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BACKGROUND: Melanoma, the most lethal form of skin cancer, has undergone a transformative treatment shift with the advent of checkpoint blockade immunotherapy (CBI). Understanding the intricate network of immune cells infiltrating the tumor and orchestrating the control of melanoma cells and the response to CBI is currently of utmost importance. There is evidence underscoring the significance of tissue-resident memory (TRM) CD8 T cells and classic dendritic cell type 1 (cDC1) in cancer protection. Transcriptomic studies also support the existence of a TCF7+ (encoding TCF1) T cell as the most important for immunotherapy response, although uncertainty exists about whether there is a TCF1+TRM T cell due to evidence indicating TCF1 downregulation for tissue residency activation. METHODS: We used multiplexed immunofluorescence and spectral flow cytometry to evaluate TRM CD8 T cells and cDC1 in two melanoma patient cohorts: one immunotherapy-naive and the other receiving immunotherapy. The first cohort was divided between patients free of disease or with metastasis 2 years postdiagnosis while the second between CBI responders and non-responders. RESULTS: Our study identifies two CD8+TRM subsets, TCF1+ and TCF1-, correlating with melanoma protection. TCF1+TRM cells show heightened expression of IFN-γ and Ki67 while TCF1- TRM cells exhibit increased expression of cytotoxic molecules. In metastatic patients, TRM subsets undergo a shift in marker expression, with the TCF1- subset displaying increased expression of exhaustion markers. We observed a close spatial correlation between cDC1s and TRMs, with TCF1+TRM/cDC1 pairs enriched in the stroma and TCF1- TRM/cDC1 pairs in tumor areas. Notably, these TCF1- TRMs express cytotoxic molecules and are associated with apoptotic melanoma cells. Both TCF1+ and TCF1- TRM subsets, alongside cDC1, prove relevant to CBI response. CONCLUSIONS: Our study supports the importance of TRM CD8 T cells and cDC1 in melanoma protection while also highlighting the existence of functionally distinctive TCF1+ and TCF1- TRM subsets, both crucial for melanoma control and CBI response.
Assuntos
Linfócitos T CD8-Positivos , Fator 1-alfa Nuclear de Hepatócito , Imunoterapia , Melanoma , Humanos , Melanoma/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Imunoterapia/métodos , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Feminino , Masculino , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , IdosoRESUMO
BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) represents one of the principal tumors of the head and neck. Human papillomavirus (HPV) and Epstein-Barr virus (EBV) are considered risk factors for the development and the clinical prognosis of LSCC. High levels of p16INK4a are suggested as a surrogate marker of HPV or EBV infection in some head and neck tumors but in LSCC is still controversial. Furthermore, pRb expression may be considered an additional biomarker but it has not been clearly defined. This work aimed to compare the expression of pRb and p16INK4a as possible biomarkers in tumor tissues with and without infection by EBV or different genotypes of HPV from patients with LSCC. METHODS: Tumor samples from 103 patients with LSCC were previously investigated for the presence and genotypes of HPV using the INNO-LiPA line probe assay and for the infection of EBV by qPCR. p16 INK4a and pRb expression was assessed by immunohistochemistry. RESULTS: Of the 103 tumor samples, expression of p16INK4a was positive in 55 (53.4%) and of this, 32 (56.1%) were positive for HPV whereas 11 (39.3%) were EBV positive but both without a significantly difference (p > 0.05). pRb expression was positive in 78 (75.7%) and a higher frequency of this expression was observed in HPV negative samples (87.0%) (p = 0.021) and in high-risk HPV negative samples (85.2%) (p = 0.010). No difference was observed when comparing pRb expression and EBV infection status (p > 0.05). CONCLUSION: Our results support the suggestion that p16INK4a is not a reliable surrogate marker for identifying HPV or EBV infection in LSCC. On the other hand, most of our samples had pRb expression, which was more frequent in tumors without HPV, suggesting that pRb could indicate HPV negativity. However, more studies with a larger number of cases are required, including controls without LSCC and evaluating other molecular markers to determine the real role of p16INK4a and pRb in LSCC.
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BACKGROUND: Prostate carcinoma is the second leading cause of cancer and the fifth cause of cancer death in men worldwide. OBJECTIVE: To know high-grade prostatic intraepithelial neoplasia and prostate acinar adenocarcinoma immunohistochemical profiles. MATERIAL AND METHODS: Observational, analytical, cross-sectional, retrospective study of specimens obtained by cutting needle biopsy and prostate resection from subjects diagnosed with acinar adenocarcinoma of the prostate and high-grade prostatic intraepithelial neoplasia between January 2015 and December 2020. Tissue microarrays were performed and, subsequently, immunohistochemical studies for BCL2, EGFR, p53, Her2/neu and Ki67. Descriptive statistics were used to analyze clinicopathological factors. Qualitative variables were compared with Fisher's exact test. RESULTS: Twenty-three patients were studied; eight (34%) with angiolymphatic invasion, 14 (60.8%) with perineural invasion, five (21.2%) with prostatitis, and four (17.3%) with fibroadenomatous hyperplasia. HER2/neu (p = 0.1023), p53 (p = 1) and BCL2 expression (p = 0.4136) was observed. CONCLUSION: HER2/neu increased expression was identified in high-grade prostatic intraepithelial neoplasia and acinar adenocarcinoma of the prostate.
