Brazilian Society of Surgical Oncology recommendations on Merkel cell carcinoma surgical treatment.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare neuroendocrine skin cancer with poor 5-year survival rates. Surgery and radiation are the current first-line treatments for local and nodal disease. OBJECTIVES: The Brazilian Society of Surgical Oncology developed this document aiming to guide the surgical oncology role in multimodal MCC management. METHODS: The consensus was established in three rounds of online discussion, achieving consensus on specific topics including diagnosis, staging, treatment, and follow-up. RESULTS: Patients suspected of having MCC should undergo immunohistochemical examination and preferably undergo pathology review by a dermatopathologist. Initial staging should be performed with dermatologic and nodal physical examination, combined with complementary imaging. Whole-body imaging, preferably with positron emission tomography (PET) or computed tomography (CT) scans, are recommended. Due to the need for multidisciplinary approaches, we recommend that all cases should be discussed in tumor boards and referred to other specialties as soon as possible, reducing potential treatment delays. We recommend that all patients with clinical stage I or II may undergo local excision associated with sentinel lymph node biopsy. The decision on margin size should consider time to recovery, patient's comorbidities, and risk factors. Patients with positive sentinel lymph nodes or the presence of risk factors should undergo postoperative radiation therapy at the primary site. Exclusive radiation is a viable option for patients with low performance. Patients with positive sentinel lymph node biopsy should undergo nodal radiation therapy or lymphadenectomy. In patients with nodal clinical disease, in addition to primary tumor treatment, nodal radiation therapy and/or lymphadenectomy are recommended. Patients with advanced disease should preferably be enrolled in clinical trials and discussed in multidisciplinary meetings. The role of surgery and radiation therapy in the metastatic/advanced setting should be discussed individually and always in tumor boards. CONCLUSION: This document aims to standardize a protocol for initial assessment and treatment for Merkel cell carcinoma, optimizing oncologic outcomes in middle-income countries such as Brazil.

Establishment and molecular characterization of HCB-541, a novel and aggressive human cutaneous squamous cell carcinoma cell line.

Cutaneous squamous cell carcinoma (cSCC) is a common type of skin cancer that can result in significant morbidity, although it is usually well-managed and rarely metastasizes. However, the lack of commercially available cSCC cell lines hinders our understanding of this disease. This study aims to establish and characterize a new metastatic cSCC cell line derived from a Brazilian patient. A tumor biopsy was taken from a metastatic cSCC patient, immortalized, and named HCB-541 after several passages. The cytokeratin expression profile, karyotypic alterations, mutational analysis, mRNA and protein differential expression, tumorigenic capacity in xenograft models, and drug sensitivity were analyzed. The HCB-541 cell line showed a doubling time between 20 and 30 h and high tumorigenic capacity in the xenograft mouse model. The HCB-541 cell line showed hypodiploid and hypotetraploidy populations. We found pathogenic mutations in TP53 p.(Arg248Leu), HRAS (Gln61His) and TERT promoter (C228T) and high-level microsatellite instability (MSI-H) in both tumor and cell line. We observed 37 cancer-related genes differentially expressed when compared with HACAT control cells. The HCB-541 cells exhibited high phosphorylated levels of EGFR, AXL, Tie, FGFR, and ROR2, and high sensitivity to cisplatin, carboplatin, and EGFR inhibitors. Our study successfully established HCB-541, a new cSCC cell line that could be useful as a valuable biological model for understanding the biology and therapy of metastatic skin cancer.

TNFRSF1B Gene Variants in Clinicopathological Aspects and Prognosis of Patients with Cutaneous Melanoma.

Regulatory T lymphocytes play a critical role in immune regulation and are involved in the aberrant cell elimination by facilitating tumor necrosis factor connection to the TNFR2 receptor, encoded by the TNFRSF1B polymorphic gene. We aimed to examine the effects of single nucleotide variants TNFRSF1B c.587T>G, c.*188A>G, c.*215C>T, and c.*922C>T on the clinicopathological characteristics and survival of cutaneous melanoma (CM) patients. Patients were genotyped using RT-PCR. TNFRSF1B levels were measured using qPCR. Luciferase reporter assay evaluated the interaction of miR-96 and miR-1271 with the 3'-UTR of TNFRSF1B. The c.587TT genotype was more common in patients younger than 54 years old than in older patients. Patients with c.*922CT or TT, c.587TG or GG + c.*922CT or TT genotypes, as well as those with the haplotype TATT, presented a higher risk of tumor progression and death due to the disease effects. Individuals with the c.*922TT genotype had a higher TNFRSF1B expression than those with the CC genotype. miR-1271 had less efficient binding with the 3'-UTR of the T allele when compared with the C allele of the SNV c.*922C>T. Our findings, for the first time, demonstrate that TNFRSF1B c.587T>G and c.*922C>T variants can serve as independent prognostic factors in CM patients.

