Publications by authors named "Clovis Antonio Lopes Pinto"

72 Publications

Intratumoral lymphatic vascular density is an independent factor for disease-free and overall survival in advanced stage oral squamous cell carcinoma.

Oral Surg Oral Med Oral Pathol Oral Radiol 2021 Jul 21. Epub 2021 Jul 21.

Department of Head and Neck Surgery and Otorhinolaryngology, A.C. Camargo Cancer Center, Sao Paulo, Brazil. Electronic address:

Objective: The presence of lymphatic and blood vessels in oral squamous cell carcinoma (OSCC) should play a key role in progression and dissemination. This study aimed to evaluate the correlation between the lymphatic and blood vessel densities with prognostic outcomes in advanced stage OSCC.

Study Design: Immunohistochemical reactions for D-240, CD34, and CD105 were performed in 88 advanced stage OSCC cases located at the oral tongue and the floor of the mouth. The lymphatic vascular density (LVD), blood vascular density (BVD), and neoformed vascular density (NVD) were assessed by counting positive reactions in 4 hotspot areas, both intratumoral (IT) and peritumoral (PT), at high magnification (× 40).

Results: High IT LVD was associated with extracapsular spread of lymph node metastasis (P = .03). Recurrence rates were correlated with IT LVD (P < .0001), IT BVD (P = .036), and IT NVD (P = .047), and overall survival was associated with high IT LVD (P = .0016) and IT NVD (P = .009). Yet, IT LVD was an independent factor for disease-free survival and for overall survival based on the Cox proportional hazards model.

Conclusions: Our results suggest that high IT LVD has a strong impact on survival outcomes in advanced stage OSCC.
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http://dx.doi.org/10.1016/j.oooo.2021.07.014DOI Listing
July 2021

A rare case of Ewing sarcoma metastasis to the oral cavity.

Imaging Sci Dent 2021 Jun 11;51(2):217-222. Epub 2021 Mar 11.

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

Ewing sarcoma in the head and neck is rare, and metastasis from other bones to the mandible accounts for 0.7% of cases. This report presents a case of oral metastasis in a 24-year-old male patient diagnosed with Ewing sarcoma of the femur (p53 gene mutation and fusion). The chief complaint was numbness in the mandible and pain for 1 month and a hardened, ulcerated exophytic lesion in the right retromolar region. Imaging exams revealed an unspecified thinning of the cortical bone of the inferior alveolar canal in the right mandibular ramus, associated with erosion of the alveolar bone. Histopathological analysis confirmed metastasis of Ewing sarcoma. The patient presented an aggressive disease progression and died 1 month after the oral diagnosis. It is important to recognize the signs and symptoms compatible with rare clinical outcomes, leading to an early diagnosis that can improve patients' quality of life and survival.
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http://dx.doi.org/10.5624/isd.20200318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219447PMC
June 2021

Pigmented lesion on the face: which is the chance of being melanoma using reflectance confocal microscopy features?

Arch Dermatol Res 2021 Jun 21. Epub 2021 Jun 21.

Derma Image, São Paulo, SP, Brazil.

Facial melanoma presents itself as a brownish macula, being difficult to differentiate it from benign pigmented lesions of the face on clinical examination. Reflectance confocal microscopy (RCM) assists in diagnosing facial lesions in which dermoscopy has limitations, allowing to increase the diagnostic accuracy. The study aimed to analyze the RCM features of pigmented isolated lesions of the face for diagnosing melanoma. Also, we sought to establish the chance of a pigmented lesion on the face being a melanoma using RCM criteria. In this retrospective and prospective study, 105 clinical pigmented lesions on the face underwent RCM, and cytoarchitectural features in the epidermis, the dermo-epidermal junction (DEJ), and dermis were described. For statistical analysis, the exact chi-square test was applied to the RCM criteria. The odds ratio was estimated using univariate logistic regression. Finally, we used the multiple logistic regression method for creating a nomogram to predict the chance of a lesion being a melanoma. After univariate and multivariate logistic regression, atypical round nucleated cells within the epidermis, pagetoid spread, and follicular dendritic cells presented as statistically significant features. Then, a complex nomogram was created to give the chance of a pigmented lesion on the face being a melanoma. The presence of these three features resulted in a 98% probability for melanoma. This study allowed to estimate the diagnosis of melanoma on the face, using RCM, practicable and feasible in the daily routine, through the presence of some RCM nomogram criteria.
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http://dx.doi.org/10.1007/s00403-021-02263-6DOI Listing
June 2021

Effect of antioxidant treatment with n-acetylcysteine and swimming on lipid expression of sebaceous glands in diabetic mice.

Sci Rep 2021 Jun 7;11(1):11924. Epub 2021 Jun 7.

Morphology and Basic Pathology Department, Jundiaí Medical School (JMS) Jundiaí, Francisco Telles, 250 - Vila Arens II, 1109, Jundiaí, SP, 13202-550, Brazil.

