Publications by authors named "Luiz Paulo Kowalski"

290 Publications

Immunohistochemical Expression of Fatty Acid Synthase (FASN) is Correlated to Tumor Aggressiveness and Cellular Differentiation in Salivary Gland Carcinomas.

Head Neck Pathol 2021 Apr 11. Epub 2021 Apr 11.

Department of Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), 126, Tessalia Vieira de Camargo Street, Cidade Universitaria, Campinas, São Paulo, 13083887, Brazil.

Fatty acid synthase (FASN) expression is closely related to cancer progression, in particular, tumor aggressiveness and poor prognosis. This study aimed to analyse the expression of FASN in carcinomas of the salivary glands and correlate it with Ki-67 expression. We analysed by immunohistochemistry the expression of FASN and Ki-67 on tissue sections from 7 cases of adenocarcinoma, not otherwise specified (AdNOS), 6 cases of polymorphous adenocarcinoma (PAC), 16 cases of acinic cell carcinoma (AcCC), 19 cases of adenoid cystic carcinoma (AdCC), 15 cases of epithelial-myoepithelial carcinoma (EMC); 10 cases of secretory carcinoma (SC), 13 cases of mucoepidermoid carcinoma (MEC), 10 cases of salivary duct carcinoma (SDC) and 7 cases of myoepithelial carcinoma (MC). These carcinomas were classified into aggressive and indolent regarding their biological behaviour. Additionally, MEC and AdCC were also classified according to the histological grade. High expression of FASN was found in SDC (100%), SC (100%), AcCC (68.7%) and AdNOS (57.2%). No association was found between FASN and Ki-67 expression. Aggressive carcinomas showed a higher rate of Ki-67 proliferation (p < 0.001) and greater expression of FASN when compared to indolent carcinomas (p < 0.05). With regards to carcinomas categorized as indolent, FASN expression was much higher in the lesions that presented cell differentiation (SC and AcCC). Also, FASN expression was significantly higher in high-grade AdCC and MEC when compared to low-grade tumors (p < 0.05). We concluded that FASN expression was correlated to tumor aggressiveness and cellular differentiation in salivary gland carcinomas.
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http://dx.doi.org/10.1007/s12105-021-01319-3DOI Listing
April 2021

MicroRNA-mediated extracellular matrix remodeling in squamous cell carcinoma of the oral cavity.

Head Neck 2021 Apr 8. Epub 2021 Apr 8.

Head and Neck Surgery Department, Instituto do Câncer do Estado de São Paulo (ICESP), Laboratório de Investigação Médica 28 (LIM28), University of Sao Paulo Medical School, Sao Paulo, Brazil.

Background: We evaluated microRNAs and extracellular matrix component profiles in squamous cell carcinoma of the oral cavity (OSCC) in comparison to healthy mucosa.

Methods: Retrospective study investigating 64 microRNAs related to oncogenic process and to constituents of the extracellular matrix. We also performed immunohistochemical assays for molecules involved in the same biological processes.

Results: High expression of miR-21-5p (p < 0.001) and miR-106-5p (p < 0.001) and low expression of miR-320a (p = 0.001) and miR-222-3p (p = 0.001) were predictors of malignancy. Individually, miR-21-5p exhibited the best statistical performance (area under the curve = 0.972; 95% confidence interval: 0.911-1.000) in the differentiation between tumor tissue and healthy mucosa. Moreover, tumor sample showed increased expression of MMP-2, MMP-9, α-laminin, and β-laminin in tumor-related fibroblasts and lower continuity of type IV collagen in the basement membrane.

Conclusion: The present study demonstrates the biological effects of microRNAs on the carcinogenesis of OSCC as well as the intense modification of the tumor microenvironment.
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http://dx.doi.org/10.1002/hed.26686DOI Listing
April 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

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

Tumor volume as a prognostic factor of locally advanced laryngeal cancer.

Eur Arch Otorhinolaryngol 2021 Mar 11. Epub 2021 Mar 11.

Department of Head and Neck Surgery, University of Sao Paulo Medical School, São Paulo, Brazil.

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http://dx.doi.org/10.1007/s00405-021-06734-4DOI Listing
March 2021

Informed consent and a risk-based approach to oncologic surgery in a cancer center during the COVID-19 pandemic.

J Surg Oncol 2021 Mar 8. Epub 2021 Mar 8.

Department of Head and Neck, AC Camargo Cancer Center, São Paulo, São Paulo, Brazil.

Background: Cancer patients configure a risk group for complications or death by COVID-19. For many of them, postponing or replacing their surgical treatments is not recommended. During this pandemic, surgeons must discuss the risks and benefits of treatment, and patients should sign a specific comprehensive Informed consent (IC).

Objectives: To report an IC and an algorithm developed for oncologic surgery during the COVID-19 outbreak.

