Publications by authors named "André Lopes Carvalho"

145 Publications

Sentinel lymph node biopsy for early squamous cell carcinoma of the lip and oral cavity: Real-world experience in Brazil.

Head Neck 2022 Apr 15. Epub 2022 Apr 15.

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

Background: This study aimed to evaluate the accuracy and oncological results of sentinel lymph node biopsy in patients with early lip and oral cavity squamous cell carcinoma (SCC) in a real-world scenario.

Methods: Retrospective study including seven Brazilian centers.

Results: Four-hundred and seven cN0 patients were accrued for 20 years. The rate of occult metastasis was 23.1% and 22 patients (5.4%) had regional failure. We found, for 5 years of follow-up, 85.3% of regional recurrence-free survival; 77.1% of disease-free survival; 73.7% of overall survival; and 86.7% of disease-specific survival. The rate of false-negative cases was 5.4%.

Conclusion: In a real-world scenario, sentinel lymph node biopsy for patients with SCC of the lip and oral cavity proved feasible in different settings and to be oncologically safe, with similar rates of occult lymph node metastasis and false-negative cases, when compared to elective neck dissection, and with similar long-term survival to that reported historically.
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http://dx.doi.org/10.1002/hed.27061DOI Listing
April 2022

Progressive Increase Trend in HPV-Related Oropharyngeal Squamous Cell Carcinoma in Brazil.

Int Arch Otorhinolaryngol 2022 Jan 13;26(1):e132-e136. Epub 2021 Aug 13.

Head and Neck Surgery Department, Hospital de Câncer de Barretos, Barretos, SP, Brazil.

 The prevalence of oropharyngeal squamous cell carcinoma (OSCC) related to Human Papillomavirus (HPV) is rising in the whole world.  To access the prevalence and temporal trend of HPV infection in oropharyngeal cancer by analyzing the expression of the p16 protein.  We conducted a transversal study in a Brazilian reference oncology center. The sample consisted of 254 patients with OSCC. The analyzed period was from 2013 to 2017. All patients underwent p16 immunohistochemistry analysis.  The overall prevalence of HPV-related OSCC was of 31.9%. During the analyzed period, we observed a trend of increasing rates of OSCC that marked positive for p16 immunohistochemistry. The annual prevalence of p16-positive cases was of 20.6% in 2013, 23.9% in 2014, 33.3% in 2015, 38.3% in 2016, and 34.2% in 2017. Most of the patients were stage III and IV (84%). Female patients (odds ratio [OR] = 2.43; 95% confidence interval [CI]: 1.003-5.888;  = 0.049) and younger patients (OR = 2.919; 95%CI: 1.682-5.067;  < 0.005) were associated with a higher risk of HPV-related OSCC. Tobacco consumption had a proportional lower risk of HPV-related OSCC (OR = 0.152; 95%CI: 0063-0.366;  < 0.005).  We observed an increasing prevalence of HPV-related OSCC in a specialized cancer hospital in Brazil.
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http://dx.doi.org/10.1055/s-0041-1730297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8789506PMC
January 2022

Comprehensive Molecular Landscape of Cetuximab Resistance in Head and Neck Cancer Cell Lines.

Cells 2022 01 4;11(1). Epub 2022 Jan 4.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, Brazil.

Cetuximab is the sole anti-EGFR monoclonal antibody that is FDA approved to treat head and neck squamous cell carcinoma (HNSCC). However, no predictive biomarkers of cetuximab response are known for HNSCC. Herein, we address the molecular mechanisms underlying cetuximab resistance in an in vitro model. We established a cetuximab resistant model (FaDu), using increased cetuximab concentrations for more than eight months. The resistance and parental cells were evaluated for cell viability and functional assays. Protein expression was analyzed by Western blot and human cell surface panel by lyoplate. The mutational profile and copy number alterations (CNA) were analyzed using whole-exome sequencing (WES) and the NanoString platform. FaDu resistant clones exhibited at least two-fold higher IC compared to the parental cell line. WES showed relevant mutations in several cancer-related genes, and the comparative mRNA expression analysis showed 36 differentially expressed genes associated with EGFR tyrosine kinase inhibitors resistance, RAS, MAPK, and mTOR signaling. Importantly, we observed that overexpression of KRAS, RhoA, and CD44 was associated with cetuximab resistance. Protein analysis revealed EGFR phosphorylation inhibition and mTOR increase in resistant cells. Moreover, the resistant cell line demonstrated an aggressive phenotype with a significant increase in adhesion, the number of colonies, and migration rates. Overall, we identified several molecular alterations in the cetuximab resistant cell line that may constitute novel biomarkers of cetuximab response such as mTOR and RhoA overexpression. These findings indicate new strategies to overcome anti-EGFR resistance in HNSCC.
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http://dx.doi.org/10.3390/cells11010154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8750399PMC
January 2022

Clinically significant changes in health-related quality of life in head and neck cancer patients following intensive nutritional care during radiotherapy.

Eur J Oncol Nurs 2022 Feb 20;56:102065. Epub 2021 Nov 20.

Departamento de Medicina Preventiva, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.

Purpose: This study aimed to explore whether adherence to intensive nutritional care during radiotherapy would avoid a meaningful worsening in quality of life in head and neck cancer patients; and whether adherence was associated with better nutritional outcomes.

Methods: Observational prospective study that assessed head and neck cancer patients treated with radiotherapy at a large oncology hospital, between August 2018 and April 2019. The main outcome was minimal clinically important difference in quality of life, assessed with EORTC QLQ-C30 and EORTC QLQ H&N35, between baseline and 12 weeks. To illustrate clinically significant changes in quality of life over timeby adherence, a heat map analysis was performed. We also evaluated nutritional outcomes.

Results: Eighty patients were included, half of them (53.8%) were considered adherent. There were no significant difference in quality of life between groups at baseline, with the exception of swallowing (p = 0.029) and coughing (p < 0.01). After treatment, the heat map demonstrated that adherent patients had nonsignificant clinical change in function scales, while non-adherent patients had a clinically significant worsening in physical, cognitive and social function. The prevalence of malnutrition increased significantly only in non-adherent patients (p < 0.01).

