Publications by authors named "Fernando Augusto Soares"

227 Publications

Single nucleotide variants in immune-response genes and the tumor microenvironment composition predict progression of mantle cell lymphoma.

BMC Cancer 2021 Mar 1;21(1):209. Epub 2021 Mar 1.

Department of Pathology, Faculty of Medical Sciences, University of Campinas, Distrito de Barão Geraldo, Campinas, SP, Brazil.

Background: There is evidence to consider that the tumor microenvironment (TME) composition associates with antitumor immune response, and may predict the outcome of various non-Hodgkin lymphoma subtypes. However, in the case of mantle cell lymphoma (MCL), a rare and aggressive disease, there is lacking a detailed study of the TME components, as well as an integrative approach among them in patients' samples. Also, from the genetic point of view, it is known that single nucleotide variants (SNVs) in immune-response genes are among important regulators of immunity. At present, it is uncertain whether SNVs in candidate immune-response genes and the TME composition are able to alter the prognosis in MCL.

Methods: We assessed a detailed TME composition in 88 MCL biopsies using immunohistochemistry, which was automatically analyzed by pixel counting (Aperio system). We also genotyped SNVs located in candidate immune-response genes (IL12A, IL2, IL10, TGFB1, TGFBR1, TGFBR2, IL17A, IL17F) in 95 MCL patients. We tested whether the SNVs could modulate the respective protein expression and TME composition in the tumor compartment. Finally, we proposed survival models in rituximab-treated patients, considering immunohistochemical and SNV models.

Results: High FOXP3/CD3 ratios (p = 0.001), high IL17A levels (p = 0.003) and low IL2 levels (p = 0.03) were individual immunohistochemical predictors of poorer survival. A principal component, comprising high quantities of macrophages and high Ki-67 index, also worsened outcome (p = 0.02). In the SNV model, the CC haplotype of IL10 (p < 0.01), the GG genotype of IL2 rs2069762 (p = 0.02) and the AA+AG genotypes of TGFBR2 rs3087465 (p < 0.01) were independent predictors of outcome. Finally, the GG genotype of TGFB1 rs6957 associated with lower tumor TGFβ levels (p = 0.03) and less CD163+ macrophages (p = 0.01), but did not modulate patients' survival.

Conclusions: Our results indicate that the TME composition has relevant biological roles in MCL. In this setting, immunohistochemical detection of T-reg cells, IL17A and IL2, coupled with SNV genotyping in IL10, TGFBR2 and IL2, may represent novel prognostic factors in this disease, following future validations.
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http://dx.doi.org/10.1186/s12885-021-07891-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919095PMC
March 2021

Hedgehog pathway activation in oral squamous cell carcinoma: cancer-associated fibroblasts exhibit nuclear GLI-1 localization.

J Mol Histol 2020 Dec 30;51(6):675-684. Epub 2020 Sep 30.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation, Waldemar Falcao Street, 121, Candeal, Salvador, Bahia, 40296-710, Brazil.

The purpose of this study was to evaluate the expression of Hedgehog (HH) signaling molecules (SHH and GLI-1) by cancer-associated fibroblasts (CAF) in oral squamous cell carcinoma (OSCC). Immunohistochemistry was used to detect molecular HH signaling and CAF-related protein expression, including α-SMA and S100A4, in 70 samples of human OSCC. The colocalization of α-SMA and S100A4 with SHH was also evaluated by double-staining. In vitro study was performed using primary normal oral fibroblast (NOF) and CAF through immunofluorescence and Western Blot for CAF-proteins, SHH, and GLI-1. Forty-five cases (64.28%) were positive for α-SMA exclusively in tumor stroma, and S100A4 was identified in the cytoplasm of CAFs in 94.28% (n = 66) of the cases. With respect to stromal cells, 64 (91.43%) OSCC cases were positive for SHH, and 31 were positive for GLI-1 (44.29%); positive correlations were found between SHH and α-SMA (p < 0.0001, φ = 0.51), as well as between SHH and S100A4 (p = 0.087, φ = 0.94). Protein expression of SHH and GLI-1 was observed in primary CAFs and NOFs. Although SHH was found to be localized in the cellular cytoplasm of both cell types, GLI-1 was present only in the nuclei of CAF. Our results indicate that CAFs are not only potential sources of HH ligands in tumor stroma, but may also respond to HH signaling through nuclear GLI-1 activation. We further observed that elevated SHH expression by OSCC cells was associated with higher CAF density, reinforcing the chemoattractant role played by these molecules.
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http://dx.doi.org/10.1007/s10735-020-09913-5DOI Listing
December 2020

An integrative microenvironment approach for follicular lymphoma: roles of inflammatory cell subsets and immune-response polymorphisms on disease clinical course.

Oncotarget 2020 Aug 18;11(33):3153-3173. Epub 2020 Aug 18.

Department of Pathology, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil.

The study of the tumor microenvironment (TME) in follicular lymphoma (FL) has produced conflicting results due to assessment of limited TME subpopulations, and because of heterogeneous treatments among different cohorts. Also, important genetic determinants of immune response, such as single-nucleotide polymorphisms (SNPs), remain underexplored in this disease. We performed a detailed study of the TME in 169 FL biopsies using immunohistochemistry, encompassing lymphocytes, macrophages, and cytokines. We also genotyped 16 SNPs within key immune-response genes ( and ) in 159 patients. We tested associations between SNPs, clinicopathological features and TME composition, and proposed survival models in R-CHOP/R-CVP-treated patients. Presence of the rs568408 "A" allele associated with the follicular pattern of FOXP3+ cells. The AA haplotype included rs583911 and rs568408 and was an independent predictor of worse survival, together with the follicular patterns of T-cells (FOXP3+ and CD8+) and high IL-17F tumor levels. The patterns of CD3+, CD4+ and CD8+ cells, displayed as a principal component, also associated with survival. Hierarchical clustering of the TME proteins demonstrated a cluster that was associated with worse prognosis (tumors enriched in IL-17A, IL-17F, CD8, PD1, and Ki-67). The survival of FL patients who were treated in the rituximab era shows a strong dependence on TME signals, especially the T-cell infiltration patterns and IL-17F tumor levels. The presence of the AA haplotype of in the genome of FL patients is an additional prognostic factor that may modulate the composition of T-reg cells in this disease.
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http://dx.doi.org/10.18632/oncotarget.27698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443366PMC
August 2020

RORγt may Influence the Microenvironment of Thyroid Cancer Predicting Favorable Prognosis.

Sci Rep 2020 03 5;10(1):4142. Epub 2020 Mar 5.

Laboratory of Cancer Molecular Genetics, Faculty of Medical Sciences, University of Campinas (Unicamp), Campinas, Brazil.