Methods: We developed an IC and a process flowchart containing a preoperative symptoms questionnaire and a PCR SARS-CoV-2 test and described all perioperative steps of this program.

Results: Patients with negative questionnaires and tests go to surgery, those with positive ones must wait 21 days and undergo a second test before surgery is scheduled. The IC focused both on risks and benefits inherent each surgery and on the risks of perioperative SARS-CoV-2 infections or related complications. Also, the IC discusses the possibility of sudden replacement of medical staff member(s) due to the pandemic; the possibility of unexpected complications demanding emergency procedures that cannot be specifically discussed in advance is addressed.

Conclusions: During the pandemic, specific tools must be developed to ensure safe experiences for surgical patients and prevent them from having misunderstandings concerning their care.
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http://dx.doi.org/10.1002/jso.26452DOI Listing
March 2021

Impacts of Environmental Factors on Head and Neck Cancer Pathogenesis and Progression.

Cells 2021 Feb 13;10(2). Epub 2021 Feb 13.

Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA.

Epidemiological and clinical studies over the past two decades have provided strong evidence that genetic elements interacting with environmental components can individually and collectively influence one's susceptibility to cancer. In addition to tumorigenic properties, numerous environmental factors, such as nutrition, chemical carcinogens, and tobacco/alcohol consumption, possess pro-invasive and pro-metastatic cancer features. In contrast to traditional cancer treatment, modern therapeutics not only take into account an individual's genetic makeup but also consider gene-environment interactions. The current review sharpens the focus by elaborating on the impact that environmental factors have on the pathogenesis and progression of head and neck cancer and the underlying molecular mechanisms involved. Recent advances, challenges, and future perspectives in this area of research are also discussed. Inhibiting key environmental drivers of tumor progression should yield survival benefits for patients at any stage of head and neck cancer.
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http://dx.doi.org/10.3390/cells10020389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917998PMC
February 2021

Oral squamous cell carcinoma around dental implants: a systematic review.

Oral Surg Oral Med Oral Pathol Oral Radiol 2021 Jan 27. Epub 2021 Jan 27.

Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas, Piracicaba, Brazil. Electronic address:

Objective: This systematic review aimed to evaluate the epidemiologic profile, screen for possible risk factors, and evaluate the spectrum of clinical characteristics of oral squamous cell carcinoma (OSCC) around dental implants (DIs).

Methods: The systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta- Analyses statement.

Results: Thirty-three articles met the eligibility criteria. In total, the sample consisted of 63 patients, and women comprised the majority (55.5%). The mean age of patients was 66.7 years. Oral potentially malignant disorders were reported in 46% of patients, of which 65.5% occurred in women. The most common lesion found in women was oral lichen planus (52.6%). In 88.8% of patients OSCC around DIs occurred in the mandible, and the most common clinical appearance of the lesions was an exophytic mass (46%). Most of these lesions were initially treated as peri-implantitis.

Conclusions: Most patients with OSCC around DIs were women without known risk factors. It is important to emphasize that these lesions may present clinical and radiographic features that could resemble peri-implantitis, which can lead to delay in the diagnosis and subsequent treatment.
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http://dx.doi.org/10.1016/j.oooo.2021.01.019DOI Listing
January 2021

Peptidomics-Driven Strategy Reveals Peptides and Predicted Proteases Associated With Oral Cancer Prognosis.

Mol Cell Proteomics 2020 Dec 3;20:100004. Epub 2020 Dec 3.

Brazilian Biosciences National Laboratory, National Center for Research in Energy and Materials, Campinas, Brazil. Electronic address:

Protease activity has been associated with pathological processes that can lead to cancer development and progression. However, understanding the pathological unbalance in proteolysis is challenging because changes can occur simultaneously at protease, their inhibitor, and substrate levels. Here, we present a pipeline that combines peptidomics, proteomics, and peptidase predictions for studying proteolytic events in the saliva of 79 patients and their association with oral squamous cell carcinoma (OSCC) prognosis. Our findings revealed differences in the saliva peptidome of patients with (pN+) or without (pN0) lymph-node metastasis and delivered a panel of ten endogenous peptides correlated with poor prognostic factors plus five molecules able to classify pN0 and pN+ patients (area under the receiver operating characteristic curve > 0.85). In addition, endopeptidases and exopeptidases putatively implicated in the processing of differential peptides were investigated using cancer tissue gene expression data from public repositories, reinforcing their association with poorer survival rates and prognosis in oral cancer. The dynamics of the OSCC-related proteolysis were further explored via the proteomic profiling of saliva. This revealed that peptidase/endopeptidase inhibitors exhibited reduced levels in the saliva of pN+ patients, as confirmed by selected reaction monitoring-mass spectrometry, while minor changes were detected in the level of saliva proteases. Taken together, our results indicated that proteolytic activity is accentuated in the saliva of patients with OSCC and lymph-node metastasis and, at least in part, is modulated by reduced levels of salivary peptidase inhibitors. Therefore, this integrated pipeline provided better comprehension and discovery of molecular features with implications in the oral cancer metastasis prognosis.
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http://dx.doi.org/10.1074/mcp.RA120.002227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950089PMC
December 2020

Co-Overexpression of TWIST1-CSF1 Is a Common Event in Metastatic Oral Cancer and Drives Biologically Aggressive Phenotype.

