Publications by authors named "Luiz Paulo Kowalski"

333 Publications

State-of-the-science concepts of HPV-related oropharyngeal squamous cell carcinoma: a comprehensive review.

Oral Surg Oral Med Oral Pathol Oral Radiol 2022 Apr 8. Epub 2022 Apr 8.

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

High-risk (HR) human papillomavirus (HPV) infection is recognized as a primary etiologic factor of anogenital cancers and more recently of a subgroup of oropharyngeal squamous cell carcinomas (OPSCC). The incidence of HPV-related OPSCC has increased dramatically in several developed countries in the past 3 decades and is currently the most common cancer caused by HR-HPV in the United States and Germany, surpassing cervical cancer. Consequently, the patient's demographic and clinicopathologic profile has shifted to nonsmoking and nondrinking younger men with higher schooling level and with a history of multiple oral sex partners. Patients with HPV-related OPSCC often show better treatment outcomes and higher survival rates than their HPV-unrelated counterparts, which has led to a change in tumor staging for HPV-related cases. HPV vaccination is emerging as an effective primary prevention strategy, and systematic screening of HPV DNA in blood and salivary oral rinse samples of HR patients is being examined to determine if it may provide a surveillance method and support early diagnosis of HPV-related OPSCC. In this context, a narrative review was conducted to provide an overview of the state-of-the-art of HPV-related OPSCC, including epidemiology, risk factors, clinicopathologic and molecular features, screening, prevention, management, and prognosis.
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http://dx.doi.org/10.1016/j.oooo.2022.03.016DOI Listing
April 2022

Decreased CD1a + and CD83 + cells in tonsillar squamous cell carcinoma regardless of HPV status.

J Appl Oral Sci 2022 16;30:e20210702. Epub 2022 May 16.

Universidade Federal de Santa Catarina - UFSC, Departamento de Patologia, Florianópolis, SC, Brasil.

Background: Dendritic cells (DCs) are specialized antigen-presenting cells that play a critical role in the immune response against human papillomavirus (HPV) infection, and represent a therapeutic target in cancer.

Objective: To identify and quantify DCs in tonsillar squamous cell carcinoma (TSCC) under the influence of HPV infection.

Methodology: CD1a and CD83 antibodies were used to identify immature dendritic cells and mature dendritic cells by immunohistochemistry in 33 primary TSCC and 10 normal tonsils (NTs), respectively. For the TSCC samples, the number of DCs per area was evaluated in the intra- and peritumoral compartments. For the NTs, the quantification of DCs was evaluated in the intra- and peritonsillar compartments. HPV detection methods were determined according to the ASCO Clinical Practice Guidelines from the College of American Pathologists Guideline (2018).

Results: There were fewer intratumoral CD1a+ DCs in the HPV-positive and HPV-negative TSCC groups than in the NT group (p<0.05). In the peritumoral compartment, there were fewer CD83+ DCs in the HPV-positive and HPV-negative TSCC groups than in the NT group (p<0.001). The quantification of DCs subtypes showed no statistical differences between HPV-positive and HPV-negative TSCC groups (p>0.137). Patients with HPV-positive TSCC had significantly better overall survival rate than those with HPV-negative TSCC (p=0.004).

Conclusion: Tumor activity contributes to DC depletion regardless of intralesional HPV positivity. An improved prognosis has been reported in patients with HPV-positive TSCC.
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http://dx.doi.org/10.1590/1678-7757-2020-0702DOI Listing
May 2022

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

Head Neck 2022 Jul 15;44(7):1604-1615. 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
July 2022

Risk factors associated with head and neck cancer in former smokers: A Brazilian multicentric study.

Cancer Epidemiol 2022 06 1;78:102143. Epub 2022 Apr 1.

Antônio Prudente Foundation, A.C.Camargo Cancer Center, Rua Professor Antônio Prudente, 211, São Paulo, Brazil; Department of Head and Neck Surgery, University of São Paulo Medical School, São Paulo, Brazil. Electronic address:

Background: Reduced tobacco consumption in the population has not been associated with reduced incidence rates of head and neck cancer in several countries.

Objective: To explore the associations between HNC and sociodemographic characteristics and lifestyle of former smokers from three Brazilian cancer centers.

Methods: A multicenter case-control study was conducted with 229 former smokers diagnosed with squamous cell carcinoma of the oral cavity, oropharynx, larynx, and 318 controls (former smokers without head and neck cancer). Bivariate and multiple logistic regression analyses were conducted to estimate odds ratios (ORs) with a 95% confidence interval (CI).

Results: 11-20 years after smoking cessation showed significant impact on HNC reduction (OR 0.22, 95% CI, 0.12-0.39), which reached 82% (95% CI, 0.09-0.35) among 20 + former smokers when compared to individuals who had stopped smoking for up to 5 years. A history of high-intensity smoking (>40 pack-years) increased HNC risk by 2.09 times (95% CI 1.13-3.89) when compared to subjects who smoked up to 20 pack-years. Past alcohol consumption (OR 1.99, 95% CI, 1.06-3.82) was also associated with head and neck cancer risk in former smokers when compared to no alcohol consumption. There was a decreased head and neck cancer risk in former smokers who had high school level of education (OR 0.38, 95% CI, 0.16-0.91) compared to illiterate former smokers; and former smokers with moderate intake of vegetables (OR 0.49, 95% CI, 0.28-0.85) and fruits (OR 0.43, 95% CI, 0.25-0.73) compared to those with low intake.