We aimed to investigate the role of RORγt (Retinoic acid-related orphan receptor gamma) in the tumor microenvironment of differentiated thyroid carcinoma. We retrospectively analyzed 56 patients (48 papillary and 8 follicular thyroid carcinomas). Immunohistochemical expression of RORγt was compared to other immune markers previously investigated by our group, clinical and pathological information. All patients presented cytoplasmic expression of RORγt in thyroid tumor cells. Seven (12.5%) patients presented no nuclear expression of RORγt. Positivity was few (up to 10%) in 14 patients; 10 to 50% in 5 patients (8.9%); and more than 50% in 30 patients (53.6%). Nuclear RORγt positivity was associated with absence of distant metastasis at diagnosis (p = 0.013) and the need of less cumulative doses of radioactive iodine (p = 0.039). Patients whose tumors were positive for nuclear RORγt presented higher 10-years relapse-free survival rate than those patients who were negative for RORγt (p = 0.023). We classified the patients according to the clustering of immunological immunohistochemical markers. We were able to distinguish a subset (A) of 38 patients who presented high expression of nuclear RORγt and tended to be scarce in proinflammatory immune markers. Other 16 patients integrated a second subset (B) whose tumor microenvironment accumulated proinflammatory markers and presented low expression of nuclear nuclear RORγt. Distant metastasis at diagnosis were more frequent among patients from cluster B than from cluster A (p = 0.008). Our results reinforce that the expression of RORγt together with other immune markers might help predict the prognosis of patients with thyroid cancer and help individualize clinical management.
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http://dx.doi.org/10.1038/s41598-020-60280-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058012PMC
March 2020

Expression of the NEK family in normal and cancer tissue: an immunohistochemical study.

BMC Cancer 2020 Jan 6;20(1):23. Epub 2020 Jan 6.

Departamento de Bioquímica e de Biologia Tecidual, Instituto de Biologia, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil.

Background: The NEK serine/threonine protein kinases are involved in cell cycle checkpoints, DNA damage repair, and apoptosis. Alterations in these pathways are frequently associated with cell malignant cellular transformations. Thyroid cancer is the most common malignant tumour in the endocrine system. Despite good treatment methods, the number of cases has increased significantly in recent years. Here, we studied the expression of NEK1, NEK2, NEK3, and NEK5 in different types of normal and malignant tissues, using tissue microarray analysis, and identified NEKs as potential markers in thyroid malignancy.

Methods: The studied cases comprised multiple cancer tissue microarrays, including breast, colon, esophagus, kidney, lung, pancreas, prostate, stomach, thyroid and uterine cervix, as well as 281 patients who underwent thyroid resection for thyroid cancer or thyroid nodules. The expression of NEK1, NEK2, NEK3, and NEK5 was analyzed by immunohistochemistry. The expression pattern was evaluated in terms of intensity by two methods, semiquantitative and quantitative, and was compared between normal and cancer tissue.

Results: We analysed the expression of each member of the NEK family in a tissue-dependent manner. Compared to normal tissue, most of the evaluated proteins showed lower expression in lung tumour. However, in the thyroid, the expression was higher in malignant tissue, especially for NEK 1, NEK3 and NEK5. Concerning characteristics of the thyroid tumour, such as aggressiveness, NEK1 expression was higher in tumours with multifocality and in patients with lymph node metastasis. NEK3 expression was stronger in patients with stage II, that involved metastasis. NEK5, on the other hand, showed high expression in patients with invasion and metastasis and in patients with tumour size > 4 cm. Furthermore, this work, demonstrated for the first time a high specificity and sensitivity of over-expression of NEK1 in classical and follicular variants of papillary thyroid cancer and NEK3 in tall-cell papillary thyroid cancer.

Conclusion: Taken together, the NEK protein kinases emerge as important proteins in thyroid cancer development and may help to identify malignancy and aggressiveness features during diagnosis.

Trial Registration: This study was retrospectively registered.  www.accamargo.org.br/cientistas-pesquisadores/comite-de-etica-em-pequisa-cep.
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http://dx.doi.org/10.1186/s12885-019-6408-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945616PMC
January 2020

miRNA's Expression Profile and Its Potential Prognostic Role in Uterine Leiomyosarcoma.

Cells 2019 11 17;8(11). Epub 2019 Nov 17.

Laboratório de Ginecologia Estrutural e Molecular (LIM 58), Disciplina de Ginecologia, Departamento de Obstetricia e Ginecologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, HCFMUSP, SP, BR Av. Dr Arnaldo 455, sala 4121, Cerqueira Cesar, São Paulo 05403-010, Brazil.

The family is an important microRNA (miRNA) group that usually exerts functions as a tumor suppressor. We aimed to evaluate the expression profile of , and and to assess their value as prognostic markers in uterine leiomyosarcoma (LMS) patients. The miRNAs expression profile was assessed in 34 LMS and 13 normal myometrium (MM) paraffin-embedded samples. All family members showed downregulation in LMS. Our findings showed that patients with downregulation had worse overall survival (OS) and is an independent prognostic factor (hazard ratio [HR] = 2.24 In addition, almost half the patients had distant metastasis LMS patients with downregulated and had worse disease-free survival (DFS); they are not independent prognostic factors (HR = 2.65 Patients' ages were associated with and = 0.0160 downregulation. In conclusion, all the family members were downregulated in LMS patients, and the greater the loss of expression of these molecules, the greater their relationship with worse prognosis of patients. expression might influence the OS, while and might influence the DFS. owest expression levels of , and were associated with the oldest patients. Our findings indicate strong evidence of ' role as a potential prognostic biomarker in LMS.
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http://dx.doi.org/10.3390/cells8111452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912804PMC
November 2019

Is the non-metastatic, locally advanced colon adenocarinoma a distinct biological tumor variant? A study based on pathological evaluation, immunohistochemical panel and survival.

Rev Col Bras Cir 2019 Aug 15;46(3):e20192098. Epub 2019 Aug 15.

Universidade de São Paulo, Faculdade de Saúde Púbica, Departamento de Epidemiologia, São Paulo, SP, Brasil.

Objective: to evaluate the clinical and pathological differences between locally advanced colonic adenocarcinomas (LACA) with adhesions between adjacent organs or structures, and colonic adenocarcinomas with other clinical presentations.

Methods: we conducted a retrospective study from a convenience sample of patients with colonic adenocarcinoma, pathological stage pT3, distributed according to clinical and pathological characteristics in three groups: locally advanced tumors (LACA), pT3 tumors without adhesions or distant metastases (SF) and tumors with metastatic disease (M1). We evaluated clinical and pathological characteristics and the expression of seven immunohistochemical markers related to proliferation/apoptosis, cell invasion/migration and metastasis.

Results: we studied 101 patients: 30 LACA, 44 SF and 27 M1. Locally advanced tumors presented larger dimensions and were associated with increased lymphocyte infiltration rates, lower levels of bax expression, and CD 44v6 when compared with SF and M1 groups. We observed significant differences between LACA and M1 in relation to colonic location, histology, lymph node status and bax and CD44v6 expression. We found differences were observed between the three groups for tumor size and lymphocytic infiltrate. Survival was similar in the LACA and SF groups (p=0.66) and was lower in the M1 group (p<0.001).