Cancers (Basel) 2021 Jan 5;13(1). Epub 2021 Jan 5.

Segal Cancer Centre and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Departments of Medicine, Oncology, and Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, QC H3T 1E2, Canada.

Invasive oral squamous cell carcinoma (OSCC) is often ulcerated and heavily infiltrated by pro-inflammatory cells. We conducted a genome-wide profiling of tissues from OSCC patients (early versus advanced stages) with 10 years follow-up. Co-amplification and co-overexpression of , a transcriptional activator of epithelial-mesenchymal-transition (EMT), and colony-stimulating factor-1 (), a major chemotactic agent for tumor-associated macrophages (TAMs), were observed in metastatic OSCC cases. The overexpression of these markers strongly predicted poor patient survival (log-rank test, = 0.0035 and = 0.0219). Protein analysis confirmed the enhanced expression of TWIST1 and CSF1 in metastatic tissues. In preclinical models using OSCC cell lines, macrophages, and an in vivo matrigel plug assay, we demonstrated that gene overexpression induces the activation of while gene silencing down-regulates preventing OSCC invasion. Furthermore, excessive macrophage activation and polarization was observed in co-culture system involving OSCC cells overexpressing . In summary, this study provides insight into the cooperation between transcription factor and to promote OSCC invasiveness and opens up the potential therapeutic utility of currently developed antibodies and small molecules targeting cancer-associated macrophages.
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http://dx.doi.org/10.3390/cancers13010153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795342PMC
January 2021

Clinicopathological analysis and survival outcomes of primary salivary gland tumors in pediatric patients: A systematic review.

J Oral Pathol Med 2020 Dec 12. Epub 2020 Dec 12.

Department of Oral Diagnosis, Piracicaba Dental School, State University of Campinas, Piracicaba, Brazil.

Background: Salivary gland tumors are a diverse group of uncommon neoplasms that are rare in pediatric patients. The aim of this study was to evaluate the clinicopathological profile and survival outcomes of pediatric patients affected by salivary gland tumors.

Materials And Methods: An extensive search was carried out using the MEDLINE/PubMed, EMBASE, Scopus databases, and grey literature. The risk of bias was available in all papers included.

Results: A total of 2,830 articles were initially retrieved with 54 remaining for data extraction, resulting in 2,937 cases. This comprised forty-five case series' and nine cohort studies. These tumors were slightly more prevalent in females (57.4%). The patients' age ranged from 0.3 to 19 years old, with a mean age of 13.3 years. Parotid was the most affected site (81.9%), and 99.2% of cases clinically exhibited a swelling. Presence of pain/tenderness was reported in 13.5% of the cases, with an average duration of 12.6 months for the appearance of symptoms. Most of the reported cases were malignant tumors (75.4%), with mucoepidermoid carcinoma the most common tumor of all tumors (44.8%), followed by pleomorphic adenoma (24.1%). Surgery alone was the leading treatment choice in 74.9% cases, and the 5-year overall survival rate of patients was 93.1%. Patients with symptoms (P = .001), local recurrence (P < .001), metastasis (P < .001), and those not undergoing surgery or surgery combined with radiotherapy (P < .001) showed lower survival rates.

Conclusion: The pediatric patients present a high frequency of malignant salivary neoplasms and a high overall survival rate.
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http://dx.doi.org/10.1111/jop.13151DOI Listing
December 2020

Two sides of the same coin: Insights into the myoepithelial cells in carcinoma ex pleomorphic adenoma development.

Crit Rev Oncol Hematol 2021 Jan 9;157:103195. Epub 2020 Dec 9.

Department of Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, Sao Paulo, Brazil. Electronic address:

The myoepithelial cell seems to play an important role as a tumor suppressor in the development of carcinoma ex pleomorphic adenoma. Nevertheless, interesting aspects concerning the other side of the coin, i.e., the contribution of the myoepithelial cell to cell proliferation, were brought to light. Here we highlighted the studies in which myoepithelial cells were presented as tumor suppressors and promoters in the context of PA malignant transformation. In conclusion, even if in a paracrine way, divergent signals can alter the suppressor role of the myoepithelial cell and induce it to compose a microenvironment propitious to the tumor progression of the malignant cells. This would cause myoepithelial cells to succumb and malignant epithelial cells to initiate progression beyond the basal membrane.
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http://dx.doi.org/10.1016/j.critrevonc.2020.103195DOI Listing
January 2021

Endonasal endoscopic surgery for sinonasal squamous cell carcinoma from an oncological perspective.