Conclusion: Adherence to intensive nutritional care may be able to avoid a meaningful worsening in quality of life and result in better nutritional outcomes in head and neck cancer patients. Our results may help to increase the awareness of the assessment of adherence and minimal clinically important difference in quality of life for research purposes and clinical practice.
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http://dx.doi.org/10.1016/j.ejon.2021.102065DOI Listing
February 2022

One-carbon metabolism and global DNA methylation in mothers of individuals with Down syndrome.

Hum Cell 2021 Nov 19;34(6):1671-1681. Epub 2021 Aug 19.

Unidade de Pesquisa em Genética e Biologia Molecular-UPGEM, Departamento de Biologia Molecular, Faculdade de Medicina de São José do Rio Preto-FAMERP, São José do Rio Preto, São Paulo, Brazil.

Down syndrome (DS) is the most common chromosomal disorder, resulting from the failure of normal chromosome 21 segregation. Studies have suggested that impairments within the one-carbon metabolic pathway can be of relevance for the global genome instability observed in mothers of individuals with DS. Based on the association between global DNA hypomethylation, genome instability, and impairments within the one-carbon metabolic pathway, the present study aimed to identify possible predictors, within the one-carbon metabolism, of global DNA methylation, measured by methylation patterns of LINE-1 and Alu repetitive sequences, in mothers of individuals with DS and mothers of individuals without the syndrome. In addition, we investigated one-carbon genetic polymorphisms and metabolites as maternal predisposing factors for the occurrence of trisomy 21 in children. Eighty-three samples of mothers of children with DS with karyotypically confirmed free trisomy 21 (case group) and 84 of mothers who had at least one child without DS or any other aneuploidy were included in the study. Pyrosequencing assays were performed to access global methylation. The results showed that group affiliation (case or control), betaine-homocysteine methyltransferase (BHMT) G742A and transcobalamin 2 (TCN2) C776G polymorphisms, and folate concentration were identified as predictors of global Alu DNA methylation values. In addition, thymidylate synthase (TYMS) 28-bp repeats 2R/3R or 3R/3R genotypes are independent maternal predisposing factors for having a child with DS. This study adds evidence that supports the association of impairments in the one-carbon metabolism, global DNA methylation, and the possibility of having a child with DS.
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http://dx.doi.org/10.1007/s13577-021-00586-0DOI Listing
November 2021

Evaluation of acetylation and methylation in oral rinse of patients with head and neck cancer history exposed to valproic acid.

Sci Rep 2021 08 12;11(1):16415. Epub 2021 Aug 12.

Head and Neck Surgery Department, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, Bairro Dr. Paulo Prata, Barretos, SP, 14784-400, Brazil.

Evaluate the biological action of valproic acid in the acetylation of histones and in the methylation of tumor suppressor genes via oral rinse in patients with a previous history of head and neck squamous cell carcinoma (HNSCC). Forty-two active or former smokers were included in this randomized, double-blind, placebo-controlled trial. Oral rinse samples were collected prior to treatment with valproic acid or placebo and after 90 days of treatment. The methylation status of five tumor suppressor genes and histone acetylation were evaluated by pyrosequencing and ELISA techniques, respectively. Differences between the 90-day and baseline oral rinse acetylation and methylation results were analyzed by comparing groups. Thirty-four patients were considered for analysis. The mean percentage adherence in the valproic and placebo groups was 93.4 and 93.0, respectively (p = 0.718). There was no statistically significant difference between groups when comparing the medians of the histone acetylation ratio and the methylation ratio for most of the studied genes. A significant reduction in the DCC methylation pattern was observed in the valproic group (p = 0.023). The use of valproic acid was safe and accompanied by good therapeutic adherence. DCC methylation was lower in the valproic acid group than in the placebo group.
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http://dx.doi.org/10.1038/s41598-021-95845-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361187PMC
August 2021

DNA Methylation Markers from Negative Surgical Margins Can Predict Recurrence of Oral Squamous Cell Carcinoma.

Cancers (Basel) 2021 Jun 11;13(12). Epub 2021 Jun 11.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, SP, Brazil.

The identification of molecular markers in negative surgical margins of oral squamous cell carcinoma (OSCC) might help in identifying residual molecular aberrations, and potentially improve the prediction of prognosis. We performed an Infinium MethylationEPIC BeadChip array on 32 negative surgical margins stratified based on the status of tumor recurrence in order to identify recurrence-specific aberrant DNA methylation (DNAme) markers. We identified 2512 recurrence-associated Differentially Methylated Positions (DMPs) and 392 Differentially Methylated Regions (DMRs) which were enriched in cell signaling and cancer-related pathways. A set of 14-CpG markers was able to discriminate recurrent and non-recurrent cases with high specificity and sensitivity rates (AUC 0.98, = 3 × 10; CI: 0.95-1). A risk score based on the 14-CpG marker panel was applied, with cases classified within higher risk scores exhibiting poorer survival. The results were replicated using tumor-adjacent normal HNSCC samples from The Cancer Genome Atlas (TCGA). We identified residual DNAme aberrations in the negative surgical margins of OSCC patients, which could be informative for patient management by improving therapeutic intervention. This study proposes a novel DNAme-based 14-CpG marker panel as a promising predictor for tumor recurrence, which might contribute to improved decision-making for the personalized treatment of OSCC cases.
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http://dx.doi.org/10.3390/cancers13122915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230600PMC
June 2021

HPV-Induced Oropharyngeal Squamous Cell Carcinomas in Brazil: Prevalence, Trend, Clinical, and Epidemiologic Characterization.

Cancer Epidemiol Biomarkers Prev 2021 09 21;30(9):1697-1707. Epub 2021 Jun 21.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.

Background: Tobacco or human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas (OPSCC) represent different clinical and epidemiologic entities. This study investigated the prevalence of HPV-positive and HPV-negative OPSCC in a reference cancer hospital in Brazil and its association with clinical and demographic data, as well as its impact on overall survival.

Methods: HPV infection was determined by p16-IHC in pre-treatment formalin-fixed paraffin-embedded samples from all patients with OPSCC diagnosed at Barretos Cancer Hospital between 2008 and 2018. The prevalence of HPV-positive cases and its temporal trend was assessed, and the association of clinical and demographic data with HPV infection and the impact on patient overall survival was evaluated.