Conclusion: the data suggest that locally advanced colonic adenocarcinomas with adhesions between adjacent organs or structures represent a distinct entity.
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http://dx.doi.org/10.1590/0100-6991e-20192098DOI Listing
August 2019

Quantification of histopathological changes in patients with psoriasis before and after phototherapy.

Photodermatol Photoimmunol Photomed 2019 Sep 26;35(5):354-359. Epub 2019 Jun 26.

Sector of Dermatology - University Hospital and School of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

Background: One of the most used resources for the treatment of psoriasis is ultraviolet radiation (UV) with psoralens (PUVA) and narrow-band UV (UVB-NB 311-312 nm). Although many researchers have assessed the histopathological effects of this therapy modality, none used a morphological classification system specific to psoriasis.

Purpose: To assess the clinical and histopathological response in the phototherapy treatment of plaque psoriasis with PUVA and UVB-NB with use of PASI and TROZAK.

Methods: Histopathological changes of plaque psoriasis were quantified with help of the grading system for psoriasis-Trozak in 20 patients of both sexes, before and after 32 PUVA phototherapy sessions (10 patients-GPUVA) and UVB-NB (10 patients-GUVB-NB). The severity and extension of psoriasis was evaluated through PASI. The slides stained with hematoxylin and eosin were scanned in an Aperio CS2 scanner (Leica Biosystems) and evaluated through the software ImageScopeTM (Aperio Technologies). Statistical analysis was performed with the use of the program SPSS 22.0, with application of the Wilcoxon and Mann-Whitney tests.

Results: All patients presented improvement in psoriatic plaques with decrease in PASI after treatment (P < 0.01) and significant reduction in histopathological changes in psoriasis from 15.4 ± 1.7 to 3.7 ± 3.2 (P < 0.01) in group GPUVA and from 13.2 ± 1.7 to 4.9 ± 5.2 (P < 0,01) in group GUVB-NB.

Conclusions: Phototherapy, regardless of type, is an effective treatment for moderate and severe psoriasis, with possibility of being quantified clinically by PASI and histopathologically by Trozak.
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http://dx.doi.org/10.1111/phpp.12492DOI Listing
September 2019

The stem cell markers expression CD44v6 and podoplanin in lip cancer: clinical significance.

Virchows Arch 2019 Jun 15;474(6):745-754. Epub 2019 Feb 15.

Department of Surgery, Stomatology, Pathology and Radiology, Area of Pathology, Bauru School of Dentistry, University of São Paulo, Alameda Octávio Pinheiro Brisola, 9-75, Bauru, SP, 17012-901, Brazil.

This study aimed to analyze the immunoexpression of cancer stem cell markers, CD44v6, and podoplanin in 91 patients with lip squamous cell carcinomas (LSCC). The immunostaining of podoplanin and CD44v6 was evaluated in ten high-power fields (× 400 magnification) at the invasive front of LSCC, using a semi-quantitative score method. Chi-square test or Fisher's exact test was used to verify the association of podoplanin and CD44v6 expressions with clinicopathologic variables. Spearman's correlation test was used to analyze the correlation between the two antibodies in lip cancer. Disease-free survival probabilities in 5 and 10 years were estimated according to the Kaplan-Meier method and compared using the log-rank test. The independent effects of the significant variables were analyzed by Cox proportional hazards regression model. A strong podoplanin expression was observed in the membrane and cytoplasm of most lip tumor cells, and this was inversely associated with locoregional recurrence (p = 0.028) and with histopathological grade of malignancy (p = 0.026). Additionally, CD44v6 immunostaining was strongly expressed in the membrane of tumor cells in 95.4% of the LSCC. Patients with strong membranous (p = 0.016) or strong cytoplasmic (p = 0.030) podoplanin-positive tumors resulted in significantly better disease-free survival than those who had podoplanin weak/negative tumors, confirming podoplanin expression as a favorable independent prognostic factor. Podoplanin and CD44v6 were strongly expressed by tumor cells and podoplanin immunoexpression can help to determine lip cancer patients with lower risk for disease recurrence.
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http://dx.doi.org/10.1007/s00428-019-02539-3DOI Listing
June 2019

Prostaglandin D2 expression is prognostic in high‑grade serous ovarian cancer.

Oncol Rep 2019 Apr 28;41(4):2254-2264. Epub 2019 Jan 28.

Molecular Gynaecology Laboratory, Department of Gynaecology, Federal University of São Paulo, São Paulo 04021‑001, Brazil.

To identify biomarkers that could predict response or lack of response to conventional chemotherapy at the time of diagnosis of high‑grade serous ovarian carcinoma (HGSOC), the present study compared large‑scale gene expression from patients with short or long disease‑free survival times, according to the last cycle of chemotherapy, and validated these findings using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and conventional immunohistochemical (IHC) analysis. Samples were selected for microarray evaluation, at the time of diagnosis, using the following criteria: Identical debulking primary surgery, International Federation of Gynaecology and Obstetrics staging, histological subtype and grade. These were divided into 2 groups, regarding the outcome after 2 years of follow-up. Prostaglandin D2 synthase 21 kDa (brain) (PTGDS) was found to be expressed at a significantly higher level in the tumours of patients with a short disease‑free survival time, and this was validated by RT‑qPCR in all samples. Furthermore, the study evaluated PGD2, the protein product of the PTGDS gene, in a large cohort of 114 HGSOC patients using the Ventana Benchmark automated platform, and IHC positivity was correlated with clinicopathological data and outcome. The global gene expression analysis identified 1,149 genes that were differentially expressed in microarray data, according to the patient outcome. Further analysis RT‑qPCR validated PTGDS gene expression in the same samples (r=0.945; P<0.001). IHC analysis showed an inverse profile, with positivity for PGD2 strongly associated with an increase in disease‑free survival (P=0.009), the absence of relapse (P=0.039) and sensitivity to platinum‑based therapy (P=0.016). Multiple Cox regression showed that IHC evaluation of PGD2 was also a prognostic marker associated with relapse (hazard ratio, 0.37; P=0.002). Overall, the results showed that IHC evaluation of PGD2 is an independent marker of good prognosis in HGSOC. This finding contributes to our understanding of the mechanism of tumour regulation and to investigations into biomarkers that predict response to chemotherapy.
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http://dx.doi.org/10.3892/or.2019.6984DOI Listing
April 2019

Characteristics of follicular and mantle cell lymphoma in Brazil: prognostic impact of clinical parameters and treatment conditions in two hospitals.

Hematol Transfus Cell Ther 2018 Oct-Dec;40(4):343-353. Epub 2018 Apr 18.

Universidade Estadual de Campinas (Unicamp), Campinas, SP, Brazil.