Immunohistochemistry assessment of tissue neutrophil-to-lymphocyte ratio predicts outcomes in melanoma patients treated with anti-programmed cell death 1 therapy.

Elevated neutrophil-to-lymphocyte ratio (NLR) is associated with diminished immunotherapy response in metastatic melanoma. Although NLR assessment in peripheral blood is established, tissue dynamics remain insufficiently explored. This study aimed to evaluate tissue NLR (tNLR)'s predictive potential through immunohistochemistry in immunotherapy-treated melanoma. Fifty melanoma patients who underwent anti-programmed cell death 1 (PD-1) therapy were assessed. Hematological, clinical and tumor features were collected from medical records. Responses were categorized using the Response Evaluation Criteria in Solid Tumors for immunotherapy (iRECIST) guidelines. Immunohistochemistry for tumor-infiltrating T cells (cluster differentiation 3) and neutrophils (myeloperoxidase) was performed on formalin-fixed paraffin-embedded tumor samples. NLR, derived NLR (dNLR) and tNLR were calculated. Overall survival (OS) and survival following immunotherapy (SFI) were calculated from diagnosis or immunotherapy start to loss of follow-up or death. Patients with high tNLR presented improved OS ( P =  0.038) and SFI with anti-PD-1 therapy ( P =  0.006). Both NLR and dNLR were associated with OS ( P =  0.038 and P =  0.046, respectively) and SFI ( P =  0.001 and P =  0.019, respectively). NLR was also associated with immunotherapy response ( P =  0.007). In conclusion, tNLR emerged as a novel potential biomarker of enhanced survival post anti-PD-1 therapy, in contrast to classical NLR and dNLR markers.

Treatment of patients with multiple brain metastases by isolated radiosurgery: Toxicity and survival.

BACKGROUND: Radiosurgery for multiple brain metastases has been more reported recently without using whole-brain radiotherapy. Nevertheless, the sparsity of the data still claims more information about toxicity and survival and their association with both dosimetric and geometric aspects of this treatment. AIM: To assess the toxicity and survival outcome of radiosurgery in patients with multiple (four or more lesions) brain metastases. METHODS: In a single institution, data were collected retrospectively from patients who underwent radiosurgery to treat brain metastases from diverse primary sites. Patients with 4-21 brain metastases were treated with a single fraction with a dose of 18 Gy or 20 Gy. The clinical variables collected were relevant to toxicity, survival, treatment response, planning, and dosimetric variables. The Spearman's rank correlation coefficients, Mann-Whitney test, Kruskal-Wallis test, and Log-rank test were used according to the type of variable and outcomes. RESULTS: From August 2017 to February 2020, 55 patients were evaluated. Headache was the most common complaint (38.2%). The median overall survival (OS) for patients with karnofsky performance status (KPS) > 70 was 8.9 mo, and this was 3.6 mo for those with KPS ≤ 70 (P = 0.047). Patients with treated lesions had a median progression-free survival of 7.6 mo. There were no differences in OS (19.7 vs 9.5 mo) or progression-free survival (10.6 vs 6.3 mo) based on prior irradiation. There was no correlation found between reported toxicities and planning, dosimetric, and geometric variables, implying that no additional significant toxicity risks appear to be added to the treatment of multiple (four or more) lesions. CONCLUSION: No associations were found between the evaluated toxicities and the planning dosimetric parameters, and no differences in survival rates were detected based on previous treatment status.

PD-L1 Tumor Expression as a Predictive Biomarker of Immune Checkpoint Inhibitors' Response and Survival in Advanced Melanoma Patients in Brazil.

Immune checkpoint blockade (ICB) agents are prominent immunotherapies for the treatment of advanced melanoma. However, they fail to promote any durable clinical benefit in a large cohort of patients. This study assessed clinical and molecular predictors of ICB response and survival in advanced melanoma. A retrospective analysis was performed on 210 patients treated with PD-1 or CTLA-4 inhibitors at Barretos Cancer Hospital, Brazil. PD-L1 expression was assessed by immunohistochemistry using formalin-fixed paraffin-embedded tumor tissues collected prior to ICB therapy. Patients were divided into responders (complete and partial response and stable disease for more than 6 months) and non-responders (stable disease for less than 6 months and progressive disease). Among them, about 82% underwent anti-PD-1 immunotherapy, and 60.5% progressed after the ICB treatment. Patients that received ICB as first-line therapy showed higher response rates than previously treated patients. Higher response rates were further associated with superficial spreading melanomas and positive PD-L1 expression (>1%). Likewise, PD-L1 positive expression and BRAF V600 mutations were associated with a higher overall survival after ICB therapy. Since ICBs are expensive therapies, evaluation of PD-L1 tumor expression in melanoma patients should be routinely assessed to select patients that are most likely to respond.