Results: A total of 797 patients with OPSCC were included in the study. The prevalence of HPV-associated tumors in the period was 20.6% [95% confidence interval, 17.5-24.0] with a significant trend for increase of HPV-positive cases over the years (annual percentage change = 12.87). In a multivariate analysis, the variables gender, level of education, smoking, tumor sublocation, region of Brazil, and tumor staging had a significant impact in HPV positivity, and a greater overall survival (OS) was observed in HPV-positive patients (5-year OS: 47.9% vs. 22.0%; = 0.0001).

Conclusions: This study represents the largest cohort of Brazilian patients with OPSCC characterized according to HPV status. We report significant differences in demographics and clinical presentation according to HPV status, and an increasing trend in prevalence for HPV-induced tumors.

Impact: These findings can potentially contribute to a better stratification and management of patients as well as assist in prevention strategies.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0016DOI Listing
September 2021

The hidden curve behind COVID-19 outbreak: the impact of delay in treatment initiation in cancer patients and how to mitigate the additional risk of dying-the head and neck cancer model.

Cancer Causes Control 2021 May 11;32(5):459-471. Epub 2021 Mar 11.

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

Purpose: The rapid spread of the SARS-CoV-2 pandemic around the world caused most healthcare services to turn substantial attention to treatment of these patients and also to alter the structure of healthcare systems to address an infectious disease. As a result, many cancer patients had their treatment deferred during the pandemic, increasing the time-to-treatment initiation, the number of untreated patients (which will alter the dynamics of healthcare delivery in the post-pandemic era) and increasing their risk of death. Hence, we analyzed the impact on global cancer mortality considering the decline in oncology care during the COVID-19 outbreak using head and neck cancer, a known time-dependent disease, as a model.

Methods: An online practical tool capable of predicting the risk of cancer patients dying due to the COVID-19 outbreak and also useful for mitigation strategies after the peak of the pandemic has been developed, based on a mathematical model. The scenarios were estimated by information of 15 oncological services worldwide, given a perspective from the five continents and also some simulations were conducted at world demographic data.

Results: The model demonstrates that the more that cancer care was maintained during the outbreak and also the more it is increased during the mitigation period, the shorter will be the recovery, lessening the additional risk of dying due to time-to-treatment initiation.

Conclusions: This impact of COVID-19 pandemic on cancer patients is inevitable, but it is possible to minimize it with an effort measured by the proposed model.
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http://dx.doi.org/10.1007/s10552-021-01411-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950430PMC
May 2021

The effect of bone marrow-derived stem cells associated with platelet-rich plasma on the osseointegration of immediately placed implants.

J Clin Exp Dent 2021 Jan 1;13(1):e8-e13. Epub 2021 Jan 1.

Research Advisor of Postgraduate Program in Oncology, Medical School of University of São Paulo (FMUSP), São Paulo, SP, Brazil.

Background: Stem cells associated with growth factors have been shown to improve bone healing and the osseointegration of dental implants. A Brazilian miniature pig model was used to evaluate the effect of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) associated with platelet-rich plasma (PRP) on the osseointegration of immediately placed dental implants.

Material And Methods: A total of four male adult miniature pigs were used in this study. BM-MSCs from each pig were isolated from the iliac crest and expanded . The undifferentiated BM-MSCs were mixed with autologous PRP and implanted in the post-extraction sockets at the experimental sites before implant placement (10 x 106 cells/ socket). The control sites did not receive either BM-MSC or PRP. Each animal received four implants in the control side and 04 on the experimental side, totalizing 32 implants. The specimens were analyzed radiographically and histomorphometrically to determine the implant loss rate (ILR), the bone-implant contact (BIC), and bone density within the threads (BDWT).

Results: The ILR, the BIC, and the BDWT for the control and experimental sites were respectively 25.0% and 18.7% (=0.686); 39.0% and 27.7% (=0.110); 46.8% and 36.5% (=0.247).

Conclusions: The use of BM-MSCs + PRP in conjunction with immediately placed implants showed a lower ILR but there was no significant effect on the osseointegration of the dental implants. More preclinical studies, in large animal models, are needed to establish whether BM-MSCs associated with PRP could be used for the enhancement of the osseointegration of dental implants. Osseointegration, bone marrow-derived mesenchymal stem cells, platelet-rich plasma, dental implants, minipigs.
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http://dx.doi.org/10.4317/jced.56743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781218PMC
January 2021

Adherence to intensive nutrition care in head and neck cancer patients undergoing radiotherapy.

Eur Arch Otorhinolaryngol 2021 Sep 1;278(9):3507-3514. Epub 2021 Jan 1.

Departamento de Medicina Preventiva, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Av. Dr Arnaldo, 455 2ºandar, Sao Paulo, SP, 01246-903, Brazil.

Purpose: The aim of this study was to determine the prevalence and effect of adherence to intensive nutritional care on nutritional outcomes and survival in head and neck cancer patients undergoing radiotherapy.

Methods: Three-hundred and seventeen head and neck cancer patients referred to intensive nutrition support during radiotherapy were retrospectively analyzed. Patients who missed less than 25% of their appointments with the dietitian were considered adherent. Primary outcome was percentage weight loss during treatment. Secondary outcomes were overall survival and patients' capacity to accomplish their caloric and protein recommendations. Logistic regression was used to examine predictors of weight loss and Kaplan-Meier to estimate survival.

Results: Less than half of the patients (n = 145, 45.7%) were adherent. Statistically significant less weight loss in the adherent group (42.8% vs 55.8%; p = 0.02) was found, despite no difference in energy or protein intake. Logistic regression models after adjusting for other variables demonstrated that adherence resulted in 43% protection from significant weight loss (odds ratio 0.57, 95% CI 0.34-0.97). Overall survival was not different between groups.

Conclusion: Findings demonstrated that patients who were adherent to weekly contacts with the dietitian had less weight loss, but not better survival or nutritional intake. Additional investigation of factors that may act as barriers or enablers for adherence could help improve the outcomes in this population.
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http://dx.doi.org/10.1007/s00405-020-06550-2DOI Listing
September 2021

Human Papillomavirus DNA Detection by Droplet Digital PCR in Formalin-Fixed Paraffin-Embedded Tumor Tissue from Oropharyngeal Squamous Cell Carcinoma Patients.