Conclusion: Head and neck cancer risk in former smokers decreases after 11 years after smoking cessation, former smokers with past alcohol consumption showed an increased risk of HNC. High school level of education and moderate intake of vegetables and fruits reduced HNC risk among former smokers.
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http://dx.doi.org/10.1016/j.canep.2022.102143DOI Listing
June 2022

Incidental thyroid carcinoma: Correlation between FNAB cytology and pathological examination in 1093 cases.

Clinics (Sao Paulo) 2022 17;77:100022. Epub 2022 Mar 17.

Departamento de Patologia, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, SP, Brazil. Electronic address:

Objective: To investigate Incidental Thyroid Carcinoma (ITC) by comparing the results of Fine Needle Aspiration Biopsy (FNAB) cytology and the postoperative pathological findings.

Methods: Data of 1479 patients who underwent total thyroidectomy were retrieved. Three hundred eighty-six patients were excluded due to insufficient data. Each surgical specimen studied received two histopathological diagnoses: the local diagnosis ‒ for the same area in which the FNAB was performed; and the final diagnosis, which includes a study of the entire surgical specimen.

Results: A thousand and ninety-three patients were investigated. FNAB result was malignant in 187 patients, benign in 204, suspicious or indeterminate in 668 cases, and inconclusive in 34 cases. The prevalence of ITC was 15.1%. Most of the ITC in this series was less than 0.5 cm. The incidence of ITC was higher in Bethesda III (17.5% ITC) and IV (19% ITC) than in Bethesda II cases (1.5% false negatives and 9% ITC).

Conclusion: Although the incidence of false-negative results in Bethesda II nodules is only 1.5%, 9% of these patients had ITC in the thyroid parenchyma outside the nodule that underwent preoperative FNAB. The incidence of ITC in the same scenario was even higher in Bethesda III (17.5%) and Bethesda IV cases (19%). Ultrasonography-guided FNAB is an excellent method for the assessment of thyroid nodules. However, biopsy sites should be carefully selected. Despite the high incidence of incidentalomas, total thyroidectomy should not always be the treatment of choice due to its rare but potentially serious complications. The findings of the present study can assist future clinical decisions towards active surveillance strategies for the management of papillary thyroid carcinoma.
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http://dx.doi.org/10.1016/j.clinsp.2022.100022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8941178PMC
April 2022

Prognostic impact of perineural invasion in oral cancer: a systematic review.

Acta Otorhinolaryngol Ital 2022 Feb;42(1):17-25

Head of the Department of Head and Neck Surgery, Hospital das Clinicas, University of São Paulo School of Medicine, São Paulo, Brazil.

Introduction: Numerous studies have evaluated the prognostic significance of perineural invasion (PNI) in oral cancer; however, the results are inconclusive.

Purpose: To identify the prognostic value of PNI in oral cancer through a metanalysis.

Methods: A literature review was carried out, searching the MedLine databases via Pubmed, Scielo, Lilacs, Cochrane and Websco.

Results: A total of 56 studies were included. The results indicate that PNI in oral cancer has an incidence of 28% (95% confidence interval (CI) 24-31%); 5-year survival with relative risk (RR) 0.67 (0.59-0.75); 5-year disease-free survival RR 0.71 (0.68-0.75); locoregional recurrence with RR 2.09 (1.86-2.35).

Conclusions: PNI is a negative prognostic factor in oral cancer.
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http://dx.doi.org/10.14639/0392-100X-N1653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9058930PMC
February 2022

Nutritional and immunological parameters as prognostic factors in patients with advanced oral cancer.

Braz J Otorhinolaryngol 2021 Dec 4. Epub 2021 Dec 4.

Universidade de São Paulo, Faculdade de Medicina, Instituto do Câncer do Estado de São Paulo (Icesp), São Paulo, SP, Brazil; Faculdade Israelita de Ciências da Saúde Albert Einstein, São Paulo, SP, Brazil. Electronic address:

Objective: The aim of the present study was to analyze the prognostic relationship of weight loss and preoperative hematological indexes in patients surgically treated for pT4a squamous cell carcinoma of the oral cavity.

Methods: A retrospective cohort study.

Results: Percent weight loss greater than 10% was identified in 49 patients (28.2%), and any weight loss in relation to the usual weight occurred in 140 patients (78.7%). Percent weight loss greater than 10% (HR = 1.679), Red cell distribution width (RDW) values greater than 14.3% (HR = 2.210) and extracapsular spread (HR = 1.677) were independent variables associated with risk of death.

Conclusion: Patients with advanced squamous cell carcinoma of the oral cavity present significant weight loss and as significantly immunocompromised. Increased values of RDW and higher percentages of weight loss in relation to the individual's usual weight, together with extracapsular spread of metastatic lymph nodes, were risk factors for lower survival, regardless of other clinical and anatomopathological characteristics.

Level Of Evidence: 3:
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http://dx.doi.org/10.1016/j.bjorl.2021.11.003DOI Listing
December 2021

Distant metastasis from head and neck cancer: role of surgical treatment.

Curr Opin Otolaryngol Head Neck Surg 2022 Apr;30(2):114-118

Head and Neck Surgery and Otorhinolaryngology Department, A. C. Camargo Cancer Center.

Purpose Of Review: The rates of distant metastases in patients with head and neck squamous cell carcinoma varies from 3 to 50%. Metastases are usually multiple, diagnosed within 24 months after treatment and sited in the lungs, bone or liver. This review highlights the importance of a personalized treatment approach in such patients.