Smoking cessation knowledge and perceptions of cancer care providers at six Latin American cancer institutions.

Objective: To assess the characteristics, self-reported tobacco use, knowledge, and perceptions about smoking cessation among cancer care providers (CCPs), as well as perceived barriers to inform interventions that can potentially improve quitting rates and the prognosis of cancer patients in Latin America. Methods: A cross-sectional study was conducted among 996 CCPs in six cancer institutions located in Argentina, Brazil, Colombia, Mexico, and Peru. An online survey consisting of 28 close-ended questions adapted from the 2012 International Association for the Study of Lung Cancer survey and the Global Adult Tobacco Survey was administered. Results: The majority of CCPs, ranging from 86.1% in Mexico to 95.9% in Brazil, agreed or strongly agreed that smoking cessation should be integrated into cancer treatment. However, inadequate training on smoking cessation was reported by 66.9%, 69.4%, 70.4%, 72.9%, 85.8%, and 86.4% in Mexico, Colombia (Floridablanca), Argentina, Peru, Brazil, and Colombia (Medellín), respectively, and this difference was statistically significant (p < 0.001). Moreover, current cigarette smoking prevalence among CCPs was 2.5% in Brazil, 4.6% in Peru, 6.3% in Colombia (Floridablanca), 10.4% in Colombia (Medellín), 11.5% in Mexico, and 15.1% in Argentina, showing a statistically significant difference (p < 0.001). Conclusions: Efforts in Latin America should be geared toward assisting CCPs with their quitting efforts and training in smoking cessation practices aimed at achieving a better prognosis and improving cancer patients' quality of life.

Smoking cessation knowledge and perceptions of cancer care providers at six Latin American cancer institutions

[ABSTRACT]. Objective. To assess the characteristics, self-reported tobacco use, knowledge, and perceptions about smok- ing cessation among cancer care providers (CCPs), as well as perceived barriers to inform interventions that can potentially improve quitting rates and the prognosis of cancer patients in Latin America. Methods. A cross-sectional study was conducted among 996 CCPs in six cancer institutions located in Argen- tina, Brazil, Colombia, Mexico, and Peru. An online survey consisting of 28 close-ended questions adapted from the 2012 International Association for the Study of Lung Cancer survey and the Global Adult Tobacco Survey was administered. Results. The majority of CCPs, ranging from 86.1% in Mexico to 95.9% in Brazil, agreed or strongly agreed that smoking cessation should be integrated into cancer treatment. However, inadequate training on smoking cessation was reported by 66.9%, 69.4%, 70.4%, 72.9%, 85.8%, and 86.4% in Mexico, Colombia (Floridab- lanca), Argentina, Peru, Brazil, and Colombia (Medellín), respectively, and this difference was statistically significant (p < 0.001). Moreover, current cigarette smoking prevalence among CCPs was 2.5% in Brazil, 4.6% in Peru, 6.3% in Colombia (Floridablanca), 10.4% in Colombia (Medellín), 11.5% in Mexico, and 15.1% in Argentina, showing a statistically significant difference (p < 0.001). Conclusions. Efforts in Latin America should be geared toward assisting CCPs with their quitting efforts and training in smoking cessation practices aimed at achieving a better prognosis and improving cancer patients’ quality of life.

[RESUMEN]. Objetivo. Evaluar entre los prestadores de atención a pacientes con cáncer las características, el consumo de tabaco referido por la misma persona, sus conocimientos y sus impresiones acerca de dejar de fumar, así como los obstáculos percibidos, para sustentar las intervenciones que puedan mejorar las tasas de aban- dono del consumo y el pronóstico de los pacientes con cáncer en América Latina. Métodos. Se realizó un estudio transversal con 996 prestadores de atención oncológica en seis instituciones oncológicas ubicadas en Argentina, Brasil, Colombia, México y Perú. Se realizó una encuesta en línea con 28 preguntas cerradas adaptadas de la encuesta de la Asociación Internacional para el Estudio del Cáncer de Pulmón del 2012 y la Encuesta Mundial de Tabaquismo en Adultos. Resultados. La mayoría de los prestadores de atención oncológica, del 86,1% en México al 95,9% en Brasil, estuvieron de acuerdo o muy de acuerdo con que el abandono del tabaco debería integrarse en el tratamiento del cáncer. Sin embargo, 66,9%, 69,4%, 70,4%, 72,9%, 85,8% y 86,4% en México, Colombia (Floridablanca), Argentina, Perú, Brasil y Colombia (Medellín), respectivamente, dieron parte de una formación inadecuada en cuanto al abandono del tabaco, y esta diferencia fue estadísticamente significativa (p < 0,001). Además, la prevalencia actual del consumo de tabaco entre los proveedores de atención oncológica fue de 2,5% en Brasil, 4,6% en Perú, 6,3% en Colombia (Floridablanca), 10,4 % en Colombia (Medellín), 11,5% en México y 15,1% en Argentina, y mostró una diferencia estadísticamente significativa (p < 0,001). Conclusiones. En América Latina, deben canalizarse los esfuerzos para ayudar a los prestadores de atención oncológica a abandonar el consumo de tabaco y apoyarlos en la capacitación acerca de las prácticas de abandono del tabaco dirigidas a lograr un pronóstico más favorable y mejorar la calidad de vida de los paci- entes con cáncer.