Objective: Follicular and mantle cell lymphoma are low-grade B-cell malignancies that lack good responses to chemoimmunotherapy. This study aimed to assess retrospectively clinicopathological features and to determine independent prognostic factors for follicular and mantle cell lymphoma patients treated at two Brazilian medical centers: the Hematology and Hemotherapy Center of the Universidade Estadual de Campinas (Unicamp), a public university hospital, and AC. Camargo Cancer Center, a specialized cancer center.

Methods: Two hundred and twenty-seven follicular and 112 mantle cell lymphoma cases were diagnosed between 1999 and 2016. Archived paraffin blocks were retrieved and reviewed. Corresponding demographics and clinical data were recovered from medical charts. Outcome analyses considered both overall and event-free survival.

Results: For follicular lymphoma treated with the R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone) and R-CVP (rituximab, cyclophosphamide, vincristine sulfate, prednisone) regimens, both B-symptoms (-value < 0.01 for overall and event-free survival) and high-risk Follicular Lymphoma International Prognostic Index (-value < 0.01 for overall survival) were independently associated to worse prognosis. Maintenance with rituximab improved the prognosis (-value < 0.01 for overall survival). For mantle cell lymphoma, B-symptoms (-value = 0.03 for overall survival and event-free survival) and bone marrow infiltration (-value = 0.01 for overall survival) independently predicted reduced survival, and rituximab at induction increased both event-free and overall survival (-value < 0.01 in both analyses). Combinations of these deleterious features could identify extremely poor prognostic subgroups. The administration of rituximab was more frequent in the AC. Camargo Cancer Center, which was the institution associated with better overall survival for both neoplasias.

Conclusion: This study represents the largest cohort of follicular and mantle cell lymphoma in South America thus far. Some easily assessable clinical variables were able to predict prognosis and should be considered in low-income centers. In addition, the underuse of rituximab in the Brazilian public health system should be reconsidered in future health policies.
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http://dx.doi.org/10.1016/j.htct.2018.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200674PMC
April 2018

Distribution of Metastatic Nodes in N0-1 Patients with Tonsillar Squamous Cell Carcinoma and Its Implications for Selective Neck Dissection.

Turk Arch Otorhinolaryngol 2018 Sep 1;56(3):139-144. Epub 2018 Sep 1.

Department of Head and Neck Surgery and Otorhinolaryngology, A. C. Camargo Cancer Center, São Paulo, Brazil.

Objective: We aimed to evaluate the pattern of neck metastasis in patients with primary tonsillar carcinoma treated by primary surgery and neck dissection. Impact of the extent of neck dissection and level of metastatic nodes on survival were also evaluated.

Methods: We evaluated 163 consecutive patients with tonsillar squamous cell carcinoma submitted for neck dissection and staged as cN0-1. Selective neck dissection was performed using a template encompassing levels I-III, whereas radical neck dissection led to the removal at levels I-V. For each patient, number of metastatic nodes, their distribution, and data regarding postoperative treatment and oncologic outcomes were analyzed.

Results: Occult neck metastasis at levels I, IV, and V were rare with two cases each. In the clinically negative (cN0) patients, there were no cases of metastasis at level V and two cases at level I or IV. The extent of neck dissection and level of metastatic nodes had no impact on disease-specific survival or neck recurrence.

Conclusion: We conclude that in cN0 patients, removal at levels II and III is mandatory but levels I, IV, and V may be spared.
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http://dx.doi.org/10.5152/tao.2018.3420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177493PMC
September 2018

Immunoexpression of claudins 4 and 7 among invasive breast carcinoma subtypes: A large diagnostic study using tissue microarray.

Mol Clin Oncol 2018 Oct 27;9(4):377-388. Epub 2018 Jul 27.

Radiology and Oncology Department (LIM24), São Paulo University, School of Medicine (FMUSP), São Paulo, SP 01246-903, Brazil.

Molecular phenotyping and tissue microarray (TMA) studies have identified distinct invasive breast carcinoma subtypes: Luminal A, luminal B, enriched with overexpressed human epidermal growth factor receptor 2 (HER-2) and triple-negative, i.e., negative for HER-2, as well as for estrogen and progesterone receptor (ER and PR, respectively) expression. These subtypes are useful in clinical management, since they bear distinct prognoses and predictive responses to targeted therapy. However, although molecular profiling provides important prognostic indicators, breast cancer risk stratification remains a challenge in triple-negative cases. What is referred to as claudin-low subtype was identified as a triple-negative subset that is associated with more aggressive tumor behavior and worse prognosis. However, the immunohistochemical expression of claudins has not yet been standardized. Our objective was to verify whether the immunoexpression of claudins 4 and 7 (the main claudins specifically expressed in human breast tissue) in TMA is associated with survival and prognosis in luminal A, HER-2 and triple-negative molecular subtypes. In this diagnostic study, we investigated ER/PR receptor status, HER-2, claudin 4 and 7 expression and stem cell CD44/24 profiles, and verified the association with prognosis and survival outcomes in 803 invasive breast carcinoma cases arranged in four TMAs. Among these, 503 (62.6%) were positive for claudin 4 and 369 (46.0%) for claudin 7. Claudin 4 exhibited the lowest expression in luminal A and triple-negative subtypes, and the highest frequency of expression in HER-2-enriched subtypes, whereas claudin 7 staining was not associated with any subtype. The stem cell phenotype was not associated with subgroups or claudins 4 and 7. Claudin immunoexpression profile was not able to distinguish between patients with better or worse prognosis, and it was not correlated to triple-negative cases. Therefore, it may be concluded that the immunoexpression of claudins 4 and 7, individually or within the usual immunohistochemical context (ER, PR and HER-2), does not provide additional prognostic information on breast cancer subtypes.
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http://dx.doi.org/10.3892/mco.2018.1685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125702PMC
October 2018

Could miRNA Signatures be Useful for Predicting Uterine Sarcoma and Carcinosarcoma Prognosis and Treatment?

Cancers (Basel) 2018 09 6;10(9). Epub 2018 Sep 6.

Laboratório de Ginecologia Estrutural e Molecular (LIM 58), Disciplina de Ginecologia, Departamento de Obstetricia e Ginecologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, HCFMUSP, SP, BR Av. Dr Arnaldo 455, sala 4121, Cerqueira Cesar, São Paulo 05403-010, Brazil.

