarray-based discovery studies that unraveled the existence of multiple molecular subtypes 10-13 .

Clinical Cancer Research, 2018

Introduction: High-grade serous ovarian carcinoma (HGSOC) is a heterogeneous disease with high mo... more Introduction: High-grade serous ovarian carcinoma (HGSOC) is a heterogeneous disease with high mortality. Initially most women respond to platinum chemotherapy, but rapidly many become resistant to the drug and progress to relapse and death. Better knowledge of the pathways responsible for the mechanisms of invasion and metastasis in women with HGSOC may help in the identification of prognostic biomarkers and in the development of new target therapies. The epithelial-mesenchymal transition (EMT) is an important cellular process related to invasion and metastasis. Some protein components such as the receptor tyrosine kinase, discoidin domain receptor 2 (DDR2), acting on the signal-regulated kinase 1/2 (ERK1/2) extracellular pathway, and the transcriptional co-activator yes-associated protein (YAP), acting in Hippo, are associated with EMT. In such pathways, microRNAs, such as miR-182, miR-96, and miR-9 are described as post-transcriptional regulators. Objective: To evaluate the expre...

Tumor Biology, 2019

The objective of this study is to evaluate the relationship between discoidin domain receptor 2 (... more The objective of this study is to evaluate the relationship between discoidin domain receptor 2 (DDR2) and miR-182 expression with response to platinum-based chemotherapy and survival in women with high-grade serous ovarian cancer (HGSOC). We evaluated 78 women with HGSOC stages I-IV, diagnosed between 1996 and 2013, and followed up until 2016. DDR2 expression was assessed using immunohistochemistry on tissue microarray slides. The microRNAs were evaluated by qRT-PCR. DDR2 expression was high in 11 (14.1%) women. PFS was significantly lower in women with FIGO stage I/II – versus III/IV, post-surgery residual disease and high expression of DDR2. Women with postsurgery residual disease, FIGO stage I/II – versus III/IV and DDR2 expression had worse OS, but only post-surgery residual disease remained an independent prognostic factor for worse OS in multivariable analysis. miR-182 expression levels were significantly lower in patients harboring tumors with higher expression of DDR2 (p &l...

Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 2018

Second-harmonic generation microscopy represents an important tool to evaluate extracellular matr... more Second-harmonic generation microscopy represents an important tool to evaluate extracellular matrix collagen structure, which undergoes changes during cancer progression. Thus, it is potentially relevant to assess breast cancer development. We propose the use of second-harmonic generation images of tumor stroma selected on hematoxylin and eosin-stained slides to evaluate the prognostic value of collagen fibers analyses in peri and intratumoral areas in patients diagnosed with invasive ductal breast carcinoma. Quantitative analyses of collagen parameters were performed using ImageJ software. These parameters presented significantly higher values in peri than in intratumoral areas. Higher intratumoral collagen uniformity was associated with high pathological stages and with the presence of axillary lymph node metastasis. In patients with immunohistochemistry-based luminal subtype, higher intratumoral collagen uniformity and quantity were independently associated with poorer relapse-fr...

Oncotarget, Jan 23, 2018

To evaluate the diagnostic and prognostic value of the immunohistochemical expression of WT1, p53... more To evaluate the diagnostic and prognostic value of the immunohistochemical expression of WT1, p53 and p16 in low- (LGSOCs) and high-grade serous ovarian carcinomas (HGSOCs). HGSOC had a significantly higher proportion of advanced stage disease, higher CA125 levels, higher proportion of post-surgery residual disease and higher recurrence or disease progression. WT1 was expressed in 71.4% of LGSOCs and in 57.1% of HGSOCs ( = 0.32). Focal and/or complete absence of p53 expression with negative p16 expression was found in 90.5% of LGSOCs, in contrast to the 88.1% of HGSOCs with diffuse or complete absence of p53 expression with positive p16 expression (<0.001). The IHC p53/p16 index and the morphological classification were closely matched ( = 0.68). In the univariate analysis, FIGO stage, post-surgery residual disease and histological grade were significantly associated with progression-free survival (PFS) and overall survival (OS). The IHC p53/p16 index was associated only with PFS...