[RESUMO]. Objetivo. Avaliar as características, o uso autorrelatado de tabaco, o conhecimento e as percepções sobre o abandono do tabagismo entre os profissionais da área de oncologia (PAO), bem como as barreiras perce- bidas, a fim de guiar intervenções que possam melhorar as taxas de abandono e o prognóstico de pacientes com câncer na América Latina. Métodos. Realizou-se um estudo transversal com 996 PAO em seis instituições de oncologia localizadas na Argentina, no Brasil, na Colômbia, no México e no Peru. Administrou-se uma pesquisa on-line com 28 pergun- tas fechadas, adaptadas do levantamento realizado em 2012 pela Associação Internacional para o Estudo do Câncer de Pulmão e do Global Adult Tobacco Survey (Levantamento Global do Tabagismo em Adultos). Resultados. A maioria dos PAO, variando de 86,1% (no México) a 95,9% (no Brasil), concordou parcial ou totalmente com a necessidade de integrar o abandono do tabagismo ao tratamento do câncer. Entretanto, o treinamento inadequado sobre o abandono do tabagismo foi relatado por 66,9% no México, 69,4% na Colôm- bia (Floridablanca), 70,4% na Argentina, 72,9% no Peru, 85,8% no Brasil e 86,4% na Colômbia (Medellín), e essa diferença foi estatisticamente significante (p < 0,001). Além disso, a prevalência atual de consumo de cigarro entre os PAO foi de 2,5% no Brasil, 4,6% no Peru, 6,3% na Colômbia (Floridablanca), 10,4% na Colômbia (Medellín), 11,5% no México, e 15,1% na Argentina, mostrando uma diferença estatisticamente significante (p < 0,001). Conclusões. Os esforços na América Latina devem ser direcionados para o auxílio aos PAO em seus esforços de abandonar o tabagismo e para o treinamento sobre métodos para abandono do tabagismo, com o objetivo de melhorar o prognóstico e a qualidade de vida dos pacientes com câncer.

Cutaneous and acral melanoma cross-OMICs reveals prognostic cancer drivers associated with pathobiology and ultraviolet exposure.

Ultraviolet radiation (UV) is causally linked to cutaneous melanoma, yet the underlying epigenetic mechanisms, known as molecular sensors of exposure, have not been characterized in clinical biospecimens. Here, we integrate clinical, epigenome (DNA methylome), genome and transcriptome profiling of 112 cutaneous melanoma from two multi-ethnic cohorts. We identify UV-related alterations in regulatory regions and immunological pathways, with multi-OMICs cancer driver potential affecting patient survival. TAPBP, the top gene, is critically involved in immune function and encompasses several UV-altered methylation sites that were validated by targeted sequencing, providing cost-effective opportunities for clinical application. The DNA methylome also reveals non UV-related aberrations underlying pathological differences between the cutaneous and 17 acral melanomas. Unsupervised epigenomic mapping demonstrated that non UV-mutant cutaneous melanoma more closely resembles acral rather than UV-exposed cutaneous melanoma, with the latter showing better patient prognosis than the other two forms. These gene-environment interactions reveal translationally impactful mechanisms in melanomagenesis.

Smoking cessation knowledge and perceptions of cancer care providers at six Latin American cancer institutions / Conocimientos e impresiones acerca de dejar de fumar entre prestadores de atención a pacientes con cáncer de seis instituciones oncológicas de América Latina / Conhecimento e percepções de profissionais de atenção oncológica sobre o abandono do tabagismo em seis instituições de oncologia da América Latina