Changes in microRNA (miRNA) expression may lead to cancer development and/or contribute to its progression; however, their role in uterine sarcomas is poorly understood. Uterine sarcomas (US) belong to a rare class of heterogeneous tumors, representing about 1% of all gynecologic neoplasms. This study aimed to assess the expression profile of 84 cancer-related miRNAs and to evaluate their correlation with clinical pathological features. Eighty-two formalin-fixed paraffin-embedded (FFPE) samples were selected. In leiomyosarcoma (LMS), there was an association of lower cancer-specific survival (CSS) with the downregulation of miR-125a-5p and miR-10a-5p, and the upregulation of miR-196a-5p and miR-34c-5p. In carcinosarcoma (CS), lower CSS was associated with the upregulation of miR-184, and the downregulation of let-7b-5p and miR-124. In endometrial stromal sarcomas (ESS), the upregulation of miR-373-3p, miR-372-3p, and let-7b-5p, and the down-expression of let-7f-5p, miR-23-3p, and let-7b-5p were associated with lower CSS. Only miR-138-5p upregulation was associated with higher survival rates. miR-335-5p, miR-301a-3p, and miR-210-3p were more highly expressed in patients with tumor metastasis and relapse. miR-138-5p, miR-146b-5p, and miR-218-5p expression were associated with higher disease-free survival (DFS) in treated patients. These miRNAs represent potential prediction markers for prognosis and treatment response in these tumors.
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http://dx.doi.org/10.3390/cancers10090315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162723PMC
September 2018

Expanding morphological and clinical aspects of hereditary leiomyomatosis and renal cell carcinoma (HLRCC): a case report in a patient with unusual morphology and clinical presentation.

Virchows Arch 2018 Dec 31;473(6):775-779. Epub 2018 Aug 31.

Department of Pathology, AC Camargo Cancer Center, Rua Professor Antônio Prudente 211, São Paulo, 01509-900, Brazil.

Renal cell carcinoma (RCC) accounts for 2-3% of all malignant disease in adults. Hereditary RCC represents 5 to 8% of kidney tumors. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) represents an autosomal dominant syndrome that results from a germline mutation in fumarate hydratase gene (FH). HLRCC patients typically present with skin or uterine leiomyomas and renal neoplasms. HLRCC was recently recognized as a distinct renal tumor subtype by the WHO 2016 classification. Many morphological patterns such as papillary, solid, tubular, and cystic had been described as part of morphological aspects of HLRCC. In this study, we describe a case of a patient that had a history of persistence of ductus arteriosus (PDA) and cryptorchidism. In addition, the renal tumor showed a very unusual hystiocytoid morphological aspect. We confirmed the presence of a FH germline mutation both in the patient and his mother.
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http://dx.doi.org/10.1007/s00428-018-2420-3DOI Listing
December 2018

Claudin-4 Expression Is Associated With Disease-Free Survival in Breast Carcinoma-in-Situ: Mean Follow-up of 8.2 Years.

Clin Breast Cancer 2018 10 18;18(5):e1111-e1116. Epub 2018 Jun 18.

Woman's Hospital Prof Dr José Aristodemo Pinotti, CAISM, UNICAMP (State University of Campinas), Campinas, Brazil.

Introduction: Claudins are tight junctions associated with breast cancer prognosis. The claudin-low intrinsic subtype of invasive carcinoma is associated with high-grade carcinoma, low junction molecule expression, and worse response to chemotherapy. However, it is not known whether the expression of claudins may provide clues as to carcinoma-in-situ (CIS) prognosis. The aim of this study was evaluate claudin-4 expression in CIS and its association with disease-free survival and histologic type of local recurrence (in situ or invasive).

Methods: A tissue microarray block, constructed from 137 pure CIS paraffin blocks, was submitted to immunohistochemical staining for claudin-4, β-catenin, E-cadherin, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and Ki-67. A claudin-4 score categorized samples as claudin-4-low or -high. Clinical and treatment data were obtained from medical records.

Results: Claudin-4 expression was evaluated in 86 samples; 88.4% were high and 11.6% low. Mean follow-up was 98.4 months, and the local recurrence rate was 10.4%. There was a significant difference in disease-free survival between claudin-4-high and -low (4.9 and 1.9 years, respectively, P = .02); however, there was no difference between them in histologic type of recurrence (invasive or in situ) (P = .44).

Conclusion: In our samples, high claudin-4 expression in CIS was more frequent than low expression. Claudin-4-low expression had a worse prognosis in CIS (inferior disease-free survival), but it was similar to high claudin-4 in histologic type of local recurrence.
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http://dx.doi.org/10.1016/j.clbc.2018.06.005DOI Listing
October 2018

High CD90 (THY-1) expression positively correlates with cell transformation and worse prognosis in basal-like breast cancer tumors.

PLoS One 2018 27;13(6):e0199254. Epub 2018 Jun 27.

NUCEL (Cell and Molecular Therapy Center), Internal Medicine Department, School of Medicine, University of São Paulo, São Paulo, Brazil.

Breast cancer is the most prevalent cancer among women, with the basal-like triple negative (TNBC) being the most agressive one, displaying the poorest prognosis within the ductal carcinoma subtype. Due to the lack of adequate molecular targets, the diagnosis and treatment of patients with the TNBC phenotype has been a great challenge. In a previous work, we identified CD90/Thy-1 as being highly expressed in the aggressive high malignancy grade Hs578T basal-like breast tumor cell line, pointing to this molecule as a promising breast tumor marker, which should be further investigated. Here, CD90 expression was analyzed in human breast cancer samples and its functional role was investigated to better assess the oncogenic nature of CD90 in mammary cells. Quantification of CD90 expression in human breast cancer samples, by tissue microarray, showed that high CD90 positivity correlates with metastasis and poor patient survival in the basal-like subtype. The functional genetic approach, by overexpression in the CD90 cDNA in a basal-like normal mammary cell line (MCF10A) and knockdown in a highly malignant cell line (Hs578T), allowed us to demonstrate that CD90 is involved with several cellular processes that lead to malignant transformation, such as: morphological change, increased cell proliferation, invasiveness, metastasis and activation of the EGFR pathway. Therefore, our results reveal that CD90 is involved with malignant transformation in breast cancer cell lines and is correlated with metastasis and poor patient survival in the basal-like subtype, being considered as a promising new breast cancer target.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0199254PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021101PMC
April 2019

Inhibition of the AnxA1/FPR1 autocrine axis reduces MDA-MB-231 breast cancer cell growth and aggressiveness in vitro and in vivo.

Biochim Biophys Acta Mol Cell Res 2018 09 20;1865(9):1368-1382. Epub 2018 Jun 20.