Auris Nasus Larynx 2021 Feb 4;48(1):41-49. Epub 2020 Dec 4.

International Head and Neck Scientific Group, Padua, Italy.

Endonasal endoscopic surgery (EES) has been applied to the management of sinonasal (SN) tumors based on recent advances in endoscopic surgical techniques and technologies over the past three decades. EES has been mainly indicated for benign tumors and less aggressive malignant tumors. Notwithstanding this, EES has been gradually adopted for squamous cell carcinoma (SCC), which is the most common histology among SN malignancies. However, an analysis of the outcomes of EES for patients with SCC is difficult because most articles included SCC a wide range of different tumor histologies. Therefore, we herein review and clarify the current status of EES focusing on SCC from an oncological perspective. The oncologic outcomes and the ability to achieve a histologically complete resection are similar between endoscopic and open approaches in highly selected patients with SN-SCC. Surgical complications associated with EES are likely similar for SN-SCC compared to other sinonasal malignancies. The indications for a minimally invasive approach such as EES in the management of patients with SN-SCC should be stricter than those for less aggressive malignant tumors because of the aggressive nature of SCC. Also, it is important to achieve negative surgical margins with EES in patients with SCC. We believe that the indications for EES for SN-SCC are widening due to advances in diagnostic imaging, and endoscopic surgical techniques and technologies. However, while expanding the indications for EES for SN-SCC we must carefully confirm that the outcomes support this strategy.
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http://dx.doi.org/10.1016/j.anl.2020.11.018DOI Listing
February 2021

Risk factors for positive sentinel lymph nodes in head and neck melanoma - a survival analysis.

Braz J Otorhinolaryngol 2021 Jan-Feb;87(1):103-109. Epub 2020 Nov 6.

Universidade Nove de Julho, Curso de Medicina, São Paulo, SP, Brazil; Instituto do Câncer do Estado de São Paulo, Ambulatório de Tumores Cutâneos na Cirurgia de Cabeça e Pescoço, São Paulo, SP, Brazil.

Introduction: Sentinel lymph node biopsy is the gold standard procedure for head and neck cutaneous melanoma staging.

Objective: To evaluate the technical aspects, positivity and prognostic effect of the cervico-facial sentinel lymph node biopsy.

Methods: Retrospective, unicentric study. From 2009 to 2014, 49 patients with cutaneous melanoma of the head and neck underwent surgery at Instituto do Câncer do Estado de São Paulo (ICESP).

Results: Of the 49 patients, 5 had cervical metastasis at the moment of admission. Clark, Breslow and mitotic index were predictors of death. Among the 31 patients undergoing sentinel lymph node biopsy, 3 had positive sentinel lymph nodes (9.7%). Deaths were recorded in two of the cases with positive sentinel lymph nodes (66.6%), and in 5 (17.8%) of the patients with negative lymph nodes. The mean Breslow index was 11.3 mm for primary melanomas with positive sentinel lymph nodes and 4.3 mm for those with negative sentinel lymph nodes. Positivity was associated with Clark and Breslow levels. Malar location showed a protective effect on prognosis. The mean survival for patients with a mitotic index <3.5 was 181 months and 63.4 months for those with a mitotic index >3.5.

Conclusion: The frequency of positive sentinel lymph node biopsy in patients with malignant melanoma of the head and neck was lower than in other studies, although the sample consisted of individuals with advanced melanomas. The mitotic index was important for prognosis prediction.
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http://dx.doi.org/10.1016/j.bjorl.2020.09.014DOI Listing
February 2021

Quality of life among total laryngectomized patients undergoing speech rehabilitation: correlation between several instruments.

Clinics (Sao Paulo) 2020 11;75:e2035. Epub 2020 Nov 11.

Programa de pos-graduacao em Ciencias da reabilitacao, Faculdade de Medicina (FMUSP), Universidade de Sao Paulo, Sao Paulo, SP, BR.

Objective: The aim of this study was to correlate several instruments currently used for the assessment of the quality of life of patients who underwent total laryngectomy and speech rehabilitation.

Methods: A cross-sectional, observational study was conducted with 38 patients after total laryngectomy and speech therapy aiming to develop oesophageal speech. The patients were divided into the following two groups (19 participants each): speakers and non-speakers. The quality of life instruments used were as follows: visual analogue scale (VAS); Voice Handicap Index (VHI); Voice-Related Quality of Life (V-RQOL); Functional Assessment of Cancer Therapy - Head & Neck (FACT-H&N); European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30); European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Head and Neck (EORTC QLQ-H&N35); and University of Washington Quality of Life (UW-QOL).