Mol Diagn Ther 2021 01 27;25(1):59-70. Epub 2020 Nov 27.

Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Vilela, 1331, Barretos, SP, 14784-400, Brazil.

Introduction: High-risk human papillomavirus infection impacts staging and prognosis of oropharyngeal squamous cell carcinomas (OPSCCs). Determination of HPV status in tumor tissue by p16-immunohistochemistry (p16-IHC) can be challenging; therefore, complementary methodologies could be useful in a clinical setting.

Objective: To test for accuracy and clinical relevance of HPV-DNA detection in formalin-fixed and paraffin-embedded (FFPE) tumor samples by droplet digital PCR (ddPCR).

Materials And Methods: Fifty OPSCCs were tested for p16-IHC status followed by HPV-16/18 DNA detection/quantification in FFPE-recovered DNA using ddPCR. Accuracy for HPV status determination and association with patient information were also evaluated.

Results: 32.0% (16/50) of the cases were p16-IHC positive (p16 +), 42.0% (21/50) had detectable levels of HPV-16 DNA, and none were positive for HPV-18 DNA. A higher median viral load of HPV-16 DNA was observed in p16 + cases (p < 0.0001). Concordance between p16-IHC and HPV-16 DNA ranged from 78.0 to 86.0% and accuracy rates were between 78.0 and 86.0%. P16-IHC and HPV-16 DNA detection was associated with gender, smoking status, and tumor subsite, while only HPV-16 DNA was associated with cT stage. The combination of HPV positivity by p16-IHC and ddPCR showed higher overall survival rates in comparison with p16 + /HPV-DNA- and p16 - /HPV-DNA- results.

Conclusions: Type-specific HPV-DNA detection by ddPCR is highly specific but moderately sensitive for the determination of HPV status and showed clinical relevance, mainly when associated with p16-IHC status. Results highlight the importance of performing HPV-DNA testing in combination with p16-IHC for proper identification of HPV-associated OPSCC and to improve clinical management of OPSCC patients.
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http://dx.doi.org/10.1007/s40291-020-00502-6DOI Listing
January 2021

Electrochemical and optical detection and machine learning applied to images of genosensors for diagnosis of prostate cancer with the biomarker PCA3.

Talanta 2021 Jan 7;222:121444. Epub 2020 Aug 7.

Sao Carlos Institute of Physics, University of Sao Paulo, 13566-590, São Carlos, Brazil. Electronic address:

The development of simple detection methods aimed at widespread screening and testing is crucial for many infections and diseases, including prostate cancer where early diagnosis increases the chances of cure considerably. In this paper, we report on genosensors with different detection principles for a prostate cancer specific DNA sequence (PCA3). The genosensors were made with carbon printed electrodes or quartz coated with layer-by-layer (LbL) films containing gold nanoparticles and chondroitin sulfate and a layer of a complementary DNA sequence (PCA3 probe). The highest sensitivity was reached with electrochemical impedance spectroscopy with the detection limit of 83 pM in solutions of PCA3, while the limits of detection were 2000 pM and 900 pM for cyclic voltammetry and UV-vis spectroscopy, respectively. That detection could be performed with an optical method is encouraging, as one may envisage extending it to colorimetric tests. Since the morphology of sensing units is known to be affected in detection experiments, we applied machine learning algorithms to classify scanning electron microscopy images of the genosensors and managed to distinguish those exposed to PCA3-containing solutions from control measurements with an accuracy of 99.9%. The performance in distinguishing each individual PCA3 concentration in a multiclass task was lower, with an accuracy of 88.3%, which means that further developments in image analysis are required for this innovative approach.
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http://dx.doi.org/10.1016/j.talanta.2020.121444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413169PMC
January 2021

In-depth transcriptome reveals the potential biotechnological application of venom gland.

J Venom Anim Toxins Incl Trop Dis 2020 Oct 21;26:e20190058. Epub 2020 Oct 21.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil.

Background: Lack of complete genomic data of impedes molecular biology research focusing on biotechnological applications of venom gland components. Identification of full-length coding regions of genes is crucial for the correct molecular cloning design.

Methods: RNA was extracted from the venom gland of one adult female specimen of . Deep sequencing of the mRNA library was performed using Illumina NextSeq 500 platform. assembly of transcriptome was done using Trinity. Annotation was performed using Blast2GO. All predicted proteins after clustering step were blasted against non-redundant protein database of NCBI using BLASTP. Metabolic pathways present in the transcriptome were annotated using the KAAS-KEGG Automatic Annotation Server. Toxins were identified in the predicted proteome using BLASTP against all protein sequences obtained from Animal Toxin Annotation Project from Uniprot KB/Swiss-Pro database. Figures and data visualization were performed using ggplot2 package in R language environment.

Results: We described the in-depth transcriptome analysis of venom gland, in which 76,765 assembled isoforms, 96,044 transcribed genes and 41,196 unique proteins were identified. The most abundant transcript was the zinc metalloproteinase-disintegrin-like jararhagin. Moreover, we identified 78 distinct functional classes of proteins, including toxins, inhibitors and tumor suppressors. Other venom proteins identified were the hemolytic lethal factors stonustoxin and verrucotoxin.

Conclusion: It is believed that the application of deep sequencing to the analysis of snake venom transcriptomes may represent invaluable insight on their biotechnological potential focusing on candidate molecules.
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http://dx.doi.org/10.1590/1678-9199-JVATITD-2019-0058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579844PMC
October 2020

Promoter Mutation C228T Increases Risk for Tumor Recurrence and Death in Head and Neck Cancer Patients.

Front Oncol 2020 28;10:1275. Epub 2020 Jul 28.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.