Laboratory of Nanobiotechnology, Institute of Genetics and Biochemistry, Federal University of Uberlândia, Uberlândia, MG, Brazil. Electronic address:

Breast Cancer (BC) is a highly heterogeneous disease whose most aggressive behavior is displayed by triple-negative breast cancer (TNBC), which lacks an efficient targeted therapy. Despite its controversial role, one of the proteins that having been linked with BC is Annexin A1 (AnxA1), which is a Ca binding protein that acts modulating the immune system, cell membrane organization and vesicular trafficking. In this work we analyzed tissue microarrays of BC samples and observed a higher expression of AnxA1 in TNBCs and in lymph node metastasis. We also observed a positive correlation in primary tumors between expression levels of AnxA1 and its receptor, FPR1. Despite displaying a lesser strength, this correlation also exists in BC lymph node metastasis. In agreement, we have found that AnxA1 was highly expressed and secreted in the TNBC cell line MDA-MB-231 that also expressed high levels of FPR1. Furthermore, we demonstrated, by using the specific FPR1 inhibitor Cyclosporin H (CsH) and the immunosuppressive drug Cyclosporin A (CsA), the existence of an autocrine signaling of AnxA1 through the FPR1. Such signaling, elicited by AnxA1 upon its secretion, increased the aggressiveness and survival of MDA-MB-231 cells. In this manner, we demonstrated that CsA works very efficiently as an FPR1 inhibitor. Finally, by using CsA, we demonstrated that FPR1 inhibition decreased MDA-MB-231 tumor growth and metastasis formation in nude mice. These results indicate that FPR1 inhibition could be a potential intervention strategy to manage TNBCs displaying the characteristics of MDA-MB-231 cells. FPR1 inhibition can be efficiently achieved by CsA.
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http://dx.doi.org/10.1016/j.bbamcr.2018.06.010DOI Listing
September 2018

Downregulation of AGR2, p21, and cyclin D and alterations in p53 function were associated with tumor progression and chemotherapy resistance in epithelial ovarian carcinoma.

Cancer Med 2018 May 29. Epub 2018 May 29.

Molecular Gynecology Laboratory, Gynecologic Department, Federal University of São Paulo, São Paulo, Brazil.

Anterior gradient 2 protein belongs to a family of chaperone-like proteins, namely protein disulfide isomerase. Generally, AGR2 is highly expressed in mucus-secreting cells and endocrine organs, and in this study, we aimed to evaluate AGR2 and cell cycle molecules in epithelial ovarian cancer and its implications on prognosis. One hundred seventy-five patient's samples that were diagnosed with primary epithelial ovarian carcinoma were selected. All the patients were treated with platinum-taxane standard chemotherapy after surgery and CA125 serum levels were routinely determined. Four-micrometer-thick sections were processed by immunohistochemistry using an automated immunostainer, Ventana BenchMark AutoStainer with AGR2, cyclin D1, p21WAF1, and p53. Forty-nine of 167 cases (29.3%) showed strong to moderate cytoplasmic marking of AGR2, and 118 (70.7%) had weak to negative expression. The absence of the AGR2 protein was observed in high-grade serous carcinoma (P < .001) and significantly associated with disease-free survival (DFS; P = .034). The expression of G1-S phase-regulatory proteins showed loss of p21 in high-grade serous carcinoma (P < .001) and was related with poor DFS (P = .003). Strong and diffuse immunoexpression of p53 plus complete absence of p53 staining was interpreted as likely indicating a TP53 gene mutation. This result showed worse DFS alone (P = .012) and combined with low levels of AGR2 (P = .005). The expression profile of AGR2 and cell cycle proteins here presented was showed as good prognosis marker in epithelial ovarian cancer. This finding suggests AGR2 and as putative biomarker of disease progression in chemotherapy-treated high-grade serous carcinoma patients.
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http://dx.doi.org/10.1002/cam4.1530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051166PMC
May 2018

Moesin Involvement in Oral Carcinogenesis of the Lower Lip.

Anticancer Res 2018 05;38(5):2755-2760

Department of Surgery, Stomatology, Pathology and Radiology, Area of Pathology, Bauru School of Dentistry, University of São Paulo, São Paulo, Brazil

Background/aim: This study analyzed moesin immunoexpression in 91 lip squamous cell carcinomas and its influence in patients' prognosis.

Materials And Methods: Moesin immunoexpression was evaluated at the invasive tumor front by a semi-quantitative score method. The association of moesin with the clinicopathological variables was analyzed by the Chi-square test, the survival rates were calculated by Kaplan-Meier and the survival curves compared using the log-rank test.

Results: The expression of moesin was strong at the invasive tumor front and weak/negative in differentiated cells such as keratin pearls. There was no association between moesin expression and the clinicopathological variables, but there was a tendency for patients with lip cancer and strong moesin expression to have lower 5- and 10-year overall and disease-free survival rates.

Conclusion: Our results confirm the participation of moesin in oral carcinogenesis and suggest that this protein can influence the survival rates of patients with lip squamous cell carcinoma.
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http://dx.doi.org/10.21873/anticanres.12518DOI Listing
May 2018

COX-2 as a determinant of lower disease-free survival for patients affected by ameloblastoma.

Pathol Res Pract 2018 Jun 15;214(6):907-913. Epub 2018 Mar 15.

Oral Medicine Department, Sírio-Libanês Hospital, Dona Adma Jafet Street, 115, Bela Vista, São Paulo, SP, 01308-050, Brazil. Electronic address:

Ameloblastoma is a locally aggressive neoplasm with a poorly understood pathogenesis. Therefore, the aim of this study is to investigate whether COX-2 expression is associated with ameloblastoma microvascular density (MVD) and with tumor aggressiveness. Sixty-three cases of primary ameloblastomas arranged in tissue microarray were submitted to immunohistochemistry against cyclooxigenase-2 (COX-2) and CD34. Clinicopathological parameters regarding sex, age, tumour size, tumour duration, tumour location, treatment, recurrences, radiographic features, vestibular/lingual and basal cortical disruption and follow-up data were obtained from patients' medical records and correlated with the proteins expression. The results on BRAF-V600E expression were obtained from our previous study and correlated with COX-2 and CD34 expressions. Log-rank univariate analysis and multivariate Cox regression model were done to investigate the prognostic potential of the molecular markers. Twenty-eight cases (44.4%) exhibited cytoplasmic positivity for COX-2, predominantly in the columnar peripheral cells, with a mean MVD of 2.2 vessels/mm. COX-2 was significantly associated with recurrences (p < 0.001) and BRAF-V600E expression (p < 0.001), whereas lower MVD was associated with the use of conservative therapy (p = 0.004). Using univariate and multivariate analyses, COX-2 was significantly associated with a lower 5-year disease-free survival (DFS) rate (p < 0.001 and p = 0.012, respectively), but not with a higher MVD (p = 0.68). In conclusion, COX-2 expression in ameloblastomas is not associated with MVD, but it is significantly associated with recurrences and with a lower DFS.
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http://dx.doi.org/10.1016/j.prp.2018.03.014DOI Listing
June 2018

Prognostic importance of FGF2 and FGFR1 expression for patients affected by ameloblastoma.

J Oral Pathol Med 2018 Apr 3;47(4):417-424. Epub 2018 Mar 3.

Oral Medicine Department, Sírio-Libanês Hospital, São Paulo, Brazil.

Background: Fibroblast growth factor 2 (FGF2) and FGF receptor 1 (FGFR1) have been investigated in different human neoplasms and were shown to play important roles in the pathogenesis of these diseases; however, very few are known regarding their prognostic importance in the context of ameloblastoma. Therefore, the aim of this study was to investigate whether the expression of FGF2 and FGFR1 is associated with ameloblastoma clinical behavior.