International journal of gynecological cancer : official journal of the International Gynecological Cancer Society, 2018

The purpose of this study was to compare the immunohistochemical expression of BRCA1, Ki67, and β... more The purpose of this study was to compare the immunohistochemical expression of BRCA1, Ki67, and β-catenin in women with low-grade (LGSOC) and high-grade serous ovarian carcinomas (HGSOC) and their relationship with clinicopathological features, response to platinum-based chemotherapy, and survival. For this study, 21 LGSOC and 85 HGSOC stage I to IV cases, diagnosed and treated from 1996 to 2013 and followed-up until December 2016, were included. BRCA1, Ki67, and β-catenin expression was assessed using tissue microarray-based immunohistochemistry. Women with HGSOC were significantly more likely to have advanced-stage disease (P < 0.001), higher CA125 levels (P < 0.001), postsurgery residual disease (P < 0.01), and higher rates of disease progression and recurrence (P = 0.001). The percentage of women with HGSOC whose tumors expressed Ki67 was significantly higher compared with women with LGSOC (P < 0.001). The expression of BRCA1 and β-catenin did not differ between LGSO...

Acta histochemica, 2017

Mucinous breast carcinoma is characterized by the production of variable amounts of mucin. Some s... more Mucinous breast carcinoma is characterized by the production of variable amounts of mucin. Some studies have addressed immunohistochemical characterization of mucinous breast carcinoma using a limited set of antibodies. However, the purpose of the present study was to investigate a larger panel of markers not widely used in daily practice and to determine their pathological implications. Forty patients diagnosed with mucinous breast carcinoma were enrolled. An immunohistochemical study was performed on whole sections of paraffin embedded tissue, using antibodies for the following markers: estrogen receptor alpha and beta, progesterone receptor, androgen receptor, HER2, EGFR, Ki-67, E-cadherin, β-catenin, p53, chromogranin, synaptophysin, GCDFP15, mammaglobin, and CDX2. The pure mucinous type was more prevalent in older patients and more frequently expressed GCDFP15. Capella type B presented more frequently with a high Ki-67 index and neuroendocrine differentiation. Although there wa...

XXIV Congresso de Iniciação Científica da Unicamp, 2016

In melanoma, collagen has been described as a potential new prognostic biomarker. In this way, ou... more In melanoma, collagen has been described as a potential new prognostic biomarker. In this way, our purpose was to evaluate the quantity, uniformity and organization of peri-and intratumoral collagen, and to correlate these parameters with clinicopathological features. For this purpose, a total of 22 specimens of cutaneous melanoma were submitted to second-harmonic generation microscopy and image evaluation. Our results suggest that the collagen fiber parameters, mainly organization, are potential candidates to determine with higher precision the border between neoplasia and nonneoplastic dermis.

Advanced Microscopy Techniques IV; and Neurophotonics II, 2015

Introduction: In breast cancer (BC), desmoplastic reaction, assembled primarily by fibroblasts, i... more Introduction: In breast cancer (BC), desmoplastic reaction, assembled primarily by fibroblasts, is associated with unfavorable prognosis, but the reason of this fact remains still unclear. In this context, nonlinear optics microscopy, including Fluorescence Lifetime Imaging Microscopy (FLIM), has provided advancement in cellular metabolism research. In this paper, our purpose is to differentiate BC cells metabolism with or without contact to desmoplastic reaction. Formalin fixed, paraffin embedded samples were used at different points of hematoxylin stained sections. Methodology: Sections from 14 patients with invasive ductal breast carcinoma were analyzed with FLIM methodology to NAD(P)H and FAD fluorescence lifetime on a Confocal Upright LSM780 NLO device (Carl Zeiss AG, Germany). Quantification of the fluorescence lifetime and fluorescence intensity was evaluated by SPC Image software (Becker &Hickl) and ImageJ (NIH), respectively. Optical redox ratio was calculated by dividing the FAD fluorescence intensity by NAD(P)H fluorescence intensity. Data value for FLIM measurements and fluorescence intensities were calculated using Wilcoxon test; p< 0.05 was considered significant. Results: BC cells in contact with desmoplastic reaction presented a significantly lower NAD(P)H and FAD fluorescence lifetime. Furthermore, optical redox ratio was also lower in these tumor cells. Conclusion: Our results suggest that contact of BC cells with desmoplastic reaction increase their metabolic activity, which might explain the adverse prognosis of cases associated with higher peritumoral desmoplastic reaction.