Head and neck squamous cell carcinoma (HNSCC) is usually associated to tobacco and alcohol consumption. Increased telomerase activity has been consistently detected in 80-90% of malignant tumors, including HNSCC. Mutations within the promoter region of telomerase reverse transcriptase () that confer enhanced promoter activity have been reported in two major hotspots, designated C228T and C250T. To evaluate promoter mutations C228T and C250T in HNSCC patients from Brazil and correlate with patients' outcome. Formalin-fixed paraffin-embedded tissues were obtained from 88 HNSCC patients and analyzed for promoter mutations C228T and C250T by pyrosequencing. The overall prevalence of hotspot mutations in HNSCC samples was of 27.3%, with 6.8% at locus C228T and 20.5% at C250T. The majority (92%) of mutated cases were located in oral cavity, mainly at the tongue. We observed that 94.4% of the patients harboring promoter mutation C250T were alcohol consumers ( = 0.032) and 66.7% of the patients harboring promoter mutation C228T were not alcohol consumers ( = 0.035). The presence of C228T mutation impacted patient outcome, with a significant decrease in disease-free survival (20.0 vs. 63.0%, =0.017) and in overall survival (16.7 vs. 45.1%, = 0.017). This is the first report of a promoter mutations in HNSCC patients from South America. The high prevalence of mutation, as well as its association with poor disease-free survival and overall survival, particular at C228T locus might serve as a prognostic biomarker in HNSCC to help clinicians in the management of treatment.
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http://dx.doi.org/10.3389/fonc.2020.01275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399085PMC
July 2020

Feasibility of methylated ctDNA detection in plasma samples of oropharyngeal squamous cell carcinoma patients.

Head Neck 2020 11 20;42(11):3307-3315. Epub 2020 Jul 20.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.

Background: Oropharyngeal squamous cell carcinomas (OpSCCs) are commonly associated with high rates of treatment failure.

Objectives: To evaluate methylation-based markers in plasma from OpSCC patients as emerging tools for accurate/noninvasive follow-up.

Methods: Pretreatment formalin-fixed paraffin-embedded (FFPE) biopsies (n = 52) and paired plasma (n = 15) were tested for the methylation of CCNA1, DAPK, CDH8, and TIMP3 by droplet digital PCR (ddPCR).

Results: Seventy-one percent (37/52) of the biopsies showed methylation of at least one of the evaluated genes and tumor CCNA1 methylation was associated with recurrence-free survival. Methylated circulating tumor DNA (meth-ctDNA) was detected in 11/15 (73.3%) plasma samples; conversely, plasma samples from healthy controls were all negative for DNA methylation (area under the curve = 0.867; 95% confidence interval = 0.720-1.000). Additionally, preliminary results on the detection of meth-ctDNA in plasma collected during follow-up closely matched patient outcome.

Conclusions: The results suggest the feasibility of detecting meth-ctDNA in plasma using ddPCR and a possible application on routine setting after further validation.
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http://dx.doi.org/10.1002/hed.26385DOI Listing
November 2020

Immunosensors containing solution blow spun fibers of poly(lactic acid) to detect p53 biomarker.

Mater Sci Eng C Mater Biol Appl 2020 Oct 27;115:111120. Epub 2020 May 27.

São Carlos Institute of Physics, University of São Paulo, 13566-590 São Carlos, Brazil. Electronic address:

This paper reports on biosensors made with a matrix of polylactic acid (PLA) fibers, which are suitable for immobilization of the anti-p53 active layer for detection of p53 biomarker. The PLA fibers were produced with solution blow spinning, a method that is advantageous for its simplicity and possibility to tune the fiber properties. For the biosensors, the optimized time to deposit the fibers was 60 s, with which detection of p53 could be achieved with the limit of detection of 11 pg/mL using electrical impedance spectroscopy. This sensitivity is also sufficient to detect the p53 biomarker in patient samples, which was confirmed by distinguishing samples from cell lines with distinct p53 concentrations in a plot where the impedance spectra were visualized with the interactive document mapping (IDMAP) technique. The high sensitivity and selectivity of the biosensors may be attributed to the specific interaction between the active layer and p53 modeled with a Langmuir-Freundlich and Freundlich isotherms and inferred from the analysis of the vibrational bands at 1550, 1650 and 1757 cm using polarization-modulated infrared reflection absorption spectroscopy (PM-IRRAS). The successful immobilization of the active layer is evidence that the approach based on solution blown spun fibers may be replicated to other types of biosensors.
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http://dx.doi.org/10.1016/j.msec.2020.111120DOI Listing
October 2020

Impact of genetic variants in clinical outcome of a cohort of patients with oropharyngeal squamous cell carcinoma.

Sci Rep 2020 06 19;10(1):9970. Epub 2020 Jun 19.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil.

Tobacco- or human papillomavirus- driven oropharyngeal squamous cell carcinomas (OpSCC) represent distinct clinical, biological and epidemiological entities. The aim of this study was to identify genetic variants based on somatic alterations in OpSCC samples from an admixed population, and to test for association with clinical features. The entire coding region of 15 OpSCC driver genes was sequenced by next-generation sequencing in 51 OpSCC FFPE samples. Thirty-five percent of the patients (18/51) were HPV-positive and current or past tobacco consumption was reported in 86.3% (44/51). The mutation profile identified an average of 2.67 variants per sample. Sixty-three percent of patients (32/51; 62.7%) were mutated for at least one of the genes tested and TP53 was the most frequently mutated gene. The presence of mutation in NOTCH1 and PTEN, significantly decreased patient's recurrence-free survival, but only NOTCH1 mutation remained significant after stepwise selection, with a risk of recurrence of 4.5 (HR 95% CI = 1.11-14.57; Cox Regression p = 0.034). These results show that Brazilian OpSCC patients exhibit a similar clinical and genetic profile in comparison to other populations. Molecular characterization is a promising tool for the definition of clinical subgroups, aiding in a more precise tailoring of treatment and prognostication.
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http://dx.doi.org/10.1038/s41598-020-66741-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305218PMC
June 2020

Near Infrared (NIR) Fluorescence is Not a Substitute for Lymphoscintigraphy and Gamma Probe for Melanoma Sentinel Node Detection: Results from a Prospective Trial.

Ann Surg Oncol 2020 Aug 7;27(8):2906-2912. Epub 2020 Apr 7.

Department of Surgery, Melanoma and Sarcoma, Barretos Cancer Hospital, Barretos, SP, Brazil.