Results: The V-RQOL global health domain exhibited a strong correlation with the VHI. The EORTC QLQ-C30 exhibited a moderate to strong correlation with the EORTC QLQ-H&N35 functional domain in both groups. The EORTC QLQ-C30 functional domain exhibited a strong to moderate correlation with all other instruments in both groups. The UW-QOL exhibited a moderate to strong correlation with the VHI and EORTC QLQ-C30 in both groups.

Conclusion: The EORTC QLQ-C30, EORTC QLQ-H&N35 and UW-QOL were the instruments that most correlated with the remaining instruments, indicating that any of the three can be used to assess the quality of life of the target population regardless of oesophageal voice development.
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http://dx.doi.org/10.6061/clinics/2020/e2035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603229PMC
December 2020

Oral leukoplakia and erythroplakia in young patients: a systematic review.

Oral Surg Oral Med Oral Pathol Oral Radiol 2021 Jan 14;131(1):73-84. Epub 2020 Sep 14.

Oral Diagnosis Department, Piracicaba Dental School, University of Campinas, Piracicaba, Brazil. Electronic address:

Objective: The aim of this study was to estimate the frequency of oral leukoplakia and oral erythroplakia in young patients.

Study Design: The systematic review was based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and performed in the following electronic databases: PubMed, Scopus, and Embase. The studies included were cross-sectional, cohort, and diagnostic, which provided with clinical and microscopic data of patients younger than 40 years. The Critical Appraisal Checklist for Prevalence Studies from the Joanna Briggs Institute and the Quality Assessment Tool for Diagnostic Accuracy Studies were used to assess the risk of bias.

Results: Five studies met eligibility criteria and were included. The total number of patients from the studies was 1246, of which 115 were young patients (9.2%) with oral leukoplakia as the only oral potentially malignant disorder reported. Oral epithelial dysplasia was identified in 40 cases (34.7%), of which 8 (6.9%) presented malignant transformation.

Conclusions: The frequency of oral leukoplakia is low in young patients. Observational studies are necessary for understanding oral leukoplakia and other oral potentially malignant disorders in younger patients.
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http://dx.doi.org/10.1016/j.oooo.2020.09.002DOI Listing
January 2021

Amelanotic melanoma presenting as a tongue tumor.

Oral Oncol 2021 Mar 11;114:105075. Epub 2020 Nov 11.

Head and Neck Surgery Department, Instituto do Câncer do Estado de São Paulo/Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil. Electronic address:

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http://dx.doi.org/10.1016/j.oraloncology.2020.105075DOI Listing
March 2021

PD-L1 expression patterns in oral cancer as an integrated approach for further prognostic classification.

Oral Dis 2020 Nov 10. Epub 2020 Nov 10.

Oral Diagnosis Department, Piracicaba Dental School, University of Campinas (UNICAMP), Piracicaba, Brazil.

Background: Despite the well-known role of programmed cell death ligand 1 (PD-L1) in promoting immune resistance in oral squamous cell carcinoma (OSCC), its potential utility as a prognostic biomarker is undetermined. We evaluated PD-L1 expression as predictor of survival in patients with OSCC and explored PD-L1 expression patterns.

Methods: We conducted a retrospective cohort study that assessed PD-L1 expression through immunohistochemistry in 123 surgical specimens of OSCC. A first approach evaluated tumor proportion scores (TPS) and combined proportion scores (CPS). Next, expression patterns were examined by evaluating PD-L1 localization in tumor nests, as well as the interfaces of tumor cells (TC) and immune cells (IC) in the tumor microenvironment.

Results: High-level PD-L1 expression determined by TPS and CPS using variable cutoffs was not associated with survival. Immunohistochemistry revealed that TC expressed PD-L1 in either patchy or diffuse patterns. The patchy pattern was an independent risk factor for overall survival. Furthermore, expression patterns in the tumor immune microenvironment showed that most cases expressed PD-L1 on both TC and IC, while PD-L1 non-expressors had the lowest overall survival.

Conclusion: PD-L1 expression patterns in the context of localization in tumor nests and TC-IC interactions represent antitumor immune responses better than either TPS or CPS. Our suggested classification system may have important implications for the characterization of OSCC and for the use of PD-L1 as a prognostic biomarker.
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http://dx.doi.org/10.1111/odi.13714DOI Listing
November 2020

Prognostic role of intraparotid lymph node metastasis in primary parotid cancer: Systematic review.

Head Neck 2021 Mar 9;43(3):997-1008. Epub 2020 Nov 9.

Coordinator of the International Head and Neck Scientific Group, Padua, Italy.

Background: The prognostic importance of intraparotid lymph node metastasis (P+) in patients with primary parotid gland carcinoma is unclear.