The sebaceous gland (SG) is involved in different inflammatory, infectious and neoplastic processes of the skin and can be related to specific diseases, e.g., diabetes mellitus. Sometimes, the histological diagnosis requires complementary tests due to the ability of diseases to mimic other tumors. We evaluated the sebaceous gland density in Non-obese diabetic mice to analyze the N-acetylcystein effects and swimming exercise treatment in sebaceous glands healing, using specific staining in histochemistry and immunohistochemistry reactions in the identification of the lipid expression in the sebaceous gland. We investigated the intracytoplasmic lipid expression and analysis of gland density from SG in dorsal skin samples from the Non-obese diabetic (NOD mice) and diabetic animals submitted to antioxidant treatment and physical exercise. For histological analysis of the sebaceous glands, specific staining in histochemistry with sudan black and immunohistochemistry reaction with adipophilin were used in the evaluation. Statistical analysis showed significant proximity between the values of the control group and the diabetic group submitted to the swimming exercise (DS group) and similar values between the untreated diabetic group (UD group) and diabetic group treated with the antioxidant N-acetylcysteine (DNa group), which did not prevent possible differences where p < 0.01. Adipophilin (ADPH) immunohistochemistry permitted more intense lipid staining in SGs, the preservation of the SG in the control group, and a morphological deformed appearance in the UD and DNa groups. However, weak morphological recovery of the SG was observed in the DS-Na group, being more expressive in the DS group. In conclusion, the groups submitted to physical exercises showed better results in the recovery of the analyzed tissue, even being in the physiological conditions caused by spontaneous diabetes.
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http://dx.doi.org/10.1038/s41598-021-91459-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184763PMC
June 2021

Neonatal consequences of maternal exposure to the chikungunya virus: Case reports.

Medicine (Baltimore) 2021 Apr;100(17):e25695

Laboratory of Paediatric Infectology, Jundiaí School of Medicine.

Rationale: The chikungunya virus (CHIKV) was first isolated in a Tanzanian epidemic area between 1952 and 1953. The best description of the CHIKV transmission during pregnancy can be found in a well-documented epidemic in 2005, in the "La Reunion" island, a French territory located in the Indian Ocean, in which about one-third of the population was infected. Reports of arbovirus infections in pregnancy are increasing over time, but the spectrum of clinical findings remains an incognita among researchers, including CHIKV.

Patient Concerns: In this report, it was possible to verify 2 cases exposed to CHIKV during foetal period and the possible implications of the infection on gestational structures and exposed children after the birth.

Diagnosis: In both cases, the mothers were positive by laboratory tests in serologic analysis for CHIKV, as ezyme-linked immunossorbent assay (ELISA), plaque reduction neutralisation testing (PRNT) and immunofluorescence (IF); but there were no positive tests in quantitative polymerase chain reaction (qPCR) for mothers or children.

Interventions: The exposed children were followed up in a paediatrics clinic in order not only to provide the medical assistance, but also to verify child development and the possible implications and neurocognitive changes caused by gestational infection.

Outcomes: There were neurological and developmental changes in one of the children followed up on an outpatient basis. There was an improvement in the neurological situation and symptoms only 3 years and 1 month after birth.

Lessons: Based on the cases presented, we can conclude that clinical symptoms of CHIKV maternal infection may occur late in new-borns and can affect their development.
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http://dx.doi.org/10.1097/MD.0000000000025695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084008PMC
April 2021

Prognostic Implications of ALDH1 and Notch1 in Different Subtypes of Oral Cancer.

J Oncol 2021 13;2021:6663720. Epub 2021 Feb 13.

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

Background: The present study aimed to investigate the clinical significance and prognostic value of the immunoexpression of cancer stem cell markers, ALDH1 and Notch1, in subtypes of oral squamous cell carcinoma.

Materials And Methods: The expression of ALDH1 and Notch1 in 63 patients with well and poorly differentiated oral squamous cell carcinomas and their subtypes, verrucous carcinoma and basaloid squamous cell carcinoma, was evaluated by immunohistochemistry. The semi-quantitative analysis of the ALDH1 and Notch immunoexpression levels, based on the capture of 10 microscopic fields, at 400X magnification, at the invasive tumor front was performed and associated with clinicopathological variables using the chi-square test or Fisher's exact test. The overall and disease-free survival rates were estimated according to the Kaplan-Meier method and the curves were compared using the log-rank test. The independent effects of variables were calculated using Cox's proportional hazards regression model.

Results: Strong ALDH1 and Notch1 expression was observed in 16 (25.4%) and 27 (42.9%) oral squamous cell carcinomas including their subtypes, respectively. Most tumors with strong immunoexpression of ALDH1 were basaloid squamous cell carcinoma (56.3%). Statistically significant associations were observed between the strong immunoexpression of Notch1 in poorly differentiated oral squamous cell carcinoma with perineural infiltration ( = 0.011) and lymph node involvement (pN+) ( = 0.034). The strong immunoexpression of ALDH1 was a prognostic factor associated with worse overall survival ( = 0.040) for patients with oral cancer.

Conclusion: The strong immunoexpression of Notch1 can contribute to identification of patients with poorly differentiated oral squamous cell carcinoma, who have perineural infiltration or lymph node metastasis. In addition, the strong immunoexpression of ALDH1 may help to identify a worse prognosis in patients with oral squamous cell carcinoma and their subtypes.
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http://dx.doi.org/10.1155/2021/6663720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020805PMC
February 2021

Increased Tumor Immune Microenvironment CD3+ and CD20+ Lymphocytes Predict a Better Prognosis in Oral Tongue Squamous Cell Carcinoma.

Front Cell Dev Biol 2020 18;8:622161. Epub 2021 Feb 18.