Methods: Fifty-eight cases of ameloblastoma arranged in tissue microarray were submitted to immunohistochemistry against FGF2 and FGFR1. Clinicopathological parameters regarding sex, age, tumor size, duration and location, treatment, recurrences, radiographic features, cortical disruptions, and follow-up data were obtained from patients' medical records and correlated with the molecules expression. Univariate and multivariate Cox regression analyses were used to investigate the prognostic potential of the biomarkers.

Results: Forty-four cases (75.9%) exhibited cytoplasmic positivity for FGF2 in central and peripheral epithelial cells, 46 of 58 (79.3%) showed FGFR1 cytoplasmic positivity predominantly in the columnar peripheral cells, and 43 cases (74.1%) were positive for both. Expression of FGF2 and FGF2 + FGFR1 was associated with tumor recurrences (P = .05). However, univariate and multivariate analyses did not demonstrate a significant influence of FGF2, FGFR1, or FGF2 + FGFR1 in the 5-year disease-free survival (DFS) rate (P = .27, P = .33, and P = .25, respectively).

Conclusion: Cytoplasmic expression of FGF2 and FGF2 + FGFR1 is associated with ameloblastoma recurrence, but FGF2 and FGFR1 are not determinants of a lower DFS.
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http://dx.doi.org/10.1111/jop.12695DOI Listing
April 2018

Frequency of EBV associated classical Hodgkin lymphoma decreases over a 54-year period in a Brazilian population.

Sci Rep 2018 01 30;8(1):1849. Epub 2018 Jan 30.

Department of Anatomic Pathology, A. C. Camargo Cancer Center, São Paulo, Brazil.

The epidemiology of classical Hodgkin lymphoma varies significantly in populations with different socioeconomic conditions. Among other changes, improvement in such conditions leads to a reduction in the association with EBV infection and predominance of the nodular sclerosis subtype. This study provides an overview of the epidemiology of 817 cases of classical Hodgkin lymphoma diagnosed in five reference hospitals of the State of Sao Paulo, Brazil, over 54 years (1954-2008). The cases were distributed in 3 periods (1954-1979; 1980-1999; and 2000-2008). EBV-positive cases decreased from 87% to 46%. In children and adolescents (<15 years) and in young adults (15-45 years), EBV-positive cases decreased respectively from 96% to 64%, and from 85% to 32%. The percentage of male patients declined from 80% to 58%. In older patients (>45 years), the decrease in EBV infection was not significant. Nodular Sclerosis was the most common subtype in all periods. These results support the hypothesis that, in the Brazilian State of Sao Paulo, classical Hodgkin lymphoma has changed and now shows characteristics consistent with Pattern III observed in populations that experienced a similar socioeconomic transition.
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http://dx.doi.org/10.1038/s41598-018-20133-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789833PMC
January 2018

Breast implant-associated anaplastic large cell lymphoma in a Li-FRAUMENI patient: a case report.

Diagn Pathol 2018 Jan 25;13(1):10. Epub 2018 Jan 25.

Department of Anatomic Pathology, A.C. Camargo Cancer Center, 211 Professor Antônio Prudente Street, Sao Paulo, Zip code 01509-900, Brazil.

Background: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare malignancy, recently recognized as a provisional entity by the World Health Organization. Although increasing data have been published on this entity in recent years, a great number of patients and health professionals remain unaware of this diagnosis.

Case Presentation: We herein report the case of a 56-year-old female with Li-FRAUMENI syndrome who presented with late right-sided recurrent breast swelling after prophylactic adenomastectomy with implant reconstruction. Imaging scans revealed an heterogeneous mass adjacent to the implant fibrous capsule. A biopsy of the lesion rendered the diagnosis of a BIA-ALCL.

Conclusions: This case presents similarities with previous reports, but also some particularities, which should be stressed in order to make the diagnosis the earliest possible. The most distinct feature is that this is the second report of BIA-ALCL arising in the setting of Li-FRAUMENI syndrome.
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http://dx.doi.org/10.1186/s13000-018-0688-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784673PMC
January 2018

Moesin expression by tumor cells is an unfavorable prognostic biomarker for oral cancer.

BMC Cancer 2018 01 8;18(1):53. Epub 2018 Jan 8.

Department of Stomatology, Area of Pathology, Bauru School of Dentistry, University of São Paulo, Alameda Octávio Pinheiro Brisolla, 9-75, Bauru, São Paulo, 17012-901, Brazil.

Background: Moesin is a member of the ERM (ezrin, radixin and moesin) proteins that participate in cell migration and tumor invasion through transductional signals sent to actin filaments by glycoproteins, such as podoplanin.

Methods: This study aimed to evaluate the participation of moesin and podoplanin in the invasive tumor front of oral squamous cell carcinomas, and their influence on patients' prognosis. Podoplanin and moesin immunoexpressions were evaluated by a semi-quantitative score method, based on the capture of 10 microscopic fields, at 400X magnification, in the invasive tumor front of oral squamous cell carcinomas. The association of moesin and podoplanin expression with clinicopathological variables was analyzed by the chi-square, or Fisher's exact test. The 5 and 10 years survival rates were calculated by the Kaplan-Meier method and the survival curves were compared by using the log-rank test.

Results: The immunohistochemical expression of moesin in the invasive front of oral squamous cell carcinomas was predominantly strong, homogenously distributed on the membrane and in the cytoplasm of tumor cells. The expression of moesin was not associated with clinical, demographic and microscopic features of the patients. Otherwise, podoplanin expression by malignant epithelial cells was predominantly strong and significantly associated with radiotherapy (p = 0.004), muscular invasion (p = 0.006) and lymph node involvement (p = 0.013). Strong moesin expression was considered an unfavorable prognostic factor for patients with oral squamous cell carcinomas, clinical stage II and III (p = 0.024).

Conclusions: These results suggested that strong moesin expression by malignant cells may help to determine patients with oral squamous cell carcinoma and poor prognosis.
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http://dx.doi.org/10.1186/s12885-017-3914-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5759236PMC
January 2018

Immunoexpression of proteins involved in cytoskeleton remodeling in benign odontogenic lesions.

Arch Oral Biol 2018 Mar 21;87:151-156. Epub 2017 Dec 21.

Department of Stomatology, Area of Pathology, Bauru School of Dentistry, University of São Paulo, Al. Dr. Octávio Pinheiro Brisolla, 9-75, Bauru, SP, 17120-901, Brazil. Electronic address:

Objective: The present study was designed to analyze the immunolocalization of proteins involved in cytoskeleton remodeling, such as moesin and Rho-A, in benign odontogenic lesions that present with expansive growth and invasive clinical behavior.

Materials And Methods: Expressions of moesin and Rho-A in odontogenic epithelium were evaluated by immunohistochemical analysis in 45 odontogenic lesions using monoclonal antibodies.