Recent Findings: In patients with primary tumor controlled and with oligometastatic disease, surgical options can be considered, especially for lung metastases. Overall survival for patients who are candidates for lung metastasectomy can be as high as 59%. In bone and liver metastases, resection is not frequently used but radiofrequency ablation is a promising option. Finally, mediastinal and axillary lymph node metastasis are classified as distant metastases, and lymph node dissection is the treatment of choice whenever the disease is limited to these sites.

Summary: Patients with distant metastases usually are considered incurable; however, an aggressive local treatment of solitary distant metastases should be considered in highly selected patients, with a potential increase of overall survival.
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http://dx.doi.org/10.1097/MOO.0000000000000789DOI Listing
April 2022

miR-22 and miR-205 Drive Tumor Aggressiveness of Mucoepidermoid Carcinomas of Salivary Glands.

Front Oncol 2021 9;11:786150. Epub 2022 Feb 9.

Department of Oral Pathology, Faculdade São Leopoldo Mandic, Campinas, Brazil.

Objectives: To integrate mRNA and miRNA expression profiles of mucoepidermoid carcinomas (MECs) and normal salivary gland (NSGs) tissue samples and identify potential drivers.

Material And Methods: Gene and miRNA expression arrays were performed in 35 MECs and six NSGs.

Results: We found 46 differentially expressed (DE) miRNAs and 3,162 DE mRNAs. Supervised hierarchical clustering analysis of the DE transcripts revealed two clusters in both miRNA and mRNA profiles, which distinguished MEC from NSG samples. The integrative miRNA-mRNA analysis revealed a network comprising 696 negatively correlated interactions (44 miRNAs and 444 mRNAs) involving cell signaling, cell cycle, and cancer-related pathways. Increased expression levels of miR-205-5p and miR-224-5p and decreased expression levels of miR-139-3p, miR-145-3p, miR-148a-3p, miR-186-5p, miR-338-3p, miR-363-3p, and miR-4324 were significantly related to worse overall survival in MEC patients. Two overexpressed miRNAs in MEC (miR-22 and miR-205) were selected for inhibition by the CRISPR-Cas9 method. Cell viability, migration, and invasion assays were performed using an intermediate grade MEC cell line. Knockout of miR-205 reduced cell viability and enhanced expression, while miR-22 knockout reduced cell migration and invasion and enhanced expression. Our results indicate a distinct transcriptomic profile of MEC compared to NSG, and the integrative analysis highlighted miRNA-mRNA interactions involving cancer-related pathways, including PTEN and PI3K/AKT.

Conclusion: The functional studies revealed that miR-22 and miR-205 deficiencies reduced the viability, migration, and invasion of the MEC cells suggesting they are potential oncogenic drivers in MEC.
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http://dx.doi.org/10.3389/fonc.2021.786150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8864291PMC
February 2022

Cushing's syndrome due to ectopic adrenocorticotropin secretion by a parotid carcinoma.

Arch Endocrinol Metab 2022 Mar 13;66(1):92-96. Epub 2022 Jan 13.

Centro de Oncologia, Hospital Sírio-Libanês, São Paulo, SP, Brasil.

We report a rare case of Cushing's syndrome in a 37-year-old female who initially presented with localized acinic cell carcinoma of the parotid gland. In January 2014, she underwent a right parotidectomy with facial nerve preservation and adjuvant radiotherapy. In August 2018, she presented a histologically-proven local regional relapse. The patient was considered for salvage surgery with facial nerve sacrifice and remained with no evidence of disease. One year later the patient developed pulmonary dissemination and started to gain weight and developed facial plethora and acne on the face and upper trunk. In a physical examination, the patient presented moon face, buffalo hump, acne and stage 2 hypertension. Biochemical evaluation confirmed ACTH-dependent Cushing's syndrome. IHC for ACTH in the lung biopsy revealed strong positive staining for ACTH confirming a diagnosis of ectopic ACTH secretion by a metastatic parotid acinic cell carcinoma. Ketoconazole (600 mg/d) was started to treat the CS. In addition, as chemotherapy was initiated to treat the metastatic disease. After the fifth cycle of chemotherapy, ketoconazole was suspended and the patient remained in remission of CS for four months, when CS recurred. A unique feature of this case is related to the clinical CS relapse associated with disease progression, which needed prompt treatment with ketoconazole, resulting in a significant improvement in the patient's condition. Although rare, should be attentive for possible CS features in patients with high-grade salivary gland carcinomas, since the diagnosis of ectopic secretion of ACTH may significantly impact their management and outcomes.
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http://dx.doi.org/10.20945/2359-3997000000426DOI Listing
March 2022

EMT in salivary gland tumors: the expression of microRNAs miR-155 and miR-200c is associated with clinical-pathological parameters.

Mol Biol Rep 2022 Mar 4;49(3):2157-2167. Epub 2022 Jan 4.

International Research Center, A.C.Camargo Cancer Center, Centro Internacional de Pesquisa, Rua Taguá, 440-Primeiro andar, São Paulo, SP, Brazil.

Background: Epithelial to mesenchymal transition promotes cell adhesion loss, enabling invasion and metastasis. MicroRNAs are a class of small non-codifying RNAs that regulate gene expression.

Objectives: The aim of this study was to evaluate the expression of microRNAs that could regulate the expression of EMT factors in salivary gland tumors (SGTs).