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

Oral tongue squamous cell carcinoma (OTSCC) causes over 350,000 cases annually and particularly impacts populations in developing countries. Smoking and alcohol consumption are major risk factors. Determining the role of the tumor immune microenvironment (TIME) in OTSCC outcomes can elucidate immune mechanisms behind disease progression, and can potentially identify prognostic biomarkers. We performed a retrospective study of 48 OTSCC surgical specimens from patients with tobacco and alcohol exposures. A panel of immunoregulatory cell subpopulations including T (CD3, CD4, CD8) and B (CD20) lymphocytes, dendritic cells (CD1a, CD83), macrophages (CD68), and immune checkpoint molecules programmed cell death protein 1 (PD-1) and ligand 1 (PD-L1) were analyzed using immunohistochemistry. The levels of immune effector cell subpopulations and markers were analyzed in relation to overall survival. Pathological characteristics of the tumor microenvironment included inflammatory infiltrates (83.3%), desmoplasia (41.6%), and perineural invasion (50.0%). The TIME contained high levels of T cells (CD3+, CD4+, and CD8+) and B cells (CD20+), as well as immature (CD1a) and mature (CD83) dendritic cells, PD-1, and PD-L1. Higher numbers of TIME infiltrating CD3+ T cells and CD20+ B cells were predictive of better survival, while higher levels of CD83+ mature dendritic cells predicted better survival. CD3+ T cells were identified as an independent prognostic marker for OTSCC. Lastly, CD3+ T cells were strongly correlated with the number of CD8+ cells and PD-L1 expression. Our findings provide evidence that the TIME profile of OTSSC impacted prognosis. The high expression of CD3+ T cells and B cells are predictive of better overall survival and indicative of an immunologically active, inflammatory TIME in patients with better survival. The number of CD3+ T cells was an independent prognostic marker.
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http://dx.doi.org/10.3389/fcell.2020.622161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951138PMC
February 2021

How does the mitotic index impact patients with T1 melanoma? Comparison between the 7th and 8th edition of the American Joint Committee on Cancer melanoma staging system.

An Bras Dermatol 2020 Nov - Dec;95(6):691-695. Epub 2020 Sep 18.

AC Camargo Cancer Center, São Paulo, SP, Brazil.

Background: The mitotic index is no longer used to classify T1 melanoma patients into T1a and T1b, so it should not be used to indicate sentinel node biopsy in these patients.

Objectives: To evaluate patients with T1 melanoma who underwent sentinel lymph node biopsy and to compare those who were classified as T1a with those classified T1b, according to the 7th and 8th Edition of the melanoma staging system, regarding a positive biopsy result. The authors also aimed to assess whether there is any difference in the results in both staging systems.

Material And Methods: This was a retrospective analysis of 1213 patients who underwent sentinel lymph node biopsy for melanoma, from 2000 to 2015, in a single institution.

Results: Of 399 patients with thin melanomas, 27 (6.7%) presented positive sentinel lymph nodes; there was no difference in positivity for sentinel node biopsy when comparing T1a vs. T1b in both staging systems. Furthermore, the clinical results were also similar between the two groups. However, in the complete cohort analysis, the mitotic index was associated with positivity for sentinel lymph node biopsy (p < 0.0001), positivity for non-sentinel lymph node (p < 0.0001), recurrence-free survival (p < 0.0001), and specific melanoma survival (p = 0.023).

Study Limitation: Unicentric study.

Conclusion: The mitotic index was shown to be a very important prognostic factor in the present study, but it was not observed in patients classified as T1. The mitotic index should no longer be used as the only reason to refer sentinel lymph node biopsy in patients with thin melanoma.
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http://dx.doi.org/10.1016/j.abd.2020.03.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672494PMC
November 2020

Characterization of BRAF mutation in patients older than 45 years with well-differentiated thyroid carcinoma.

Braz J Otorhinolaryngol 2020 Sep 12. Epub 2020 Sep 12.

A.C. Camargo Cancer Center, Departamento de Cirurgia de Cabeça e Pescoço e Otorrinolaringologia, Sao Paulo, SP, Brazil; Faculdade de Medicina da USP, São Paulo, SP, Brazil. Electronic address:

Introduction: Papillary thyroid carcinoma is the most frequent endocrine neoplasia and its incidence has tripled over the past 35 years. Although papillary thyroid carcinoma carries a good prognosis, 10%-30% of patients still develop recurrence and metastasis. Some clinical and genetic features are associated with worse prognosis. The most frequent mutation is the BRAF p.V600E, which has been associated with many clinical features of poor prognosis. However, many studies have produced controversial results without any association between BRAF mutation and clinicopathological features of poor prognosis.

Objective: Since the prognostic value of BRAF mutations remains controversial, this study aims to investigate the importance of this mutation in therapeutic decisions for papillary thyroid carcinoma.

Methods: Therefore, we evaluated whether the presence of BRAF mutation is associated with features of poor prognosis in 85 patients with papillary thyroid carcinoma older than 45 years treated at A.C. Camargo Cancer Center, from 1980 to 2007. BRAF mutation was evaluated by pyrosequencing. Statistical analysis was performed using SPSS.

Results: The mean age of patients was 54 years (range: 45 - 77 years), 73 were women (85.8%) and 12 were men (14.2%). Among them, 39 cases (45.9%) presented extrathyroidal extension and 11 cases had recurrent disease. BRAF mutation was detected in 57 (67%) patients. No significant association was observed between BRAF mutation and gender (p  = 0.743), age (p  = 0.236), N-stage (p  = 0.423), vascular and perineural infiltration (p  = 0.085 or multifocality (p  = 1.0). Although not statistically significant, the majority of patients with recurrent disease were BRAF positive (9 out of 11) (p  = 0.325). Patients affected by BRAF mutation are associated with tumors larger than 1 cm (p  = 0.034) and with extrathyroidal extension (p  = 0.033).

Conclusion: Although BRAF testing is widely available, there are no consistent data to support improvement in outcomes from incorporating it into therapeutic decision for thyroid cancer.
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http://dx.doi.org/10.1016/j.bjorl.2020.07.007DOI Listing
September 2020

Claudin expression is maintained in mucoepidermoid carcinoma of the salivary gland.

Pathol Res Pract 2020 Nov 11;216(11):153161. Epub 2020 Aug 11.

General Pathology Department, Dental School, University of São Paulo, Brazil.

Objective: The aim of the present study was to investigate the expression of claudin-1, -3, -4, -5 and -7 proteins in mucoepidermoid carcinoma of oral cavity and analyze whether EGF may interfere in the expression of the genes that encode claudins using in vitro models.