Background: Sentinel lymph node (SLN) biopsy is the standard care for early detection and staging of lymph node metastasis in melanomas. Radiocolloids (RC) and blue dyes are used for SLN detection. Recently, near infrared (NIR) fluorescence tracing using indocyanine green has been developed as an alternative method for SLN detection. The relatively high tissue penetration depth of several millimeters and the ability to detect low concentrations of tracer both suggest that NIR may have significant advantages over RC and the blue dye methods. The objective of this study was to prospectively compare the performance of all three SLN detection techniques using them sequentially to evaluate the same group of patients.

Methods: One hundred twenty-one primary cutaneous melanoma patients with an indication for SLN biopsy were assigned to the procedure following NIR, blue dye, and RC detection techniques.

Results: No adverse event was reported. SLN was not detected in only 4.1% of cases. In 90.9%, an SLN was identified with NIR, but without any auxiliary technique in only 70.2% of cases. RC detected the SLN in 92.6% of cases. Patent blue was found in the sentinel node in 76.9%. The combination of all three techniques detected an SLN in 95.9% of cases. Metastases were present in 26.7%. The false-negative rate was 8.8%, with a negative predictive value of 91.2%.

Conclusions: RC was the only technique with high SLN detection. Both the blue dye and NIR methods added sensitivity to the detection rate but should not be a substitute for RC.
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http://dx.doi.org/10.1245/s10434-020-08409-6DOI Listing
August 2020

Genosensor made with a self-assembled monolayer matrix to detect MGMT gene methylation in head and neck cancer cell lines.

Talanta 2020 Apr 2;210:120609. Epub 2019 Dec 2.

São Carlos Institute of Physics, University of São Paulo, 13566-590, São Carlos, Brazil. Electronic address:

DNA methylation is involved in the oncogenesis of head and neck squamous cell carcinoma and could be used for early detection of cancer to increase the chances of cure, but unfortunately diagnosis is usually made at late stages of the disease. In this work we developed genosensors to detect DNA methylation of the MGMT gene in head and neck cancer cell lines. The probe for MGMT promoter methylation was immobilized on gold electrodes modified with 11-mercaptoundecanoic acid (11-MUA) self-assembled monolayers (SAM). Detection was performed with electrochemical impedance spectroscopy, with clear distinction between methylated and non-methylated DNA from head and neck cell lines. The genosensor is sensitive with a low detection limit of 0.24 × 10 mol L. In addition, the cell lines FaDu, JHU28 and SCC25 for the MGMT gene, could be distinguished from the HN13 cell line which has a high degree of MGMT methylation (97%), thus confirming the selectivity. Samples with different percentages of MGMT DNA methylation could be separated in multidimensional projections using the visualization technique interactive document mapping (IDMAP). The genosensor matrix and the immobilization procedures are generic, and can be extended to other DNA methylation biomarkers.
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http://dx.doi.org/10.1016/j.talanta.2019.120609DOI Listing
April 2020

Detection of the Prostate Cancer Biomarker PCA3 with Electrochemical and Impedance-Based Biosensors.

ACS Appl Mater Interfaces 2019 Dec 9;11(50):46645-46650. Epub 2019 Dec 9.

São Carlos Institute of Physics , University of São Paulo , 13566-590 São Carlos , Brazil.

Diagnosis of prostate cancer via PCA3 biomarker detection is promising to be much more efficient than with the prostatic specific antigens currently used. In this study, we present the first electrochemical and impedance-based biosensors that are capable of detecting PCA3 down to 0.128 nmol/L. The biosensors were made with a layer of PCA3-complementary single-stranded DNA (ssDNA) probe, immobilized on a layer-by-layer (LbL) film of chitosan (CHT) and carbon nanotubes (MWCNT). They are highly selective to PCA3, which was confirmed in impedance measurements and with polarization-modulated infrared reflection absorption spectroscopy (PM-IRRAS). Using information visualization methods, we could also distinguish between cell lines expressing the endogenous PCA3 long noncoding RNA (lncRNA) from cells that did not contain detectable levels of this biomarker. Since the methods involved in fabrication the biosensors are potentially low cost, one may hope to deploy PCA3 tests in any laboratory of clinical analyses and even for point-of-care diagnostics.
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http://dx.doi.org/10.1021/acsami.9b19180DOI Listing
December 2019

The role of single-nucleotide polymorphism (SNPs) in toxicity of induction chemotherapy based on cisplatin and paclitaxel in patients with advanced head and neck cancer.

Oral Oncol 2019 11 17;98:48-52. Epub 2019 Sep 17.

Department of Medical Oncology, Barretos Cancer Hospital, Barretos, SP, Brazil.

Background: Induction chemotherapy in locally-advanced head and neck squamous cell carcinoma (LAHNSCC) patients is potentially associated to serious adverse events. Biomarkers associated with toxicity could tailor its indication. This study evaluated the association between single-nucleotide polymorphisms (SNPs) in metabolic genes and toxicity to induction chemotherapy.

Methods: 59 LAHNSCC phase II clinical trial patients (NCT00959387) were assessed regarding 47 metabolic genes (366 SNPs). Toxicities were graded (CTCAE 3.0) and statistical analysis was performed.

Results: The SNPs rs8187710 (ABCC2) and rs1801131 (MTHFR) were associated to increased risk of gastrointestinal toxicity, whereas the SNPs rs3788007 (ABCG1) and rs4148943 (CHST3) were associated to decreased risk. Two other SNPs, rs2301159 (SLC10A2) and rs2470890 (CYP1A2), were associated with increased risk of hematological toxicity. Nevertheless, these SNPs did not remain significant after adjusting for multiple comparisons.

Conclusions: This study could not demonstrate relationship between SNPs and toxicity to induction chemotherapy in LAHNSCC patients. The small number of patients may have affected the results.
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http://dx.doi.org/10.1016/j.oraloncology.2019.09.013DOI Listing
November 2019

Circulating extracellular vesicle-associated TGFβ3 modulates response to cytotoxic therapy in head and neck squamous cell carcinoma.

Carcinogenesis 2019 Dec;40(12):1452-1461

Department of Biological Sciences, Universidade Federal de São Paulo, Diadema, Brazil.