Methods And Results: The expression of microRNAs miR-9, miR-34a, miR-101, miR-138, miR-155, and miR-200c-described in the literature to target EMT factors-was evaluated by Real-time RT-PCR (qPCR) in pleomorphic adenoma (PA), mucoepidermoid carcinoma (MEC) and adenoid cystic carcinoma (ACC) samples. Bioinformatics tools were applied to identify miR targets and immunohistochemistry was used to examine the expression of the proteins E-cadherin, Twist, ZEB-1, β-Catenin, and c-Kit. Comparing miR expression among SGT types, we observed increased expression of miR-9, and miR-138 in PAs, and increased miR-155 expression in MECs. Low-grade MECs exhibited increased miR-155 expression (p = 0.032). MECs that generated lymph node metastases had increased miR-200c levels (p = 0.018). MECs tended to have decreased expression of EMT-related proteins when compared to the other SGT types (c-Kit p < 0.001, Twist p = 0.014, and ZEB p = 0.012). Notably, increased c-Kit expression was associated with the presence of perineural infiltration in ACC (p = 0.050).

Conclusions: This study provides evidence of alterations in the expression of EMT-factors regulating miRs, especially of miR-9, miR-138, miR-155, and miR-200c. No significant relationships were found between the expression of these miRs and proteins associated with EMT in SGTs.
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http://dx.doi.org/10.1007/s11033-021-07033-1DOI Listing
March 2022

The impact of worst pattern of invasion on the extension of surgical margins in oral squamous cell carcinoma.

Head Neck 2022 03 14;44(3):691-697. Epub 2021 Dec 14.

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

Background: To evaluate margins for oral carcinoma according to types of invasion front.

Methods: Retrospective cohort of 772 patients with worst pattern of invasion (WPOI) graded 1-5. Local recurrence was the outcome of interest.

Results: Local recurrences occurred in 164 patients (21.2%) and was affected by WPOI type 4/5, margin distance, perineural invasion, and adjuvant radiotherapy. In patients with WPOI types 1/2/3, a cutoff of 1.7 mm was considered ideal margin extent and in patients with WPOI types 4/5, the cutoff was 7.8 mm. Patients below these thresholds had a significantly higher incidence of local recurrence.

Conclusions: Different WPOI determine the ideal extent of surgical margins as 1.7 mm for patients with types 1-3, and 7.8 mm in patients with types 4/5.
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http://dx.doi.org/10.1002/hed.26956DOI Listing
March 2022

Discovery proteomics reveals potential protein signature associated with malignant phenotype acquisition in pleomorphic adenoma.

Oral Dis 2021 Dec 13. Epub 2021 Dec 13.

Pathology Department, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, Brazil.

Objective: To analyze the proteomic profile of salivary pleomorphic adenoma (PA) and carcinoma ex pleomorphic adenoma (CXPA) samples and correlate them with the malignant transformation of the PA.

Materials And Methods: Thirty samples (10 PA, 16 CXPA, and 4 residual PA) were microdissected and submitted to liquid chromatography-tandem mass spectrometry (LC-MS/MS). The proteomic data and protein identification were analyzed through LC-MS/MS spectra using the MaxQuant software.

Results: The proteomic analysis identified and quantified a total of 240 proteins in which 135 were found in PA, residual PA, and CXPA. The shared proteins were divided into six subgroups, and the proteins that showed statistically significant differences (p > 0.05) and fold-change > or <2.5 in one subgroup to another subgroup were included. Seven proteins (Apolipoprotein A-I-APOA1, haptoglobin-HP, protein of the synaptonemal complex 1-SYCP1, anion transport protein of band 3-SLC4A1, subunit μ1 of AP-1 complex-AP1M1, beta subunit of hemoglobin-HBB, and dermcidin-DCD) were classified as potential protein signatures, being HP, AP1M1, and HBB with higher abundance for PA to residual PA, APOA1 with higher abundance for PA to CXPA, SLC4A1 with lower abundance in the PA to CXPA, SYCP1with lower abundance for residual PA to CXPA, and DCD with higher abundance in the CXPA with epithelial differentiation to myoepithelial differentiation.

Conclusions: In this work, we demonstrated the comparative proteomic profiling of PA, residual PA, and CXPA, and seven were proposed as protein signatures, some of which may be associated with the malignant phenotype acquisition.
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http://dx.doi.org/10.1111/odi.14102DOI Listing
December 2021

Achieving negative resection margins in oral cavity cancer with masticator space involvement-Is it feasible? International collaborative study.

Head Neck 2022 02 29;44(2):453-459. Epub 2021 Nov 29.

Department of Otolaryngology, Head and Neck Surgery and Maxillofacial Surgery, Tel-Aviv Sourasky Medical Center, Affiliated to the Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Background: Masticator space involvement in oral cavity squamous cell carcinoma (OCSCC) is considered an unresectable disease. Nevertheless, achieving negative resection margins is feasible in limited masticatory space involvement.

Materials And Methods: A multi-institutional study on OCSCC patients with masticator space invasion who underwent surgical resection. Margin status was assessed according to anatomic tumor involvement of the inframandibular and supra-mandibular notch.