Material And Methods: Using immunohistochemistry, the expression of claudins was searched in 36 histologically graded cases of mucoepidermoid carcinoma. The association of expression of claudins with clinical-pathological parameters was evaluated. An in vitro step investigated the influence of EGF on gene expression of claudins by real time RT-PCR technique.

Results: Claudin-1, -3, -4, -5, and -7 were highly expressed in most mucoepidermoid carcinomas. These expressions were compared with clinicopathological parameters. High expression of claudin-1 was associated with patients over 40 years-old (p = 0.05) and Caucasians (p = 0.024). In vitro experiments demonstrated a tendency for Claudin gene expression increase after EGF stimulus.

Conclusions: The expression of claudins is maintained in mucoepidermoid carcinoma cells and EGF could be related with this expression. Our results point out to a fundamental biological importance to CLDNs in normal and neoplastic tissue. The expression patterns of CLDNs does not yet allow a clinical application, but the biological knowledge will ground evidence to new studies towards possible target-therapies.
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http://dx.doi.org/10.1016/j.prp.2020.153161DOI Listing
November 2020

Sentinel Node Status is the Most Important Prognostic Information for Clinical Stage IIB and IIC Melanoma Patients.

Ann Surg Oncol 2020 Oct 7;27(11):4133-4140. Epub 2020 Aug 7.

Skin Cancer Department, A. C. Camargo Cancer Center, São Paulo, SP, Brazil.

Background: Sentinel node biopsy (SNB) for melanoma patients has been questioned. We aimed to study high-risk stage II melanoma patients who underwent SNB to determine what the prognostic factors regarding recurrence and mortality were, and evaluate how relevant SNB status is in this scenario.

Methods: This was a retrospective analysis of clinical stage IIB/IIC melanoma patients who underwent SNB from 2000 to 2015 in a single institution. Prognostic factors related to distant recurrence-free survival (DRFS) and melanoma-specific survival (MSS) were assessed from multiple Cox regression. Relevant variables were used to create risk predictor nomograms for DRFS and MSS.

Results: From 1213 SNB, 259 were performed for clinical stage IIB/IIC melanoma patients. SNB status was the most important variable for both endpoints. Patients with positive SNB presented median DRFS of 35.73 months (95% CI 21.38-50.08, SE 7.32) and median MSS of 66.4 months (95% CI 29.76-103.03, SE 18.69), meanwhile both median DRFS and MSS were not achieved for those with negative SNB (logrank < 0.0001). Both nomograms have been internally validated and presented adequate calibration (C-index was 0.734 for DRFS and 0.718 for MSS).

Conclusions: SNB status was the most important risk factor in our cohort of clinical stage IIB and IIC patients and, in conjunction with well-established primary tumor characteristics, should not be abandoned. Their use in prognosis for these patients remains extremely useful for daily practice.
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http://dx.doi.org/10.1245/s10434-020-08959-9DOI Listing
October 2020

Retrospective application of the Milan System for reporting salivary gland cytopathology: A Cancer Center experience.

Diagn Cytopathol 2020 Sep 6;48(9):821-826. Epub 2020 May 6.

Department of Pathology, Santa Casa Medical School, São Paulo, Brazil.

Background: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) was recently proposed. Herein, we retrospectively applied this nomenclature system to salivary gland lesions sampled by ultrasound-guided fine-needle aspiration (FNA).

Methods: All cases of salivary gland FNA with available surgical follow-up, in the period from 2014 to 2017 at our institution were reviewed and reclassified according to one of the six categories of the MSRSGC, blind to the surgical outcome. Overall sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated, as well as risks of neoplasm (RON) and risk of malignancy (ROM) for each of the proposed categories.

Results: There were 104 salivary gland lesions, with a female predominance (57.7%), most cases from the parotid gland (89.4%). Mean age was 53.2 years. Distribution of the specimens according to the Milan System was as follows: 19.2% nondiagnostic (ND), 8.7% non-neoplastic (NN), 9.6% atypia of undetermined significance (AUS), 40.4% benign neoplasm (BN), 14.4% salivary gland neoplasm of uncertain malignant potential (SUMP), 1.9% suspicious for malignancy (SFM), and 5.8% malignant. Sensitivity, specificity, PPV, and NPV using MSRSGC were calculated as 75%, 98.4%, 88.9%, and 95.3%, respectively. RON/ROM for each category were 60%/15% for ND, 44.4%/0% for NN, 90%/40% for AUS, 100%/9.5% for BN, 100%/13.3% for SUMP, 50%/50% for SFM and 100%/100% for malignant.

Conclusion: The use of the Milan System proved to be a useful method to predict the risk of neoplasm and malignancy in the sample studied, with high sensitivity and specificity.
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http://dx.doi.org/10.1002/dc.24464DOI Listing
September 2020

Response rates of cutaneous melanoma metastases to diphencyprone: A meta-analysis.

J Am Acad Dermatol 2020 Dec 11;83(6):1812-1813. Epub 2020 Apr 11.

Skin Cancer Department, A.C. Camargo Cancer Center, São Paulo, SP, Brazil.

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http://dx.doi.org/10.1016/j.jaad.2020.04.023DOI Listing
December 2020

Increased DSG2 plasmatic levels identified by transcriptomic-based secretome analysis is a potential prognostic biomarker in laryngeal carcinoma.

Oral Oncol 2020 04 19;103:104592. Epub 2020 Feb 19.

Department of Clinical Genetics, University Hospital, Institute of Regional Health Research, University of Southern Denmark, Vejle, Denmark. Electronic address:

Objectives: The tumor secretome deconvolution is a promising strategy to identify diagnostic and prognostic biomarkers. Here, transcriptomic-based secretome analysis was performed aiming to discover laryngeal squamous cell carcinomas (LSCC) biomarkers from potentially secreted proteins (PSPs).