ABSTRACT Objective. To assess the characteristics, self-reported tobacco use, knowledge, and perceptions about smoking cessation among cancer care providers (CCPs), as well as perceived barriers to inform interventions that can potentially improve quitting rates and the prognosis of cancer patients in Latin America. Methods. A cross-sectional study was conducted among 996 CCPs in six cancer institutions located in Argentina, Brazil, Colombia, Mexico, and Peru. An online survey consisting of 28 close-ended questions adapted from the 2012 International Association for the Study of Lung Cancer survey and the Global Adult Tobacco Survey was administered. Results. The majority of CCPs, ranging from 86.1% in Mexico to 95.9% in Brazil, agreed or strongly agreed that smoking cessation should be integrated into cancer treatment. However, inadequate training on smoking cessation was reported by 66.9%, 69.4%, 70.4%, 72.9%, 85.8%, and 86.4% in Mexico, Colombia (Floridablanca), Argentina, Peru, Brazil, and Colombia (Medellín), respectively, and this difference was statistically significant (p < 0.001). Moreover, current cigarette smoking prevalence among CCPs was 2.5% in Brazil, 4.6% in Peru, 6.3% in Colombia (Floridablanca), 10.4% in Colombia (Medellín), 11.5% in Mexico, and 15.1% in Argentina, showing a statistically significant difference (p < 0.001). Conclusions. Efforts in Latin America should be geared toward assisting CCPs with their quitting efforts and training in smoking cessation practices aimed at achieving a better prognosis and improving cancer patients' quality of life.

RESUMEN Objetivo. Evaluar entre los prestadores de atención a pacientes con cáncer las características, el consumo de tabaco referido por la misma persona, sus conocimientos y sus impresiones acerca de dejar de fumar, así como los obstáculos percibidos, para sustentar las intervenciones que puedan mejorar las tasas de abandono del consumo y el pronóstico de los pacientes con cáncer en América Latina. Métodos. Se realizó un estudio transversal con 996 prestadores de atención oncológica en seis instituciones oncológicas ubicadas en Argentina, Brasil, Colombia, México y Perú. Se realizó una encuesta en línea con 28 preguntas cerradas adaptadas de la encuesta de la Asociación Internacional para el Estudio del Cáncer de Pulmón del 2012 y la Encuesta Mundial de Tabaquismo en Adultos. Resultados. La mayoría de los prestadores de atención oncológica, del 86,1% en México al 95,9% en Brasil, estuvieron de acuerdo o muy de acuerdo con que el abandono del tabaco debería integrarse en el tratamiento del cáncer. Sin embargo, 66,9%, 69,4%, 70,4%, 72,9%, 85,8% y 86,4% en México, Colombia (Floridablanca), Argentina, Perú, Brasil y Colombia (Medellín), respectivamente, dieron parte de una formación inadecuada en cuanto al abandono del tabaco, y esta diferencia fue estadísticamente significativa (p < 0,001). Además, la prevalencia actual del consumo de tabaco entre los proveedores de atención oncológica fue de 2,5% en Brasil, 4,6% en Perú, 6,3% en Colombia (Floridablanca), 10,4 % en Colombia (Medellín), 11,5% en México y 15,1% en Argentina, y mostró una diferencia estadísticamente significativa (p < 0,001). Conclusiones. En América Latina, deben canalizarse los esfuerzos para ayudar a los prestadores de atención oncológica a abandonar el consumo de tabaco y apoyarlos en la capacitación acerca de las prácticas de abandono del tabaco dirigidas a lograr un pronóstico más favorable y mejorar la calidad de vida de los pacientes con cáncer.

RESUMO Objetivo. Avaliar as características, o uso autorrelatado de tabaco, o conhecimento e as percepções sobre o abandono do tabagismo entre os profissionais da área de oncologia (PAO), bem como as barreiras percebidas, a fim de guiar intervenções que possam melhorar as taxas de abandono e o prognóstico de pacientes com câncer na América Latina. Métodos. Realizou-se um estudo transversal com 996 PAO em seis instituições de oncologia localizadas na Argentina, no Brasil, na Colômbia, no México e no Peru. Administrou-se uma pesquisa on-line com 28 perguntas fechadas, adaptadas do levantamento realizado em 2012 pela Associação Internacional para o Estudo do Câncer de Pulmão e do Global Adult Tobacco Survey (Levantamento Global do Tabagismo em Adultos). Resultados. A maioria dos PAO, variando de 86,1% (no México) a 95,9% (no Brasil), concordou parcial ou totalmente com a necessidade de integrar o abandono do tabagismo ao tratamento do câncer. Entretanto, o treinamento inadequado sobre o abandono do tabagismo foi relatado por 66,9% no México, 69,4% na Colômbia (Floridablanca), 70,4% na Argentina, 72,9% no Peru, 85,8% no Brasil e 86,4% na Colômbia (Medellín), e essa diferença foi estatisticamente significante (p < 0,001). Além disso, a prevalência atual de consumo de cigarro entre os PAO foi de 2,5% no Brasil, 4,6% no Peru, 6,3% na Colômbia (Floridablanca), 10,4% na Colômbia (Medellín), 11,5% no México, e 15,1% na Argentina, mostrando uma diferença estatisticamente significante (p < 0,001). Conclusões. Os esforços na América Latina devem ser direcionados para o auxílio aos PAO em seus esforços de abandonar o tabagismo e para o treinamento sobre métodos para abandono do tabagismo, com o objetivo de melhorar o prognóstico e a qualidade de vida dos pacientes com câncer.