Results: One-hundred and thirty-two patients met the inclusion criteria. Then, 67 patients (50.8%) were diagnosed with a supra-notch tumor and 65 (49.2%) with an infra-notch disease. Negative margins were more common in the infra-notch group (43.3 vs. 23.1%, p = 0.014), and positive margins were more common in the supra-notch group (41.5 vs. 23.9%, p = 0.041). Multivariable analysis demonstrated that supra-notch tumors had an increased likelihood for involved resection margins (odds ratio = 2.46, p = 0.036).

Conclusion: OCSCC patients with masticator space involvement are prone for positive surgical margins in tumors extending above the supra-mandibular notch.
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http://dx.doi.org/10.1002/hed.26943DOI Listing
February 2022

Oral squamous cell carcinoma outcome in adolescent/young adult: Systematic review and meta-analysis.

Head Neck 2022 02 22;44(2):548-561. Epub 2021 Nov 22.

Department of Oral and Maxillofacial Surgery, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, Texas, USA.

To perform a systematic review focusing on the prognosis of oral cavity squamous cell carcinoma (OSCC) in young patients (≤40 years old) compared to older (>40 years old). Four databases were used in our search strategy. First, all titles were systematically organized using the Covidence platform online. In the second phase, 118 full texts of potentially eligible studies were analyzed by reviewers independently and in pairs. Twelve studies were considered eligible for data extraction. The relapse was higher in the young than in controls (pooled relative risk (RR) = 1.31; 95% CI [1.10-1.56]). The 5-year disease-free survival (DFS) was worse in young group (pooled hazard ratio (HR) = 0.73; 95% CI [0.63-0.85]) but the 5-year overall survival (OS) estimate was similar between the groups (pooled HR = 0.84; 95% CI [0.70-1.00]). While the 5-year OS was similar between groups, the number of relapses and 5-year DFS were worse in patients with OSCC ≤40 years old.
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http://dx.doi.org/10.1002/hed.26940DOI Listing
February 2022

Predictive Factors of Recurrence of Papillary Thyroid Microcarcinomas: Analysis of 2,538 Patients.

Int Arch Otorhinolaryngol 2021 Oct 19;25(4):e585-e593. Epub 2021 Feb 19.

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

 The incidence of papillary thyroid microcarcinoma (PTMC) has increased, and its treatment remains controversial.  To identify the clinical and pathological factors predictive of tumor recurrence.  We retrospectively analyzed 2,538 consecutive patients treated for PTMC, most submitted to total thyroidectomy (98%) followed by radioactive iodine (RAI) ablation (51.7%) at a cancer center from 1996 to 2015. The patients were stratified according to the American Thyroid Association (ATA) risk categories (low, intermediate, or high), and the clinicopathological features were evaluated by multivariate Cox regression analysis to identify independent prognostic factors for recurrence.  After a mean follow-up of 58 months (range: 3 to 236.5 months), tumor recurrence was diagnosed in 63 (2.5%) patients, mostly in the lymph nodes. Distant metastasis occurred in 2 (0.1%) patients. There were no cancer-related deaths. The multivariate analysis showed that age < 55 years (  = 0.049; hazard ratio [HR]: 2.54; 95% confidence interval [95%CI]: 0.95 to 0.99), multifocality (  = 0.032; HR: 1.76; 95%CI: 1.05 to 2.96), and the presence of lymph-node metastasis (  < 0.001; HR: 3.69; 95%CI: 2.07-6.57) were independent risk factors for recurrence. Recurrence was observed in 29 (1.5%) out of 1,940 low-risk patients, 32 (5.4%) out of 590 intermediate-risk patients, and in 2 (25%) out of 8 high-risk patients.  The prognosis of PTMC is excellent, favoring a conservative treatment for most patients. Age < 55 years, multifocality, and node metastasis at diagnosis, as well the ATA staging system effectively predict the risk of recurrence. The presence of these risk factors can help identify patients who should be considered for more aggressive management and more frequent follow-up.
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http://dx.doi.org/10.1055/s-0040-1722253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8558954PMC
October 2021

Risk factors associated with disease-specific mortality in papillary thyroid cancer patients with distant metastases.

Endocrine 2022 Mar 19;75(3):814-822. Epub 2021 Oct 19.

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.

Purpose: Papillary thyroid carcinoma (PTC) is among the most curable cancer types. Even though uncommon, some patients present distant metastatic disease at diagnosis or during the follow-up and most of them have long-term survival. However, there continues to be controversies regarding what clinicopathological features are associated with mortality in these patients. This paper evaluates the factors related to poor disease-specific survival (DSS) in patients with metastatic PTC.

Methods: A retrospective cohort study included PTC patients with distant metastasis from a tertiary public oncological center. Clinicopathological features, treatment modalities, and outcome were reviewed.

Results: Between 1986 and 2014, 108 patients were diagnosed with metastatic PTC. In the multivariate analysis male sex (HR = 2.65; 95%CI: 1.08-6.53; P = 0.033), radioiodine refractory disease (HR = 9.50; 95%CI: 1.23-73.38; P = 0.031) and metastasis at multiple sites (HR = 5.91; 95%CI: 1.80-19.32; P = 0.003) were independent risk factors for death in patients with metastatic PTC.

Conclusion: Male patients with metastatic PTC, with radioiodine refractory disease and metastasis at multiple sites have a high risk of death.
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http://dx.doi.org/10.1007/s12020-021-02901-zDOI Listing
March 2022

Cephaeline is an inductor of histone H3 acetylation and inhibitor of mucoepidermoid carcinoma cancer stem cells.

J Oral Pathol Med 2021 Oct 18. Epub 2021 Oct 18.