Material And Methods: The tumor expression profile (35 LSCC biopsies compared with surrounding normal tissues - SN) revealed 589 overexpressed genes. This gene list was used for secretome analysis based on laryngeal tumors and related secretome databases.

Results: Forty-nine (Laryngeal tumor secretome database) and 50 (Human Protein Atlas and Cancer Secretome Database) PSPs presented an association with worse overall survival. Specifically, DSG2 overexpression was strongly correlated with poor survival and distant metastasis. DSG2 increased expression was confirmed in the LSCC dataset (LSCC = 111; SN = 12) from TCGA. A significant association between shorter survival and DSG2 overexpression was also detected. In an independent cohort of cases, we analyzed and confirmed high protein levels of DSG2 in plasma from LSCC patients.

Conclusion: A set of PSPs including the circulating DSG2, were associated with shorter overall survival in LSCC. DSG2 overexpression was also correlated with distant metastasis. The high plasmatic protein levels of DSG2 suggest its potential to be tested in liquid biopsies and applied as prognostic biomarker of LSCC.
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http://dx.doi.org/10.1016/j.oraloncology.2020.104592DOI Listing
April 2020

Aquaporin 1, 3, and 5 Patterns in Salivary Gland Mucoepidermoid Carcinoma: Expression in Surgical Specimens and an In Vitro Pilot Study.

Int J Mol Sci 2020 Feb 14;21(4). Epub 2020 Feb 14.

International Research Center, A.C.Camargo Cancer Center, Rua Taguá 440, São Paulo 01508-010, Brazil.

Salivary gland aquaporins (AQPs) are essential for the control of saliva production and maintenance of glandular structure. However, little is known of their role in salivary gland neoplasia. Salivary gland tumors comprise a heterogeneous group of lesions, featuring variable histological characteristics and diverse clinical behaviors. Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy. The aim of this study was to evaluate the expression of AQP1, AQP3, and AQP5 in 24 MEC samples by immunohistochemistry. AQP1 expression was observed in vascular endothelium throughout the tumor stroma. AQP3 was expressed in epidermoid and mucosal cells and AQP5 was expressed in mucosal cells of MEC. These proteins were expressed in the human MEC cell line UH-HMC-3A. Cellular ultrastructural aspects were analyzed by electron microscopy to certificate the tumor cell phenotype. In summary, our results show that, despite the fact that these molecules are important for salivary gland physiology, they may not play a distinct role in tumorigenesis in MEC. Additionally, the in vitro model may offer new possibilities to further investigate mechanisms of these molecules in tumor biology and their real significance in prognosis and possible target therapies.
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http://dx.doi.org/10.3390/ijms21041287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073006PMC
February 2020

Proliferating trichilemmal cyst with clinical, radiological, macroscopic, and microscopic correlation.

An Bras Dermatol 2019 17;94(4):452-454. Epub 2019 Oct 17.

Department of Pathology, A.C. Camargo Cancer Center, São Paulo (SP), Brazil.

Proliferating trichilemmal cyst is an uncommon neoplasm arising from the follicular isthmus, whose histopathological hallmark is the presence of trichilemmal keratinization. We describe a case of proliferating trichilemmal cyst in a 57-year-old woman with a broad clinical, radiological, macroscopic and microscopic correlation.
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http://dx.doi.org/10.1590/abd1806-4841.20198199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007035PMC
October 2019

Bronchial carcinoid tumors: second primary neoplasms and outcomes of surgical treatment.

J Bras Pneumol 2019 Sep 16;45(5):e20180140. Epub 2019 Sep 16.

. A.C. Camargo Cancer Center, São Paulo (SP) Brasil.

Objective: To analyze determinants of prognosis in patients with bronchial carcinoid tumors treated surgically and the potential concomitance of such tumors with second primary neoplasms.

Methods: This was a retrospective analysis of 51 bronchial carcinoid tumors treated surgically between 2007 and 2016. Disease-free survival (DFS) was calculated by the Kaplan-Meier method, and determinants of prognosis were evaluated. Primary neoplasms that were concomitant with the bronchial carcinoid tumors were identified by reviewing patient charts.

Results: The median age was 51.2 years, 58.8% of the patients were female, and 52.9% were asymptomatic. The most common histology was typical carcinoid (in 80.4%). Five-year DFS was 89.8%. Ki-67 expression was determined in 27 patients, and five-year DFS was better among the patients in whom Ki-67 expression was ≤ 5% than among those in whom it was > 5% (100% vs. 47.6%; p = 0.01). Concomitant primary neoplasms were observed in 14 (27.4%) of the 51 cases. Among the concomitant primary neoplasms that were malignant, the most common was lung adenocarcinoma, which was observed in 3 cases. Concomitant primary neoplasms were more common in patients who were asymptomatic and in those with small tumors.

Conclusions: Surgical resection is the mainstay treatment of bronchopulmonary carcinoid tumors and confers a good prognosis. Bronchial carcinoid tumors are likely to be accompanied by second primary neoplasms.
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http://dx.doi.org/10.1590/1806-3713/e20180140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247769PMC
September 2019

Breast sarcoidosis as the first manifestation of the disease.

Breast J 2020 03 8;26(3):543-544. Epub 2019 Sep 8.

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

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http://dx.doi.org/10.1111/tbj.13560DOI Listing
March 2020

DNA Methylation-Based Method to Differentiate Malignant from Benign Thyroid Lesions.

Thyroid 2019 09 16;29(9):1244-1254. Epub 2019 Aug 16.