Methods: Nineteen retrospective and noncomparative cohort studies, published between 1992 and 2020, met the inclusion criteria and included 2202 patients for this systematic review.

Results: The pooled prevalence of the P in adult patients in the unselected studies was 24.10% (95% confidence interval = 17.95-30.25). The number of P+ lymph nodes per patient was counted in only three studies and ranged from 1 to 11. The 5-year recurrence-free survival rate based on Kaplan-Meier analysis varied from 83% to 88% in P- patients compared to 36% to 54% in P+ patients. The average hazard ratio for tumor recurrence in patients with P+ compared to P- was 2.67 ± 0.58.

Conclusions: P+ is an independent negative prognostic factor in primary parotid gland cancer and should be included into the treatment planning.
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http://dx.doi.org/10.1002/hed.26541DOI Listing
March 2021

Epidemiological profile and clinical implications of oral squamous cell carcinoma adjacent to dental implants.

Oral Dis 2020 Nov 3. Epub 2020 Nov 3.

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

Objectives: Describe the epidemiological profile of patients with oral squamous cell carcinoma (OSCC) around dental implants (DI), investigate the spectrum of clinical and pathological characteristics, and discuss the implications of diagnosis delay of these lesions.

Methods: Retrospective analysis of patients treated of OSCC adjacent to DI at A.C. Camargo Cancer Center between 2009 and 2020.

Results: Thirty one patients were identified, being women the majority (58.1%). The mean age of the patients was 68.8 years. Never smoker corresponds to 46.9% and never alcohol consumer to 54.9% of the sample. OPMD was reported in 45.2% of patients, affecting mainly women (78.5%). Leukoplakia (63.7%) followed by oral lichen planus (36.3%) was the most common OPMD found in women. OSCC adjacent to DI occurred in the inferior gingiva/alveolar mucosa in 48.3% of cases, and ulceration was the most common clinical appearance (87%). Peri-implantitis (PI) was initial clinical diagnosis in 16.1% of cases.

Conclusions: Oral squamous cell carcinoma adjacent to DI was more common in women over 70 years old, non-smokers and non-drinker, and the majority had oral leukoplakia before the diagnosis of OSCC. OSCC may present clinical and radiographic features that resemble PI which can delay the diagnosis and impair the prognosis.
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http://dx.doi.org/10.1111/odi.13710DOI Listing
November 2020

"Green July" 2020 and Another Good Reason to Quit Smoking: Help to Stop Spreading SARS-COV-2 and Save Lives!

Int Arch Otorhinolaryngol 2020 Oct 20;24(4):e395-e396. Epub 2020 Oct 20.

Head and Neck Surgery Division LIM-28, Laboratório de Cirurgia de Cabeça e Pescoço, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.

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http://dx.doi.org/10.1055/s-0040-1716571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593112PMC
October 2020

Global prevalence of human papillomavirus-driven oropharyngeal squamous cell carcinoma following the ASCO guidelines: A systematic review and meta-analysis.

Crit Rev Oncol Hematol 2020 Dec 25;156:103116. Epub 2020 Oct 25.

Oral Diagnosis Department, Piracicaba Dental School, University of Campinas (UNICAMP), Piracicaba, Brazil.

Objectives: to provide accurate information about the global prevalence of human papillomavirus (HPV) in oropharyngeal squamous cell carcinomas (OPSCC).

Material And Methods: a systematic review was performed using three main electronic databases. Studies were independently assessed by two reviewers based on established eligibility criteria, to identify the prevalence of HPV-driven OPSCC following criteria defined by the American Society of Clinical Oncology. Risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklist. Statistical software MedCalc was used to perform meta-analyses.

Results: from 2215 records found, 15 were included, reporting data from 6009 patients (time period range: 1980-2016), distributed in 11 countries. Eleven studies were considered as presenting low risk, and four as moderate risk of bias. Using proportion meta-analysis, pooled prevalence of HPV-driven OPSCC was 44.8 % (95 %CI: 36.4-53.5 %; i = 97.6 %), with the highest rates in New Zealand (74.5 %; 95 %CI: 60.9-85.3 %), and the lowest in Brazil (11.1 %; 95 %CI: 4.5-21.5 %). HPV prevalence was similar between males (45.7 %; 95 %CI: 36.5-55.0 %; i = 96.4 %) and females (42.2 %; 95 %CI: 34.3-50.5 %; i = 85.4 %). Mean/median age ranged from 59.1-67.1 years in the HPV-negative group, and from 55.7-63.5 years in the HPV-positive group. There was an overall discordance between testing by p16 (49.4 %; 95 %CI, 38.2-60.5 %; i = 96.2 %) and p16+ISH/PCR (44.7 %; 95 %CI, 33.5-56.2 %; i = 96.4 %).