Exploring a Region on Chromosome 8p23.1 Displaying Positive Selection Signals in Brazilian Admixed Populations: Additional Insights Into Predisposition to Obesity and Related Disorders.

We recently reported a deviation of local ancestry on the chromosome (ch) 8p23.1, which led to positive selection signals in a Brazilian population sample. The deviation suggested that the genetic variability of candidate genes located on ch 8p23.1 may have been evolutionarily advantageous in the early stages of the admixture process. In the present work, we aim to extend the previous work by studying additional Brazilian admixed individuals and examining DNA sequencing data from the ch 8p23.1 candidate region. Thus, we inferred the local ancestry of 125 exomes from individuals born in five towns within the Southeast region of Brazil (São Paulo, Campinas, Barretos, and Ribeirão Preto located in the state of São Paulo and Belo Horizonte, the capital of the state of Minas Gerais), and compared to data from two public Brazilian reference genomic databases, BIPMed and ABraOM, and with information from the 1000 Genomes Project phase 3 and gnomAD databases. Our results revealed that ancestry is similar among individuals born in the five Brazilian towns assessed; however, an increased proportion of sub-Saharan African ancestry was observed in individuals from Belo Horizonte. In addition, individuals from the five towns considered, as well as those from the ABRAOM dataset, had the same overrepresentation of Native-American ancestry on the ch 8p23.1 locus that was previously reported for the BIPMed reference sample. Sequencing analysis of ch 8p23.1 revealed the presence of 442 non-synonymous variants, including frameshift, inframe deletion, start loss, stop gain, stop loss, and splicing site variants, which occurred in 24 genes. Among these genes, 13 were associated with obesity, type II diabetes, lipid levels, and waist circumference (PRAG1, MFHAS1, PPP1R3B, TNKS, MSRA, PRSS55, RP1L1, PINX1, MTMR9, FAM167A, BLK, GATA4, and CTSB). These results strengthen the hypothesis that a set of variants located on ch 8p23.1 that result from positive selection during early admixture events may influence obesity-related disease predisposition in admixed individuals of the Brazilian population. Furthermore, we present evidence that the exploration of local ancestry deviation in admixed individuals may provide information with the potential to be translated into health care improvement.

Genetic variability in COVID-19-related genes in the Brazilian population.

SARS-CoV-2 utilizes the angiotensin-converting enzyme 2 (ACE2) receptor and transmembrane serine protease (TMPRSS2) to infect human lung cells. Previous studies have suggested that different host ACE2 and TMPRSS2 genetic backgrounds might contribute to differences in the rate of SARS-CoV-2 infection or COVID-19 severity. Recent studies have also shown that variants in 15 genes related to type I interferon immunity to influenza virus might predispose patients toward life-threatening COVID-19 pneumonia. Other genes (SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6, XCR1, IL6, CTSL, ABO, and FURIN) and HLA alleles have also been implicated in the response to infection with SARS-CoV-2. Currently, Brazil has recorded the third-highest number of COVID-19 cases worldwide. We aimed to investigate the genetic variation present in COVID-19-related genes in the Brazilian population. We analyzed 27 candidate genes and HLA alleles in 954 admixed Brazilian exomes. We used the information available in two public databases (http://www.bipmed.org and http://abraom.ib.usp.br/) and additional exomes from individuals born in southeast Brazil, the region of the country with the highest number of COVID-19 patients. Variant allele frequencies were compared with the 1000 Genomes Project phase 3 (1KGP) and gnomAD databases. We detected 395 nonsynonymous variants; of these, 325 were also found in the 1KGP and/or gnomAD. Six of these variants were previously reported to influence the rate of infection or clinical prognosis of COVID-19. The remaining 70 variants were identified exclusively in the Brazilian sample, with a mean allele frequency of 0.0025. In silico analysis revealed that seven of these variants are predicted to affect protein function. Furthermore, we identified HLA alleles previously associated with the COVID-19 response at loci DQB1 and DRB1. Our results showed genetic variability common to other populations and rare and ultrarare variants exclusively found in the Brazilian population. These findings might lead to differences in the rate of infection or response to infection by SARS-CoV-2 and should be further investigated in patients with this disease.

Circulating tumor DNA (ctDNA) detection is associated with shorter progression-free survival in advanced melanoma patients.