Department of Clinical Genetics, Vejle Hospital, Institute of Regional Health Research, University of Southern Denmark, Vejle, Denmark.

The differential diagnosis of thyroid nodules using fine-needle aspiration biopsy (FNAB) is challenging due to the inherent limitation of the cytology tests. The use of molecular markers has potential to complement the FNAB-based diagnosis and avoid unnecessary surgeries. In this study, we aimed to identify DNA methylation biomarkers and to develop a diagnostic tool useful for thyroid lesions. Genome-wide DNA methylation profiles (Illumina 450K) of papillary thyroid carcinoma (PTC = 60) and follicular thyroid carcinoma (FTC = 10) were compared with non-neoplastic thyroid tissue samples (NT = 50) and benign thyroid lesions (BTL = 17). The results were confirmed in publicly available databases from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) using the same DNA methylation platform. Two classifiers were trained to discriminate FTC and PTC from BTL. To increase the applicability of the method, six differentially methylated CpGs were selected and evaluated in 161 thyroid tumors and 69 BTL postsurgical specimens and 55 prospectively collected FNAB using bisulfite-pyrosequencing. DNA methylation analysis revealed 2130 and 19 differentially methylated CpGs in PTC and FTC, respectively. The CpGs confirmed by GEO and TCGA databases showing high areas under the receiver operating characteristic curve in all sample sets were used to train our diagnostic classifier. The model based on six CpGs was able to differentiate benign from malignant thyroid lesions with 94.3% sensitivity and 82.4% specificity. A similar performance was found applying the algorithm to TCGA and GEO external data sets (91.3-97.4% sensitivity and 87.5% specificity). We successfully evaluated the classifiers using a bisulfite-pyrosequencing technique, achieving 90.7% sensitivity and 75.4% specificity in surgical specimens (five of six CpGs). The study comprising FNAB cytology materials corroborated the applicability and performance of the methodology, demonstrating 86.7% sensitivity and 89.5% specificity in confirmed malignant tumors, and 100% sensitivity and 89% specificity in cases with indeterminate cytology. A novel diagnostic tool with potential application in preoperative screening of thyroid nodules is reported here. The proposed protocol has the potential to avoid unnecessary thyroidectomies.
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http://dx.doi.org/10.1089/thy.2018.0458DOI Listing
September 2019

Promoter Hypomethylation as Recurrence Predictive Marker in Well-Differentiated Thyroid Carcinomas.

Int J Mol Sci 2019 Mar 16;20(6). Epub 2019 Mar 16.

Department of Clinical Genetics, Vejle Hospital, Institute of Regional Health Research, University of Southern Denmark, 7100 Vejle, Denmark.

Despite the low mortality rates, well-differentiated thyroid carcinomas (WDTC) frequently relapse. and mutations have been extensively related to prognosis in thyroid cancer. In this study, the methylation levels of selected CpGs (5-cytosine-phosphate-guanine-3) comprising a classifier, previously reported by our group, were assessed in combination with and mutations. We evaluated 121 WDTC, three poorly-differentiated/anaplastic thyroid carcinomas (PDTC/ATC), 22 benign thyroid lesions (BTL), and 13 non-neoplastic thyroid (NT) tissues. (V600E) and promoter (C228T and C250T) mutations were tested by pyrosequencing and Sanger sequencing, respectively. Three CpGs mapped in , , and were evaluated by bisulfite pyrosequencing. hypermethylation and hypomethylation were detected in poor-prognosis (PDTC/ATC and relapsed WDTC) compared with good-prognosis (no relapsed WDTC) and non-malignant cases (NT/BTL). was hypomethylated in both poor and good-prognosis cases. Shorter disease-free survival was observed in WDTC patients presenting lower methylation levels ( = 0.004). No association was observed on comparing (60.7%) and (3.4%) mutations and prognosis. Lower methylation levels was an independent factor of high relapse risk (Hazard Ratio = 3.2; CI = 1.1⁻9.5). promoter methylation analysis has potential applicability to better stratify WDTC patients according to the recurrence risk, independently of and mutations.
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http://dx.doi.org/10.3390/ijms20061334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471408PMC
March 2019

Ameloblastoma with distinctive granular cell pattern: an 8 case study.

Autops Case Rep 2018 Oct-Dec;8(4):e2018052. Epub 2018 Oct 9.

Universidade de São Paulo (USP), School of Dentistry, Department of Stomatology. São Paulo, SP, Brazil.

Ameloblastoma with granular cell pattern (AGC) is classified as an unusual histological subtype of solid/multicystic ameloblastoma, characterized by granular changes in stellate-like cells located within the inner portion of the epithelial follicles. Studies have revealed that lysosomal overload causes cytoplasmic granularity; however, the mechanism involved remains poorly understood. Here we report on eight cases of granular cell ameloblastoma, in the posterior region of the mandible. The age of the patients included in this case series ranged from 35 -64 years old and 87.5% of cases occurred in non-Caucasians, with a slight gender predilection for men (62.5%). There was no evidence of recurrence, and the majority of the cases were treated with surgical resection (87.5%). All tumors displayed histopathological features consistent with the diagnosis of ameloblastoma with granular cell pattern.
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http://dx.doi.org/10.4322/acr.2018.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360828PMC
October 2018

Validation of a Nomogram for Non-sentinel Node Positivity in Melanoma Patients, and Its Clinical Implications: A Brazilian-Dutch Study.

Ann Surg Oncol 2019 Feb 19;26(2):395-405. Epub 2018 Nov 19.

Department of Surgical Oncology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.

Background: Non-sentinel node (NSN) positivity impacts the prognosis of melanoma patients; however, the benefits of completion lymph node dissection in patients with positive sentinel nodes (SNs) are limited.