Conclusion: Overall pooled prevalence of HPV-driven OPSCC was approximately 45 %, with similar distribution among males and females. Double p16/HPV-DNA/RNA testing may be considered to increase specificity and prognostic accuracy.
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http://dx.doi.org/10.1016/j.critrevonc.2020.103116DOI Listing
December 2020

Tumor volume as a prognostic factor of locally advanced laryngeal cancer.

Eur Arch Otorhinolaryngol 2020 Oct 23. Epub 2020 Oct 23.

Department of Head and Neck Surgery, University of Sao Paulo Medical School, Sao Paulo, Brazil.

Purpose: The TNM tumor staging system is the most widely used for laryngeal cancer. However, in the same T stage, lesions with different primary tumor volumes (TV) can be found, impacting treatment outcomes.

Methods: 145 patients with T3 and T4a laryngeal cancer, according to Union for International Cancer Control, who underwent surgical treatment from 2008 to 2017, were analyzed. TV measurements were collected and compared to different outcomes.

Results: The mean TV was 23.0 ± 16.4 cm. A cutoff point for TV of 14.2 cm was established. Cumulative sample 5-year overall survival (OS) was 62.1%, while 5-years disease-free survival (DFS) was 65.5%. In univariate analysis, TV ≥ 14.2 cm was associated with a higher risk of distant metastases (p = 0.045), and worse rates of OS (p = 0.009) and DFS (p = 0.035). In multivariate analysis, TV was not an independent risk factor of worse DFS (p = 0.569) or OS (p = 0.094).

Conclusion: Primary lesion TV showed significant association, in univariate analysis, with worse rates of recurrence and survival in advanced laryngeal cancer undergoing surgical treatment and can be a promising prognostic for these patients.
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http://dx.doi.org/10.1007/s00405-020-06438-1DOI Listing
October 2020

Salivary alpha-1-antitrypsin and macrophage migration inhibitory factor may be potential prognostic biomarkers for oncologic treatment-induced severe oral mucositis.

Support Care Cancer 2020 Oct 2. Epub 2020 Oct 2.

Dental Oncology Service, Instituto do Câncer do Estado de São Paulo, ICESP-FMUSP, São Paulo, Brazil.

Aims: Evaluate the abundance of the selected targets, alpha-1-antitrypsin (A1AT) and macrophage migration inhibitory factor (MIF), and correlate these findings with the risk of developing severe oral mucositis (OM).

Materials And Methods: Head and neck squamous cell carcinoma (HNSCC) patients submitted to radiotherapy (RT) or chemoradiotherapy (CRT) were assessed. OM grade and pain were evaluated daily during treatment. Two protein targets, A1AT and MIF, were evaluated, using selected reaction monitoring-mass spectrometry (SRM-MS), in whole saliva, collected prior to oncologic treatment. The results obtained from the targeted proteomic analysis were correlated with OM clinical outcomes.

Results: A total of 27 patients were included, of whom 21 (77.8%) had locally advanced disease (clinical stage III or IV). Most patients (70.4%) received CRT. OM grades 2 (40.8%) and 3 (33.3%) were the most prevalent during RT with a mean highest reported OM-related pain of 3.22 through the visual analogue scale (VAS). The abundance of A1AT and MIF correlated significantly with severe (grades 3 or 4, p < 0.02) compared with moderate-low (grades 1 or 2, p < 0.04) OM grade.

Conclusions: There is a correlation between the abundance of salivary A1AT and MIF and oncologic treatment-induced OM. The correlation of MIF expression with severe OM appears to be compatible with its physiological pro-inflammatory role. These results open up great possibilities for the use of salivary MIF and A1AT levels as prognostic markers for effective therapeutic interventions, such as photobiomodulation therapy, patient-controlled analgesia, or personalized medicaments.
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http://dx.doi.org/10.1007/s00520-020-05805-2DOI Listing
October 2020

Health-Related Quality of Life Outcomes in Head and Neck Cancer: Results From a Prospective, Real-World Data Study With Brazilian Patients Treated With Intensity Modulated Radiation Therapy, Conformal and Conventional Radiation Techniques.

Int J Radiat Oncol Biol Phys 2021 Feb 29;109(2):485-494. Epub 2020 Sep 29.

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

Purpose: To compare global health-related quality of life (HRQoL) and overall survival (OS) in patients with head and neck cancer treated with intensity modulated radiation therapy (IMRT), conformal radiation therapy (3DCRT) or conventional radiation therapy (2DRT).

Methods And Materials: In this real-world, multi-institutional and prospective study, HRQoL outcomes were assessed using the European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 (EORTC QLQ-C30) and European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Head and Neck 43 (H&N43) questionnaires. Item response theory was used to generate a global HRQoL score, based on the 71 questions from both forms. The effect of treatment modality on HRQoL was studied using multivariate regression analyses. Survival was estimated using the Kaplan-Meyer method, and groups were compared by the log-rank test.