BRAF, NRAS and TERT mutations occur in more than 2/3 of melanomas. Its detection in patient's blood, as circulating tumor DNA (ctDNA), represents a possibility for identification and monitoring of metastatic disease. We proposed to standardize a liquid biopsy platform to identify hotspot mutations in BRAF, NRAS and TERT in plasma samples from advanced melanoma patients and investigate whether it was associated to clinical outcome. Firstly, we performed digital polymerase chain reaction using tumor cell lines for validation and determination of limit of detection (LOD) of each assay and screened plasma samples from healthy individuals to determine the limit of blank (LOB). Then, we selected 19 stage III and IV patients and determined the somatic mutations status in tumor tissue and track them in patients' plasma. We established a specific and sensitive methodology with a LOD ranging from 0.13 to 0.37%, and LOB ranging from of 0 to 5.201 copies/reaction. Somatic mutations occurred in 17/19 (89%) patients, of whom seven (41%) had ctDNA detectable their paired plasma. ctDNA detection was associated with shorter progression free survival (p = 0.01). In conclusion, our data support the use of ctDNA as prognosis biomarker, suggesting that patients with detectable levels have an unfavorable outcome.

Inherited variations in human pigmentation-related genes modulate cutaneous melanoma risk and clinicopathological features in Brazilian population.

Ultraviolet light exposure and cutaneous pigmentation are important host risk factors for cutaneous melanoma (CM), and it is well known that inherited ability to produce melanin varies in humans. The study aimed to identify single-nucleotide variants (SNVs) on pigmentation-related genes with importance in risk and clinicopathological aspects of CM. The study was conducted in two stages. In stage 1, 103 CM patients and 103 controls were analyzed using Genome-Wide Human SNV Arrays in order to identify SNVs in pigmentation-related genes, and the most important SNVs were selected for data validation in stage 2 by real-time polymerase-chain reaction in 247 CM patients and 280 controls. ADCY3 c.675+9196T>G, CREB1 c.303+373G>A, and MITF c.938-325G>A were selected for data validation among 74 SNVs. Individuals with CREB1 GA or AA genotype and allele "A" were under 1.79 and 1.47-fold increased risks of CM than others, respectively. Excesses of CREB1 AA and MITF AA genotype were seen in patients with tumors at Clark levels III to V (27.8% versus 13.7%) and at III or IV stages (46.1% versus 24.9%) compared to others, respectively. When compared to others, patients with ADCY3 TT had 1.89 more chances of presenting CM progression, and those with MITF GA or AA had 2.20 more chances of evolving to death by CM. Our data provide, for the first time, preliminary evidence that inherited abnormalities in ADCY3, CREB1, and MITF pigmentation-related genes, not only can increase the risk to CM, but also influence CM patients' clinicopathological features.

Indoleamine 2,3-dioxygenase in melanoma progression and BRAF inhibitor resistance.

Indoleamine 2,3-dioxygenase (IDO) is associated with the progression of many types of tumors, including melanoma. However, there is limited information about IDO modulation on tumor cell itself and the effect of BRAF inhibitor (BRAFi) treatment and resistance. Herein, IDO expression was analyzed in different stages of melanoma development and progression linked to BRAFi resistance. IDO expression was increased in primary and metastatic melanomas from patients' biopsies, especially in the immune cells infiltrate. Using a bioinformatics approach, we also identified an increase in the IDO mRNA in the vertical growth and metastatic phases of melanoma. Using in silico analyses, we found that IDO mRNA was increased in BRAFi resistance. In an in vitro model, IDO expression and activity induced by interferon-gamma (IFNγ) in sensitive melanoma cells was decreased by BRAFi treatment. However, cells that became resistant to BRAFi presented random IDO expression levels. Also, we identified that treatment with the IDO inhibitor, 1-methyltryptophan (1-MT), was able to reduce clonogenicity for parental and BRAFi-resistant cells. In conclusion, our results support the hypothesis that the decreased IDO expression in tumor cells is one of the many additional outcomes contributing to the therapeutic effects of BRAFi. Still, the IDO production changeability by the BRAFi-resistant cells reiterates the complexity of the response arising from resistance, making it not possible, at this stage, to associate IDO expression in tumor cells with resistance. On the other hand, the maintenance of 1-MT off-target effect endorses its use as an adjuvant treatment of melanoma that has become BRAFi-resistant.

Caution is needed in interpreting the results of comparative studies regarding oncological operations by minimally invasive versus laparotomic access.

We aim to alert the difference between groups while comparing studies of abdominal oncological operations performed either by minimally invasive or laparotomic approaches and potential conflicts of interest in presenting or interpreting the results. Considering the large volume of scientific articles that are published, there is a need to consider the quality of the scientific production that leads to clinical decision making. In this regards, it is important to take into account the choice of the surgical access route. Randomized, controlled clinical trials are the standard for comparing the effectiveness between these interventions. Although some studies indicate advantages in minimally invasive access, caution is needed when interpreting these findings. There is no detailed observation in each of the comparative study about the real limitations and potential indications for minimally invasive procedures, such as the indications for selected and less advanced cases, in less complex cavities, as well as its elective characteristic. Several abdominal oncological operations via laparotomy would not be plausible to be completely performed through a minimally invasive access. These cases should be carefully selected and excluded from the comparative group. The comparison should be carried out, in a balanced way, with a group that could also have undergone a minimally invasive access, avoiding bias in selecting those cases of minor complexity, placed in the minimally invasive group. It is not a question of criticizing the minimally invasive technologies, but of respecting the surgeon's clinical decision regarding the most convenient method, revalidating the well-performed traditional laparotomy route, which has been unfairly criticized or downplayed by many people.