Management of locally advanced head and neck squamous cell carcinoma (HNSCC) requires a multi-prong approach comprising surgery, radiation and/or chemotherapy, yet outcomes are limited. This is largely due to a paucity of biomarkers that can predict response to specific treatment modalities. Here, we evaluated TGFβ3 protein levels in extracellular vesicles (EVs) released by HNSCC cells as a predictor for response to chemoradiation therapy (CRT). To this end, specific EV-fractions were isolated from cell lines or HNSCC patient plasma, and TGFβ3 protein was quantified. In patients treated with CRT, TGFβ3 levels were found to be significantly higher in plasma EV-fractions or non-responders compared with responders. High levels of TGFβ3 levels in Annexin V-EVs were associated with the worst progression-free survival. In vitro experiments demonstrated that TGFβ3 silencing sensitized HNSCC cells to cytotoxic therapies, and this phenotype could be rescued by treatment with exogenous. In addition, specific EV-fractions shed by cisplatin-resistant cells were sufficient to transfer the resistant phenotype to sensitive cells through activation of TGFβ-signaling pathway. Therefore, our data show that TGFβ3 transmitted through EV plays a significant role in response to cytotoxic therapy, which can be exploited as a potential biomarker for CRT response in HNSCC patients treated with curative intent.
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http://dx.doi.org/10.1093/carcin/bgz148DOI Listing
December 2019

A preliminary investigation of circulating extracellular vesicles and biomarker discovery associated with treatment response in head and neck squamous cell carcinoma.

BMC Cancer 2019 Apr 23;19(1):373. Epub 2019 Apr 23.

Department of Biological Science, Laboratório de Biologia Molecular do Câncer, UNIFESP, Universidade Federal de São Paulo, Rua Pedro de Toledo, 669 - 11° andar, São Paulo, SP, 04039-032, Brazil.

Background: There is a paucity of plasma-based biomarkers that prospectively segregate the outcome of patients with head and neck squamous-cell carcinoma (HNSCC) treated with chemoradiation therapy (CRT). Plasma extracellular vesicles (EVs) might be an alternative source for discovery of new specific markers present in patients with HNSCC, which could help to re-direct patients to appropriate curative therapies without delay.

Methods: In order to identify new markers in plasma compartments, Cholerae toxin B chain (CTB) and Annexin V (AV) were used to isolate EVs from pooled plasma samples from patients with locally advanced HNSCC who responded (CR, n = 6) or presented incomplete response (NR, n = 6) to CRT. The crude plasma and EVs cargo were screened by antibody array.

Results: Of the 370 polypeptides detected, 119 proteins were specific to NR patients while 38 were exclusive of the CR subjects. The Gene Set Enrichment Analysis (GSEA) and Search Tool for the Retrieval of Interacting Genes (STRING) database analysis indicated that the content of circulating plasma EVs might have a relevant function for the tumor intercellular communication in the HNSCC patients.

Conclusion: This study provides a list of potential markers present in plasma compartments that might contribute to the development of tools for prediction and assessment of CRT response and potentially guide therapeutic decisions in this context.
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http://dx.doi.org/10.1186/s12885-019-5565-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480898PMC
April 2019

Study of Dysphagia in Patients with Advanced Oropharyngeal Cancer Subjected to an Organ Preservation Protocol Based on Concomitant Radiotherapy and Chemotherapy

Asian Pac J Cancer Prev 2019 Mar 26;20(3):977-982. Epub 2019 Mar 26.

Head and Neck Surgery Department, Barretos Cancer Hospital, Barretos – SP, Brazil.

Introduction: Organ preservation protocol (based on chemo-radiotherapy) for oropharyngeal tumors include dysphagia as a possible sequel leading to function impairment and changes in patient’s quality of life. Objectives: The aim of this study is to assess dysphagia severity after treatment in advanced oropharyngeal cancer patients treated with concurrent chemo-radiation. Methods: This prospective cross-sectional study included 64 participants who had been disease free for at least six months after primary treatment. Dysphagia severity was assessed by fibre-optic endoscopic evaluation of swallowing (FEES) and the Dysphagia Outcome and Severity Scale (DOSS); the occurrence of penetration/aspiration during swallowing was also investigated. All participants also completed the M. D. Anderson Dysphagia Inventory (MDADI). The correlation of FEES results with clinical-demographic variables and MDADI scores was assessed. Descriptive analysis was performed, and qualitative variables were compared using either the chi-square or Fisher’s exact test. Results: FEES revealed silent aspiration in 18.8% of the patients. Approximately 6.3% of the patients exhibited severe dysphagia (scores 1-2 in DOSS). Dysphagia severity was significantly associated with the MDADI physical domain scores. The participants with scores 5-7 in DOSS (no or mild dysphagia) exhibited less limitations in the MDADI physical domain (p=0.015). Conclusions: Silent aspiration was detected in one of every five patients treated with concurrent chemo-radiotherapy; almost half of the patients exhibit at least moderate dysphagia. Assessment of the participant’s quality of life via the MDADI revealed an association between the physical domain scores and dysphagia severity
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http://dx.doi.org/10.31557/APJCP.2019.20.3.977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825780PMC
March 2019

High expression of MLANA in the plasma of patients with head and neck squamous cell carcinoma as a predictor of tumor progression.

Head Neck 2019 05 25;41(5):1199-1205. Epub 2019 Feb 25.

Cancer Therapeutics Research Laboratory, National Cancer Centre, Singapore.

Background: There is a paucity of plasma-based biomarkers that predict outcome in patients with head and neck squamous cell carcinoma (HNSCC) treated with chemoradiation therapy (CRT). Here, we evaluate the prognostic potential of plasma Melanoma-Antigen Recognized by T-cells 1 (MLANA) in this setting.

Methods: MLANA expression in HNSCC lines were evaluated by reverse transcription polymerase chain reaction, whereas plasma levels were quantified using ELISA in 48 patients with locally advanced HNSCC undergoing a phase 2 trial with CRT.

Results: MLANA is expressed at variable levels in a panel of HNSCC lines. In plasma, levels were elevated in patients with tumor relapse compared to those without (P < .004); 73.9% of the patients expressing high plasma MLANA levels progressed with recurrent disease (P = .020). Multivariate analysis showed that plasma MLANA levels and tumor resectability were independent prognostic factors for progression free survival.