Results: Our results demonstrated strong membranous and cytoplasmic expressions of moesin in the epithelial cells in 66.7% and 44.4% of the odontogenic lesions, respectively. Furthermore, Rho-A expression in odontogenic epithelium was strong in the membrane and cytoplasm of 51.1% and 62.2% of the odontogenic lesions, respectively. A statistically significant correlation was found between the membranous and cytoplasmic expressions of moesin (p = 0.000) and those of Rho-A (p = 0.048) in odontogenic epithelial cells, while no statistically significant correlation was found between moesin and Rho-A expressions (p > 0.05).

Conclusions: The present study confirmed the strong expressions of moesin and Rho-A by odontogenic epithelial cells, suggesting their involvement in the development of benign odontogenic lesions. However, this study has failed to detect the connection between the moesin and Rho-A interaction in expansive growth and local invasiveness of these lesions.
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http://dx.doi.org/10.1016/j.archoralbio.2017.12.017DOI Listing
March 2018

Prognostic value of GRIM-19, NF-κB and IKK2 in patients with high-grade serous ovarian cancer.

Pathol Res Pract 2018 Feb 6;214(2):187-194. Epub 2017 Dec 6.

Laboratory of Molecular Gynaecology, Department of Gynaecology, Federal University of São Paulo, Brazil.

Aims: High grade serous carcinoma (HGSC) is an aggressive tumour, and most patients relapse after treatment, acquiring resistance to platinum-based chemotherapy. One of the resistance mechanisms proposed is apoptosis evasion triggered by drug-related cytotoxic effect in the cell. In this context, this study aims to evaluate the protein expression of GRIM-19, NF-κB and IKK2, their association with chemotherapy response and to determine their prognostic values in HGSC.

Methods: GRIM-19, NF-κB and IKK2 expression was evaluated by immunohistochemistry (IHC) in 71 patients with HGSC selected between 2003 and 2013, whose underwent primary debulking surgery with complete cytoreduction. Protein expression was analyzed in relation to platinum response groups, tumour progression, clinicopathological data and survival.

Results: Positive IKK2 expression was related to resistance (p = 0.011), shorter disease-free survival (p = 0.001) and overall survival (p = 0.026) and was also a risk factor for relapse (p = 0.002) and death (p = 0.032). The association between IKK2 and NF-κB positivity predicted a subgroup with shorter overall survival (p = 0.004), disease-free survival (p = 0.003) and resistance to platinum-based chemotherapy (p = 0.036). NF-κB positivity was associated with worse overall survival (p = 0.005) and disease-free survival (p = 0.027) and was a positive predictor for relapse (p = 0.032) and death (p = 0.008). Higher expression of GRIM-19 was associated with higher disease-free survival (p = 0.039) and was a negative predictor for relapse (p = 0.046).

Conclusions: GRIM-19 is a potential predictor of prognosis and disease recurrence in HGSC. IKK2 and NF-κB are related to poor prognosis and are potential predictors of response to platinum-based chemotherapy in HGSC. IHC analyses of GRIM19, IKK2 and NF-κB may be important in the attempt to provide prognostic values for relapse and response to treatment in patients with HGSC.
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http://dx.doi.org/10.1016/j.prp.2017.12.002DOI Listing
February 2018

MicroRNAs expression pattern related to mast cell activation and angiogenesis in paraffin-embedded salivary gland tumors.

Pathol Res Pract 2017 Dec 18;213(12):1470-1476. Epub 2017 Oct 18.

Laboratory of Oral Surgical Pathology, School of Dentistry, Federal University of Bahia, Faculdade de Odontologia, Laboratório de Patologia Cirúrgica, Avenida Araújo Pinho, 62, Canela, Salvador, Bahia, 40110-150, Brazil. Electronic address:

The aim of this study was evaluate the expression profile of microRNAs related to mast cells activation and angiogenesis in salivary glands tumors.

Method: We have analyzed the expression of miR-9, miR-16, miR-17, miR-132, miR-195 and miR-221 by real-time RT-PCR, in 11 adenoid cystic carcinomas, 9 mucoepidermoid carcinomas and 11 pleomorphic adenomas. Immunohistochemical investigation was performed to detect mast cells tryptase and CD-34 for microvessels biomarkers. miR-16, miR-17, miR-132, miR-195 and miR-221 showed a decreased expression, whereas miR-9 showed an increased expression in most cases compared to normal tissues. However, in all tumors studied only miR-9 showed a statistical significant negative correlation with microvessel density (p=0.001). It was observed a higher density of mast cells in mucoepidermoid carcinomas (10.55 cells/mm2) when compared to adenoid cystic carcinomas (6.27 cells/mm2) and between mucoepidermoid carcinomas and pleomorphic adenomas (5.97células/mm2). miR-17, miR-132, miR-195 and miR-221 seem to play an important role as tumor suppressor in salivary gland tumors. In addition, the significant correlation between mast cell and microvessel density contributes to the growth and pathogenesis of these tumors and they may become strong therapeutic targets in the future.
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http://dx.doi.org/10.1016/j.prp.2017.10.012DOI Listing
December 2017

Assessment of HER-2 status in invasive breast cancer in Brazil.

Rev Assoc Med Bras (1992) 2017 Jul;63(7):566-574

Department of Pathologic Anatomy, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.

Objective: To characterize the frequency of HER-2-positive breast cancer in Brazil.

Method: In this prospective observational study, we first ascertained the HER-2 status of invasive breast cancer specimens by automated immunohistochemistry (IHC). For specimens classified as 2+ by IHC, we performed in situ hybridization (ISH).

Results: From February, 2011 to December, 2012, 1,495 breast specimens were registered, and 1,310 samples collected at 24 centers were analyzed. Median patient age was 54 years, and the majority of samples were obtained from segmental (46.9%) or radical mastectomy (34.4%). The predominant histological type was invasive breast carcinoma of no special type (85%), 64.3% had tubule formation (grade 3), and estrogen/progesterone receptors (ER/PR) were positive in 77.4/67.8% of the specimens analyzed, respectively. Using IHC, we found a negative HER-2 status (0 or 1+) in 72.2% of specimens, and 3+ in 18.5%; the 9.3% scored as 2+ were further analyzed by ISH, of which 15.7% were positive (thus, 20.0% of samples were HER-2- -positive by either method). We found no association between HER-2 scores and menopausal status or histological type. Tumors classified as 3+ came from younger patients, and had higher histological grade and less frequent expression of ER/PR. In the North region of Brazil, 34.7% of samples were 3+, with lower frequencies in the other four regions of the country.

Conclusion: Our findings provide estimates for the frequency of HER-2 positivity in Brazil and raise the hypothesis that biological differences may underlie the different distribution of breast-cancer phenotypes among different Brazilian regions.
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http://dx.doi.org/10.1590/1806-9282.63.07.566DOI Listing
July 2017