Demographic, Clinical, and Pathologic Features of Patients With Cutaneous Melanoma: Final Analysis of the Brazilian Melanoma Group Database.

PURPOSE: National epidemiologic data on melanoma are scarce in Brazil. The current work presents final demographic, clinical, and pathologic results from the Brazilian Melanoma Group database to detail how patients with melanoma present at diagnosis. METHODS: The online database includes patients diagnosed between 1982 and 2015 and evaluated at their centers of origin between 2001 and 2016. The primary objective was to describe the demographic, clinical, and pathologic characteristics of the patients, and secondary objectives were to investigate the association between clinical and pathologic variables of interest. RESULTS: A total of 1,596 patients were included. Median age was 52 years, 57% were women, and the majority were identified as white. Invasive melanoma was diagnosed in 1,297 patients, mostly localized, whereas 299 (19%) had in situ disease (TisN0M0). Only 165 patients had initial lymph node involvement. Fitzpatrick skin types I or II were slightly more frequent with in situ melanoma (73%) than with invasive disease (67%; P = .054). The median Breslow thickness was 0.95 mm, Clark levels 2 and 3 comprised nearly 70% of cases, and ulceration was present in 18% of patients. The mitotic rate was significantly associated with the presence of ulceration and both vascular and perineural invasion but not with margin positivity, whereas histologic regression was associated with both intratumoral and peritumoral inflammatory infiltrates. CONCLUSION: Despite the limitations of an observational, registry-based study, the current results provide a general profile of patients with cutaneous melanoma in Brazil at the time of diagnosis.

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

BACKGROUND: Sentinel lymph node (SLN) biopsy is the standard care for early detection and staging of lymph node metastasis in melanomas. Radiocolloids (RC) and blue dyes are used for SLN detection. Recently, near infrared (NIR) fluorescence tracing using indocyanine green has been developed as an alternative method for SLN detection. The relatively high tissue penetration depth of several millimeters and the ability to detect low concentrations of tracer both suggest that NIR may have significant advantages over RC and the blue dye methods. The objective of this study was to prospectively compare the performance of all three SLN detection techniques using them sequentially to evaluate the same group of patients. METHODS: One hundred twenty-one primary cutaneous melanoma patients with an indication for SLN biopsy were assigned to the procedure following NIR, blue dye, and RC detection techniques. RESULTS: No adverse event was reported. SLN was not detected in only 4.1% of cases. In 90.9%, an SLN was identified with NIR, but without any auxiliary technique in only 70.2% of cases. RC detected the SLN in 92.6% of cases. Patent blue was found in the sentinel node in 76.9%. The combination of all three techniques detected an SLN in 95.9% of cases. Metastases were present in 26.7%. The false-negative rate was 8.8%, with a negative predictive value of 91.2%. CONCLUSIONS: RC was the only technique with high SLN detection. Both the blue dye and NIR methods added sensitivity to the detection rate but should not be a substitute for RC.

Independent external validation of nomogram to predict extracapsular extension in patients with prostate cancer.

INTRODUCTION: The objective of this study was to perform an independent external validation of the Giganti-Coppola nomogram (GCN), which uses clinical and radiological parameters to predict prostate extracapsular extension (ECE) on the final pathology of patients undergoing radical prostatectomy (RP). MATERIAL AND METHODS: Seventy-two patients diagnosed with prostate cancer (PCa), who were RP candidates from two institutions, were prospectively included. All patients underwent preoperative multi-parametric magnetic resonance imaging (mpMRI) at 1.5 T, without the use of an endorectal coil, with multiplanar images in T1WI, T2WI, DWI, and DCE. The AUC and a calibration graph were used to validate the nomogram, using the regression coefficients of the Giganti-Coppola study. RESULTS: The original nomogram had an AUC of 0.90 (p = 0.001), with a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 100%, 5.1%, 47.1%, 100%, and 48%, respectively. The calibration graph showed an overestimation of the nomogram for ECE. CONCLUSION: The GCN has an adequate ability in predicting ECE; however, in our sample, it showed limited accuracy and overestimated likelihood of ECE in the final pathology of patients with PCa submitted to RP. KEY POINTS: • Knowledge of preoperative local staging of prostate cancer is essential for surgical treatment. Extracapsular extension increases the chance of positive surgical margins. • Imaging modalities such as mpMRI alone does not have suitable accuracy in local staging. • Giganti-Coppola's nomogram achieved an adequate ability in predicting ECE.