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

Aim: To evaluate the potential use of Cephaeline as a therapeutic strategy to manage mucoepidermoid carcinomas (MEC) of the salivary glands.

Material And Methods: UM-HMC-1, UM-HMC-2, and UM-HMC-3A MEC cell lines were used to establish the effects of Cephaeline over tumor viability determined by MTT assay. In vitro wound healing scratch assays were performed to address cellular migration while immunofluorescence staining for histone H3 lysine 9 (H3k9ac) was used to identify the acetylation status of tumor cells upon Cephaeline administration. The presence of cancer stem cells was evaluated by the identification of ALDH enzymatic activity by flow cytometry and through functional assays using in vitro tumorsphere formation.

Results: A single administration of Cephaeline resulted in reduced viability of MEC cells along with the halt on tumor growth and cellular migration potential. Administration of Cephaeline resulted in chromatin histone acetylation as judged by the increased levels of H3K9ac and disruption of tumorspheres formation. Interestingly, ALDH levels were increased in UM-HMC-1 and UM-HMC-3A cell lines, while UM-HMC-2 showed a reduced enzymatic activity.

Conclusion: Cephaeline has shown anti-cancer properties in all MEC cell lines tested by regulating tumor cells' viability, migration, proliferation, and disrupting the ability of cancer cells to generate tumorspheres.
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http://dx.doi.org/10.1111/jop.13252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9013730PMC
October 2021

Sphingolipids signature in plasma and tissue as diagnostic and prognostic tools in oral squamous cell carcinoma.

Biochim Biophys Acta Mol Cell Biol Lipids 2022 01 13;1867(1):159057. Epub 2021 Oct 13.

Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirao Preto, University of São Paulo, Brazil; CEPID-FAPESP, Center for Cell Based Therapy, Regional Blood Center of Ribeirão Preto, SP, Brazil. Electronic address:

Enzymes related to sphingolipids metabolism has been suggested as altered in oral squamous cell carcinoma (OSCC). However, clinical relevance of diverse sphingolipids in OSCC is not fully known. Here, we evaluated sphingolipidomics in plasma and tumor tissues as a tool for diagnosis/prognosis in OSCC patients. Plasma was obtained from 58 controls and 56 OSCC patients, and paired tumor and surgical margin tissues (n = 42). The levels of 28 sphingolipids molecules were obtained by mass spectrometry. Furthermore, sphingolipids were analyzed with clinical and pathological characteristics to search the potential for diagnosis and prognosis. Lower levels of 17 sphingolipids was found in the plasma of OSCC patients compared to controls while four were elevated in tumor tissues. C18:0 dyhidroceramide and C24:0 lactosylceramide in plasma were associated with perineural invasion, while tissue levels of ceramide and dyhidroceramide were associated with advanced tumor stage and perineural invasion. High plasma levels of C24:0 ceramide (HR = 0.10, p = 0.0036) and C24:1 glucosylceramide (HR = 6.62, p = 0.0023), and tissue levels of C24:0 dyhidroceramide (HR = 3.95, p = 0.032) were identified as independent prognostic factors. Moreover, we identified signatures composed by i) sphinganine-1-phosphate and C16 ceramide-1-phosphate in plasma with significant diagnostic accuracy, while ii) C24:0 ceramide, C24:0 dyhidroceramide, and C24:1 glucosylceramide plasma levels, and iii) C24:0 dyhidrosphingomyelin and C24:0 ceramide tissue levels showed value to predict survival in patients aged 60 years or older. We proposed the sphingolipids signatures in plasma and tumor tissues as biomarkers candidates to diagnosis and prognosis in OSCC.
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http://dx.doi.org/10.1016/j.bbalip.2021.159057DOI Listing
January 2022

Germline variants in DNA repair genes are associated with young-onset head and neck cancer.

Oral Oncol 2021 11 28;122:105545. Epub 2021 Sep 28.

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

The genetic predisposition to head and neck carcinomas (HNSCC) and how the known risk factors (papillomavirus infection, alcohol, and tobacco consumption) contribute to the early-onset disease are barely explored. Although HNSCC at early onset is rare, its frequency is increasing in recent years. Germline and somatic variants were assessed to build a comprehensive genetic influence pattern in HNSCC predisposition and patient outcome. Whole-exome sequencing was performed in 45 oral and oropharynx carcinomas paired with normal samples of young adults (≤49 years). We found FANCG, CDKN2A, and TPP germline variants previously associated with HNSCC risk. At least one germline variant in DNA repair pathway genes was detected in 67% of cases. Germline and somatic variants (including copy number variations) in FAT1 gene were identified in 9 patients (20%) and 12 tumors (30%), respectively. Somatic variants were found in HNSCC associated genes, such as TP53, CDKN2A, and PIK3CA. To date, 55 of 521 cases from the large cohort of TCGA presented < 49 years old. A comparison between the somatic alterations of TCGA-HNSCC at early onset and our dataset revealed strong similarities. Protein-protein interaction analysis between somatic and germline altered genes revealed a central role of TP53. Altogether, germline alterations in DNA repair genes potentially contribute to an increased risk of developing HNSCC at early-onset, while FAT1 could impact the prognosis.
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http://dx.doi.org/10.1016/j.oraloncology.2021.105545DOI Listing
November 2021

Organ preservation and oncological outcomes in early laryngeal cancer: a propensity score-based study.