Objective: We aimed to present a predictive nomogram for NSN positivity in melanoma patients with a positive SN biopsy.

Methods: This retrospective analysis from patients who underwent SN biopsy in a Brazilian institution from 2000 to 2015 was used for the construction and internal validation of the nomogram. This nomogram was then externally validated in a cohort of Dutch patients.

Results: The Brazilian cohort comprised 1213 patients, with a mean follow-up of 5.11 years. Breslow thickness (odds ratio [OR] 1.170, 95% confidence interval [CI] 1.043-1.314]; p = 0.008), number of positive SNs (OR 1.092, 95% CI 1.034-1.153; p = 0.001), and largest diameter of the metastatic deposit (OR 3.217, 95% CI 1.551-6.674; p = 0.002) were statistically significant for NSN positivity. Internal validation was performed using a bootstrapping technique. A good performance was observed (Brier score 0.097) and an excellent power of discrimination was achieved (area under the curve [AUC] 0.822). The nomogram was then applied to the Dutch cohort, and its overall performance (Brier score 0.085), calibration (Hosmer-Lemeshow goodness-of-fit test; p = 0.198), and discriminatory power (AUC 0.752, 95% CI 0.615-0.890) were all adequate.

Conclusions: We presented a nomogram for assessing NSN probability that should not only be used for surgical considerations but also for risk stratification and clinical decisions. Internal validation has shown that this is an adequate model, while external validation increases the model's reliability and suggests that it can be globally incorporated.
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http://dx.doi.org/10.1245/s10434-018-7038-9DOI Listing
February 2019

Loss of DNA methylation is related to increased expression of miR-21 and miR-146b in papillary thyroid carcinoma.

Clin Epigenetics 2018 11 20;10(1):144. Epub 2018 Nov 20.

Department of Clinical Genetics, Vejle Hospital, Institute of Regional Health Research, University of Southern Denmark, Beriderbakken 4, 7100, Vejle, Denmark.

Background: DNA methylation in miRNA genes has been reported as a mechanism that may cause dysregulation of mature miRNAs and consequently impact the gene expression. This mechanism is largely unstudied in papillary thyroid carcinomas (PTC).

Methods: To identify differentially methylated miRNA-encoding genes, we performed global methylation analysis (Illumina 450 K), integrative analysis (TCGA database), data confirmation (pyrosequencing and RT-qPCR), and functional assays.

Results: Methylation analysis revealed 27 differentially methylated miRNA genes. The integrative analyses pointed out miR-21 and miR-146b as potentially regulated by methylation (hypomethylation and increased expression). DNA methylation and expression patterns of miR-21 and miR-146b were confirmed as altered, as well as seven of 452 mRNAs targets were down-expressed. The combined methylation and expression levels of miR-21 and miR-146b showed potential to discriminate malignant from benign lesions (91-96% sensitivity and 96-97% specificity). An increased expression of miR-146b due to methylation loss was detected in the TPC1 cell line. The miRNA mimic transfection highlighted putative target mRNAs.

Conclusions: The increased expression of miR-21 and miR-146b due to loss of DNA methylation in PTC resulted in the disruption of the transcription machinery and biological pathways. These miRNAs are potential diagnostic biomarkers, and these findings provide support for future development of targeted therapies.
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http://dx.doi.org/10.1186/s13148-018-0579-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6245861PMC
November 2018

A nomogram to identify high-risk melanoma patients with a negative sentinel lymph node biopsy.

J Am Acad Dermatol 2019 Mar 2;80(3):722-726. Epub 2018 Nov 2.

Skin Cancer Department, AC Camargo Cancer Center, São Paulo, Brazil.

Background: Melanoma patients with negative nodes after sentinel lymph node biopsy are a heterogeneous group. Current guidelines fail to adequately stratify surveillance and treatment for this group. Also, there is scarce data on adjuvant treatments for these patients.

Objective: To create a nomogram including clinical and pathologic characteristics capable of evaluating the risk for recurrence of primary melanoma patients with negative sentinel lymph node biopsies (SLNBs).

Methods: We used a retrospective cohort of patients who underwent SLNB during 2000-2015 at a single institution.

Results: Our cohort comprised 1213 patients. Among these patients, 967 (79.7%) had a negative SLNB, and mean follow-up was 59.67 months. There were 133 recurrences (13.8%); 45 (33.8%) presented with nodal recurrence, and 35 (26.3%) recurred where a SLNB was performed. Breslow thickness, ulceration, and microsatellitosis were found to be predictive of risk for recurrence at 1, 2, 5, and 10 years.

Limitation: Single center analysis.

Conclusion: We created a predictive nomogram for melanoma patients with negative SLNBs. This nomogram is easy to use and identifies high-risk patients who should have more strict surveillance and be considered for adjuvant treatment.
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http://dx.doi.org/10.1016/j.jaad.2018.10.060DOI Listing
March 2019

Use of an anionic collagen matrix made from bovine intestinal serosa for in vivo repair of cranial defects.

PLoS One 2018 12;13(7):e0197806. Epub 2018 Jul 12.

Department of Morphology and Pathology, Faculty of Medicine of Jundiaí, São Paulo, Brazil, Jundiaí -SP, Brazil.