Conclusion: Plasma MLANA expression appears to be an effective noninvasive biomarker for outcomes in patients treated with CRT, and could potentially guide therapeutic decisions in this context.
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http://dx.doi.org/10.1002/hed.25510DOI Listing
May 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

Effect of Induction Chemotherapy on Swallowing in Head and Neck Cancer Patients

Asian Pac J Cancer Prev 2019 Jan 25;20(1):91-96. Epub 2019 Jan 25.

SLP Head and Neck Department, Barretos Cancer Hospital, Barretos-SP, Brazil. Email:

Objective: To evaluate the effect of induction chemotherapy on swallowing and swallowing-related quality of life of patients with oropharyngeal, laryngeal and hypopharyngeal cancer. Study design: Prospective study of 33 patients with locally advanced tumors who were eligible for treatment with neoadjuvant chemotherapy followed by radiotherapy and concurrent chemotherapy. A multidimensional assessment of swallowing was performed using the following tools: (1) Clinical analysis, numerical scale for general pain and painful swallowing, American Speech and Hearing Association (ASHA) Functional Communication Measures (FCM) swallowing assessment scales, (2) assessment of Swallowing-Related Quality of Life (The MD Anderson Dysphagia Inventory - MDADI), and (3) swallowing videofluoroscopy. Results: There was a reduction in general pain scale (p=0.021), and quality of life (emotional, functional and physical) improved from average limitation (score of 61-80) to minimal limitation (81-100) after induction chemotherapy. According to the swallowing videofluoroscopy results, 26 (78.7%) of the patients had some degree of dysphagia pre-treatment, which decreased to 21 (63.6%) after induction. Conclusion: Our results suggest that induction chemotherapy improves numerous aspects of swallowing and has a positive impact on the quality of life of pre-chemoradiotherapy patients.
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http://dx.doi.org/10.31557/APJCP.2019.20.1.91DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485558PMC
January 2019

Feasibility of concomitant cisplatin with hypofractionated radiotherapy for locally advanced head and neck squamous cell carcinoma.

BMC Cancer 2018 Oct 23;18(1):1026. Epub 2018 Oct 23.

Department of Head and Neck, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, Barretos, SP, 14.784-400, Brazil.

Background: The evolution of radiotherapy over recent decades has reintroduced the hypofractionation for many tumor sites with similar outcomes to those of conventional fractionated radiotherapy. The use of hypofractionation in locally advanced head and neck cancer (LAHNC) has been already used, however, its use has been restricted to only a few countries. The aim of this trial was to evaluate the safety and feasibility of moderate hypofractionated radiotherapy (HYP-RT) with concomitant cisplatin (CDDP).

Methods: This single-arm trial was designed to evaluate the safety and feasibility of HYP-RT with concomitant CDDP in LAHNC. Stage III and IV patients withnonmetastatic disease were enrolled. Patients were submitted to intensity modulatedradiation therapy, which comprised 55 Gy/20 fractions to the gross tumor and44-48 Gy/20 fractions to the areas of subclinical disease. Concomitant CDDPconsisted of 4 weekly cycles of 35 mg/m2. The primary endpoints were the treatment completion rate and acute toxicity.

Results: Twenty patients were enrolled from January 2015 to September 2016, and 12 (60%) were classified as unresectable. All patients completed the total dose of radiotherapy, and 19 patients (95%) received at least 3 of 4 cycles of chemotherapy. The median overall treatment time was 29 days (27-34). Grade 4 toxicity was reported twice (1 fatigue and 1 lymphopenia). The rates of grade 3 dermatitis and mucositis were 30% and 40%, respectively, with spontaneous resolution. Nasogastric tubes were offered to 15 patients (75%) during treatment; 4 patients (20%) needed feeding tubes after 2 months, and only 1 patient needed a feeding tube after 12 months.

Conclusion: HYP-RT with concomitant CDDP was considered feasible for LAHNC, and the rate of acute toxicity was comparable to that of standard concomitant chemoradiation. A feeding tube was necessary for most patients during treatment. Further investigation of this strategy is warranted.

Trial Registration: ClinicalTrials, NCT03194061 . Registered 21 Jun 2017 - Retrospectively registered.
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http://dx.doi.org/10.1186/s12885-018-4893-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199702PMC
October 2018

Molecular Classification of Thyroid Nodules with Indeterminate Cytology: Development and Validation of a Highly Sensitive and Specific New miRNA-Based Classifier Test Using Fine-Needle Aspiration Smear Slides.

Thyroid 2018 12 22;28(12):1618-1626. Epub 2018 Nov 22.

Department of Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos/SP, Brazil.

Thyroid nodules can be identified in up to 68% of the population. Fine-needle aspiration (FNA) cytopathology classifies 20%-30% of nodules as indeterminate, and these are often referred for surgery due to the risk of malignancy. However, histological postsurgical reports indicate that up to 84% of cases are benign, highlighting a high rate of unnecessary surgeries. We sought to develop and validate a microRNA (miRNA)-based thyroid molecular classifier for precision endocrinology (mir-THYpe) with both high sensitivity and high specificity, to be performed on the FNA cytology smear slide with no additional FNA. The expression of 96 miRNA candidates from 39 benign/39 malignant thyroid samples, (indeterminate on FNA) was analyzed to develop and train the mir-THYpe algorithm. For validation, an independent set of 58 benign/37 malignant FNA smear slides (also classified as indeterminate) was used. In the training set, with a 10-fold cross-validation using only 11 miRNAs, the mir-THYpe test reached 89.7% sensitivity, 92.3% specificity, 90.0% negative predictive value and 92.1% positive predictive value. In the FNA smear slide validation set, the mir-THYpe test reached 94.6% sensitivity, 81.0% specificity, 95.9% negative predictive value, and 76.1% positive predictive value. Bayes' theorem shows that the mir-THYpe test performs satisfactorily in a wide range of cancer prevalences. The presented data and comparison with other commercially available tests suggest that the mir-THYpe test can be considered for use in clinical practice to support a more informed clinical decision for patients with indeterminate thyroid nodules and potentially reduce the rates of unnecessary thyroid surgeries.
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http://dx.doi.org/10.1089/thy.2018.0254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308280PMC
December 2018
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