Acta Otorhinolaryngol Ital 2021 Aug;41(4):317-326

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

Background: The rates of laryngeal preservation according to therapeutic modality in patients with initial laryngeal squamous cell carcinoma (LSCC) are still controversial. This study evaluated the rates of laryngeal preservation in patients who underwent treatment with surgery or radiotherapy.

Methods: This retrospective cohort study evaluated 151 patients with stage I or II LSCC. Ninety-six patients were matched using a propensity-score and outcomes were compared within this group.

Results: Regarding overall, cancer-specific survival and larynx preservation, no differences were observed according to the therapeutic modalities, but patients who underwent radiotherapy had a higher rate of local recurrence than those who underwent surgery. Patients classified as ASA 3 or 4 and treated with radiotherapy showed a tendency of higher risk of larynx loss.

Conclusions: Patients with stage I or II laryngeal tumours can be submitted to surgery or radiotherapy with similar rates of laryngeal preservation.
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http://dx.doi.org/10.14639/0392-100X-N0870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448187PMC
August 2021

FASN inhibition sensitizes metastatic OSCC cells to cisplatin and paclitaxel by downregulating cyclin B1.

Oral Dis 2021 Sep 12. Epub 2021 Sep 12.

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

Objectives: To investigate the potential effect of fatty acid synthase (FASN) inhibitor orlistat to enhance the effectiveness of chemotherapy drugs widely used to treat oral squamous cell carcinomas (OSCC), such as 5-fluorouracil, cisplatin, and paclitaxel.

Methods: The OSCC SCC-9 LN-1 metastatic cell line, which expresses high levels of FASN, was used for drug combination experiments. Cell viability was analyzed by crystal violet staining and automatic cell counting. Apoptosis and cell cycle were analyzed by flow cytometry with Annexin-V/7-AAD and propidium iodide staining, respectively. Cyclin B1, Cdc25C, Cdk1, FASN, and ERBB2 levels were assessed by Western blotting. Finally, cell scratch and transwell assays were performed to assess cell migration and invasion.

Results: Inhibition of FASN with orlistat sensitized SCC-9 LN-1 cells to the cytotoxic effects of paclitaxel and cisplatin, but not 5-fluorouracil, which was accompanied by a significant reduction in cyclin B1. The suppression of proliferation, migration, and invasion of SCC-9 LN-1 cells induced by orlistat plus cisplatin or paclitaxel was not superior to the effects of chemotherapy drugs alone.

Conclusion: Our results suggest that orlistat enhances the chemosensitivity of SCC-9 LN-1 cells to cisplatin and paclitaxel by downregulating cyclin B1.
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http://dx.doi.org/10.1111/odi.14017DOI Listing
September 2021

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

Oral Surg Oral Med Oral Pathol Oral Radiol 2021 11 21;132(5):580-588. Epub 2021 Jul 21.

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

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

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

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

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

Impact of smoking on dendritic cells in patients with oral squamous cell carcinoma.

Braz Oral Res 2021 3;35:e075. Epub 2021 Sep 3.

Universidade Federal de Santa Catarina - UFSC, Department of Pathology, Florianópolis, SC, Brazil.

Smoking has been shown to alter innate and adaptive immune responses and is directly associated with the onset of oral squamous cell carcinoma (OSCC). The purpose of this study was to evaluate the effect of cigarette smoke exposure on dendritic cells (DCs) from OSCC patients. CD1a and CD83 antibodies were used to identify immature and mature DCs, respectively, by immunohistochemistry in OSCC samples of 24 smokers and 24 non-smokers. Density of DCs was calculated in intra and peritumoral areas. Clinical and microscopic findings were reviewed and analyzed for all patients. Smokers with OSCC had a lower density of intra and peritumoral DCs when compared to non-smokers. Tumors classified as moderately/poorly differentiated had lower peritumoral CD1a+ DCs than well-differentiated tumors (p < 0.001). Smoking contributed to a depletion of immature and mature DCs in the OSCC.
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http://dx.doi.org/10.1590/1807-3107bor-2021.vol35.0075DOI Listing
September 2021

Transoral endoscopic thyroidectomy vestibular approach (TOETVA) and complications.

Rev Col Bras Cir 2021 30;48:e20213084. Epub 2021 Aug 30.

- AC Camargo Cancer Center, Departamento de Cirurgia de Cabeça e Pescoço - São Paulo - SP - Brasil.

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http://dx.doi.org/10.1590/0100-6991e-20213084DOI Listing
November 2021

Induction Chemotherapy for Advanced Oral Cavity Cancer.

Curr Oncol Rep 2021 08 27;23(11):129. Epub 2021 Aug 27.

Department of Head and Neck Surgery, University of Sao Paulo Medical School. Head and Neck Surgery and Otorhinolaryngology Department, A C Camargo Cancer Center, Latin American Cooperative Oncology Group, São Paulo, Brazil.

Purpose Of Review: Head and neck cancer is a heterogeneous disease, comprising multiple subsites with diverse etiologic factors, pathology and molecular features, response to treatment, and prognosis. Systemic treatment is usually incorporated in the management of locally advanced head and neck squamous cell carcinoma, and the use of induction chemotherapy has theoretical benefits on reducing the risk of distant metastasis, provide an in vivo testing of response and tumor biology and the potential to allow a more personalized and less toxic local treatment after downstaging. The aim of this review is to access the role of induction chemotherapy in patients with locally advanced oral cavity cancer.