Polymeric biomaterials composed of extracellular matrix components possess osteoconductive capacity that is essential for bone healing. The presence of collagen and the ability to undergo physicochemical modifications render these materials a suitable alternative in bone regenerative therapies. The objective of this study was to evaluate the osteogenic capacity of collagen-based matrices (native and anionic after alkaline hydrolysis) made from bovine intestinal serosa (MBIS). Twenty-five animals underwent surgery to create a cranial defect to be filled with native and anionic collagen matrixes, mmineralized and non mineralized. The animals were killed painlessly 6 weeks after surgery and samples of the wound area were submitted to routine histology and morphometric analysis. In the surgical area there was new bone formation projecting from the margins to the center of the defect. More marked bone neoformation occurred in the anionic matrices groups in such a way that permitted union of the opposite margins of the bone defect. The newly formed bone matrix exhibited good optical density of type I collagen fibers. Immunoexpression of osteocalcin by osteocytes was observed in the newly formed bone. Morphometric analysis showed a greater bone volume in the groups receiving the anionic matrices compared to the native membranes. Mineralization of the biomaterial did not increase its osteoregenerative capacity. In conclusion, the anionic matrix exhibits osteoregenerative capacity and is suitable for bone reconstruction therapies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197806PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6042682PMC
December 2018

Diphencyprone as a therapeutic option in cutaneous metastasis of melanoma. A single-institution experience.

An Bras Dermatol 2018 03;93(2):299-301

Skin Cancer Center, A.C. Camargo Cancer Center, São Paulo, SP, Brazil, Brazil.

Diphencyprone has been reported as a local immunotherapy for cutaneous melanoma metastases. We aim to report cases of melanoma patients treated with diphencyprone in a single Brazilian institution and highlight their outcomes. Since 2012, we have treated 16 melanoma patients with cutaneous metastases with topical diphencyprone. To date, we have had 37.5% of complete response, 25% of partial responses, and 31.25% patients without any response. Treatment was well tolerated and local toxicity was easily controlled. We believe topical diphencyprone is a feasible treatment that can be another option for treating melanoma patients, especially in cases of in-transit or extensive disease.
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http://dx.doi.org/10.1590/abd1806-4841.20187162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916415PMC
March 2018

Panniculitis associated with amyopathic dermatomyositis.

An Bras Dermatol 2018 Jan-Feb;93(1):119-121

Department of Pathology, Faculdade de Medicina de Jundiaí (FMJ) - Jundiaí (SP), Brasil.

Panniculitis is a rare clinical finding in dermatomyositis, with less than 30 cases reported and there is only one case associated with the amyopathic subtype described in the literature. The present report describes a 49-year-old female patient that one year after being diagnosed with amyopathic dermatomyositis, presented indurated, painful, erythematous to violaceous nodules located on the upper limbs, thighs and gluteal region. Skin biopsy revealed lobular panniculitis with a lymphocytic infiltrate. The patient was treated with prednisone and methotrexate, but remained unresponsive to treatment.
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http://dx.doi.org/10.1590/abd1806-4841.20186597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871377PMC
April 2018

EGFR is not amplified in ameloblastoma.

Oral Surg Oral Med Oral Pathol Oral Radiol 2018 05 6;125(5):454-458. Epub 2018 Mar 6.

Department of Biosciences and Oral Diagnosis, Institute of Science and Technology, São Paulo State University (Unesp), São José dos Campos, Brazil. Electronic address:

Objective: The aim of this study was to investigate alterations in the EGFR gene and its protein expression for a better understanding of the biologic behavior of ameloblastoma.

Study Design: Twenty-five samples of ameloblastoma were selected, and dual-color fluorescence in situ hybridization assay was performed. The results of the assay and immunohistochemistry reaction for EGFR and Ki67 were associated with clinicopathologic features and recurrence.

Results: All analyzed cases presented disomy without any gene polysomy or amplification. With regard to EGFR immunoexpression, 3 cases (12%) were considered negative, and 22 (88%) were positive, of which 13 (52%) were weak and 9 (36%) were strong. All samples presented low positivity for Ki67. There was no association between EGFR expression and clinicopathologic features or recurrence (P > .05). In some cases, EGFR immunoexpression was observed without gene amplification.

Conclusions: Ameloblastoma development, progression, or recurrence does not appear to be related to EGFR amplification or polysomy.
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http://dx.doi.org/10.1016/j.oooo.2018.02.014DOI Listing
May 2018

Prognostic implications of phosphatidylinositol 3-kinase/AKT signaling pathway activation in gastric carcinomas.

Arch Med Sci 2017 Oct 7;13(6):1262-1268. Epub 2016 Jun 7.

AC Camargo Cancer Center, São Paulo, Brazil.

Introduction: Activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway plays a critical role in carcinogenesis and resistance to anticancer drugs. In this study, gastric carcinomas (GC) were investigated and statistical analyses were performed concerning the correlation between the clinicopathological features and activation of the PI3K/AKT pathway.

Material And Methods: Immunohistochemistry for p-AKT, p-mTOR and PTEN was performed in 239 GC and 200 non-neoplastic gastric tissues. The clinicopathological parameters were recorded from the medical charts. Statistical significance was defined by a -value < 0.05.

Results: High p-AKT expression was observed in 10% of the normal gastric tissue and in 90% of GC, and it was significantly associated with tumor size ( < 0.001), T3/T4 tumors ( < 0.001), and presence of metastases ( = 0.02). Similarly, p-mTOR positivity was found in GC cells, but not in the normal gastric mucosa, and was correlated with perineural invasion ( = 0.02) and T3/T4 tumors ( = 0.03). On the other hand, PTEN expression was weak and focal in the tumor cells, while in the normal gastric tissue this staining was strong and diffuse. Importantly, the expression of p-mTOR and PTEN was associated with overall survival.

Conclusions: The results of the present study, characterized by the loss of PTEN expression and higher expression of p-AKT and p-mTOR in the majority of tumor cells, apparently are implicated in the carcinogenesis and progression of GC. The identification of p-mTOR and PTEN expression as prognostic factors corroborates the identification and use of potential target drugs that could be more efficient for the treatment of these patients.
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http://dx.doi.org/10.5114/aoms.2016.60394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701681PMC
October 2017
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