Results: Five hundred and seventy patients from 13 institutions were included. Median follow-up was 12.2 months. Concerning the radiation technique, 29.5% of the patients were treated with 2DRT, 43.7% received 3DCRT, and 26.8% were treated with IMRT. A higher proportion of patients receiving 2DRT had a treatment interruption of more than 5 days (69% vs 50.2% for 3DCRT and 42.5% for IMRT). IMRT had a statistically significant positive effect on HRQoL compared with 3DCRT (β= 2.627, standard error = 0.804, P = .001) and 2DRT had a statistically significant negative effect compared with 3DCRT (β= -5.075, standard error = 0.926, P < .001). Patients receiving 2DRT presented a worse OS (P = .01). There were no differences in OS when IMRT was compared with 3DCRT.

Conclusions: IMRT provided better HRQoL than 3DCRT, which provided better HRQoL than 2DRT. Patients receiving 2DRT presented a worse OS, which might be related to more frequent treatment interruptions.
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http://dx.doi.org/10.1016/j.ijrobp.2020.09.044DOI Listing
February 2021

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

Stromal categorization in early oral tongue cancer.

Virchows Arch 2020 Sep 21. Epub 2020 Sep 21.

Institute of Biomedicine, Pathology, University of Turku and Turku University Hospital, Turku, Finland.

Stromal categorization has been used to classify many epithelial cancer types. We assessed the desmoplastic reaction and compared its significance with other stromal characteristics in early (cT1-2N0) oral tongue squamous cell carcinoma (OTSCC). In this multi-institutional study, we included 308 cases treated for early OTSCC at five Finnish university hospitals or at the A.C. Camargo Cancer Center in São Paulo, Brazil. The desmoplastic reaction was classified as immature, intermediate, or mature based on the amount of hyalinized keloid-like collagen and myxoid stroma. We compared the prognostic value of the desmoplastic reaction with a stromal grading system based on tumor-stroma ratio and stromal tumor-infiltrating lymphocytes. We found that a high amount of stroma with a weak infiltration of lymphocytes was associated statistically significantly with a worse disease-free survival with a hazard ratio (HR) of 2.68 (95% CI 1.26-5.69), worse overall survival (HR 2.95, 95% CI 1.69-5.15), and poor disease-specific survival (HR 2.66, 95% CI 1.11-6.33). Tumors having a high amount of stroma with a weak infiltration of lymphocytes were also significantly associated with a high rate of local recurrence (HR 4.13, 95% CI 1.67-10.24), but no significant association was found with lymph node metastasis (HR 1.27, 95% CI 0.37-4.35). Categorization of the stroma based on desmoplastic reaction (immature, intermediate, mature) showed a low prognostic value for early OTSCC in all survival analyses (P > 0.05). In conclusion, categorization of the stroma based on the amount of stroma and its infiltrating lymphocytes shows clinical relevance in early OTSCC superior to categorization based on the maturity of stroma.
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http://dx.doi.org/10.1007/s00428-020-02930-5DOI Listing
September 2020

Oral cancer adjacent to dental implants mimicking benign lesions: a case series study.

Aust Dent J 2021 03 4;66(1):112-118. Epub 2020 Oct 4.

Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas, Piracicaba, Brazil.

Despite the long-term survival rates of osseointegrated dental implants, several biological complications are known to affect the peri-implant tissues, such as peri-implant mucositis and peri-implantitis. Occasionally, the clinical features of these more common benign lesions, or others nonrelated to implants, might be similar to oral malignancies, leading to misdiagnosis. The objective of this study was to present a case series of oral cancer located adjacent to dental implants, aimed to identify the reasons for initial misinterpretation of diagnosis. Thirteen patients, 10 females and 3 males, aged 59 to 90, were assessed. Among the differential diagnoses established, a malignant or premalignant lesion was not considered in 10 out of the 13 patients. Peri-implantitis was the most common preliminary diagnosis, followed by fungal infection, viral infections, and traumatic ulcers. The meantime for the diagnosis of oral cancer was 21.5 months. The clinical presentation of peri-implant malignancy, such as ulceration, white and red plaques, and exophytic lesions, might mimic benign diseases that are more common in the oral cavity. Suspicious lesions with treatment failure that persist for more than 2 weeks require biopsy and histopathological analysis to establish an early definitive diagnosis to improve the prognosis and quality of life of the patients.
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http://dx.doi.org/10.1111/adj.12793DOI Listing
March 2021

Head and neck surgery recommendations during the COVID-19 pandemic.

Lancet Oncol 2020 09;21(9):e416

Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.

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http://dx.doi.org/10.1016/S1470-2045(20)30440-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462552PMC
September 2020