Recent Findings: Clinical trials analyzing this treatment strategy in patients with resectable disease, followed by surgery, and in unresectable disease, followed by (chemo)radiotherapy or surgery are discussed, pointing out strengths and limitations of this data and highlighting the standard treatment in each clinical scenario. Future perspectives, including the incorporation of checkpoint inhibitors and biomarkers for patient selection are discussed. Surgery followed by (chemo)radiation is the standard of care for resectable oral cavity cancer patients, and chemoradiation is the standard for those considered as unresectable. Future trials with the incorporation of immunotherapy and better patient selection based on clinical and molecular biomarkers can bring new hopes for better therapeutic results in these patients.
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http://dx.doi.org/10.1007/s11912-021-01119-6DOI Listing
August 2021

Transoral endoscopic thyroidectomy vestibular approach: Experience from a multicenter national group with 412 patients.

Head Neck 2021 11 12;43(11):3468-3475. Epub 2021 Aug 12.

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

Background: Well-established conventional thyroidectomy has satisfactory outcomes; however, robotic and endoscopic thyroid surgery can avoid visible anterior neck scars. Transoral endoscopic thyroidectomy vestibular approach (TOETVA) is the most recent of these techniques.

Methods: This was a retrospective review of 412 patients who underwent TOETVA from 2017 to 2020 in 13 Brazilian centers.

Results: The study included 359 (87.1%) females and 53 (12.9%) males, with a mean age of 40 years. There were 231 (56.1%) total thyroidectomies. The conversion rate was 0.7%. The transient vocal cord palsy rate was 7.6% (30 patients). Temporary and persistent hypocalcemia rates were 4.0% and 0.8%, respectively. There were two cases of infection (0.5%).

Discussion: This is a large multi-institute TOETVA study, with one of the largest cohorts published to date that; despite its retrospective nature and selection bias, reached outcomes comparable to previously reported series, this study reinforced safeness, feasibility, and nationwide reproducibility for this technique.
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http://dx.doi.org/10.1002/hed.26846DOI Listing
November 2021

Risk Factors and Outcomes of Postoperative Neck Hematomas: An Analysis of 5,900 Thyroidectomies Performed at a Cancer Center.

Int Arch Otorhinolaryngol 2021 Jul 30;25(3):e421-e427. Epub 2020 Sep 30.

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

 Postoperative neck hematoma (PNH) is an uncommon but potentially-lethal complication of thyroid surgery.  To identify the risk factors for postthyroidectomy hematoma requiring reoperation, the timing, the source of the bleeding, the related respiratory distress requiring tracheotomy, and the late outcomes.  We retrospectively analyzed the records of 5,900 consecutive patients submitted to surgery for thyroid diseases at a single institution.  In total, PNH occurred in 62 (1.1%) patients. Most cases of bleeding occurred within the first 6 hours after thyroidectomy, but 12.5% of the hematomas were observed after 24 hours. Obvious bleeding points were detected in 58.1% of the patients during the reoperation, with inferior thyroid artery branches and superior thyroid vessels being the most frequent bleeding sources. Only two patients required urgent tracheostomy. There were no hematoma-related deaths. Permanent hypoparathyroidism and recurrent laryngeal nerve injury are more frequent following reoperation for PNH. The factors significantly associated with PNH were: older age, concurrent lymph node dissection, and chronic lymphocytic thyroiditis. Gender, previous neck irradiation, presentation at diagnosis (symptomatic or incidental), substernal goiter, thyroidectomy for hyperthyroidism, prior thyroid surgery, malignant histology, the extent of the surgery (total versus non-total thyroidectomy), the use of energy-based vessel sealing devices, the use of the hemostatic agent Surgicel, and the placement of a surgical drain were not significantly associated with PNH.  Hematoma after thyroid surgery is an uncommon complication, but it is related to significant postoperative morbidity. A better understanding of the risk factors and of the time until hematoma formation can help target high-risk patients for preventive measures and closer postoperative observation.
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http://dx.doi.org/10.1055/s-0040-1714129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321642PMC
July 2021

The Impact of the COVID-19 Pandemic on Head and Neck Surgery Training: A Brazilian National Survey.

Int Arch Otorhinolaryngol 2021 Jul 25;25(3):e339-e342. Epub 2021 Jun 25.

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

 The COVID-19 pandemic has had a high impact on surgical training around the world due to required measures regarding the suspension of elective procedures and the dismissal of nonessential personnel.  To understand the impact the pandemic had on head and neck surgery training in Brazil.  We conducted a 29-question online survey with head and neck surgery residents in Brazil, assessing the impact the pandemic had on their training.  Forty-six residents responded to the survey, and 91.3% of them reported that their residency was affected by the pandemic, but most residents were not assigned to work directly with patients infected with the new coronavirus (71.4%). All residents reported decrease in clinic visits and in surgical procedures, mostly an important reduction of ∼ 75%. A total of 56.5% of the residents described that the pandemic has had a negative impact on their mental, health and only 4 (8.7%) do not have any symptoms of burnout. The majority (78.3%) of the residents reported that educational activities were successfully adapted to online platforms, and 37% were personally infected with the virus.  Most surgical residencies were greatly affected by the pandemic, and residents had an important decrease in surgical training. Educational activities were successfully adapted to online modalities, but the residency programs should search for ways of trying to compensate for the loss of practical activities.
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http://dx.doi.org/10.1055/s-0041-1730019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321628PMC
July 2021
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