ANTECEDENTES: En el mundo, el carcinoma de próstata constituye la segunda causa de cáncer y la quinta causa de muerte por cáncer en hombres. OBJETIVO: Conocer el perfil inmunohistoquímico de la neoplasia intraepitelial prostática de alto grado y del adenocarcinoma acinar de próstata. MATERIAL Y MÉTODOS: Estudio observacional, analítico, transversal y retrospectivo de especímenes obtenidos por biopsia con aguja cortante y resección de próstata debido a diagnóstico de adenocarcinoma acinar de próstata y neoplasia intraepitelial de alto grado, entre enero de 2015 y diciembre de 2020. Se realizaron microarreglos tisulares y, posteriormente, estudios de inmunohistoquímica para BCL2, EGFR, p53, Her2/neu y Ki67. Se realizó estadística descriptiva para analizar los factores clinicopatológicos; las variables cualitativas se compararon con prueba exacta de Fisher. RESULTADOS: Se estudiaron 23 pacientes, ocho (34 %) con invasión angiolinfática, 14 (60.8 %) con invasión perineural, cinco (21.2 %) con prostatitis y cuatro (17.3 %) con hiperplasia fibroadenomatosa. Se observó expresión de HER2/neu (p = 0.1023), p53 (p = 1) y BCL2 (p = 0.4136). CONCLUSIÓN: Se identificó mayor expresión de HER2/neu en la neoplasia intraepitelial prostática de alto grado y el adenocarcinoma acinar de próstata.
Assuntos
Adenocarcinoma , Neoplasia Prostática Intraepitelial , Neoplasias da Próstata , Masculino , Humanos , Neoplasia Prostática Intraepitelial/patologia , Próstata/patologia , Estudos Retrospectivos , Estudos Transversais , Proteína Supressora de Tumor p53 , Neoplasias da Próstata/patologia , Adenocarcinoma/patologia , Proteínas Proto-Oncogênicas c-bcl-2RESUMO
Resumen Antecedentes: En el mundo, el carcinoma de próstata constituye la segunda causa de cáncer y la quinta causa de muerte por cáncer en hombres. Objetivo: Conocer el perfil inmunohistoquímico de la neoplasia intraepitelial prostática de alto grado y del adenocarcinoma acinar de próstata. Material y métodos: Estudio observacional, analítico, transversal y retrospectivo de especímenes obtenidos por biopsia con aguja cortante y resección de próstata debido a diagnóstico de adenocarcinoma acinar de próstata y neoplasia intraepitelial de alto grado, entre enero de 2015 y diciembre de 2020. Se realizaron microarreglos tisulares y, posteriormente, estudios de inmunohistoquímica para BCL2, EGFR, p53, Her2/neu y Ki67. Se realizó estadística descriptiva para analizar los factores clinicopatológicos; las variables cualitativas se compararon con prueba exacta de Fisher. Resultados: Se estudiaron 23 pacientes, ocho (34 %) con invasión angiolinfática, 14 (60.8 %) con invasión perineural, cinco (21.2 %) con prostatitis y cuatro (17.3 %) con hiperplasia fibroadenomatosa. Se observó expresión de HER2/neu (p = 0.1023), p53 (p = 1) y BCL2 (p = 0.4136). Conclusión: Se identificó mayor expresión de HER2/neu en la neoplasia intraepitelial prostática de alto grado y el adenocarcinoma acinar de próstata.
Abstract Background: Prostate carcinoma is the second leading cause of cancer and the fifth cause of cancer death in men worldwide. Objective: To know high-grade prostatic intraepithelial neoplasia and prostate acinar adenocarcinoma immunohistochemical profiles. Material and methods: Observational, analytical, cross-sectional, retrospective study of specimens obtained by cutting needle biopsy and prostate resection from subjects diagnosed with acinar adenocarcinoma of the prostate and high-grade prostatic intraepithelial neoplasia between January 2015 and December 2020. Tissue microarrays were performed and, subsequently, immunohistochemical studies for BCL2, EGFR, p53, Her2/neu and Ki67. Descriptive statistics were used to analyze clinicopathological factors. Qualitative variables were compared with Fisher's exact test. Results: Twenty-three patients were studied; eight (34%) with angiolymphatic invasion, 14 (60.8%) with perineural invasion, five (21.2%) with prostatitis, and four (17.3%) with fibroadenomatous hyperplasia. HER2/neu (p = 0.1023), p53 (p = 1) and BCL2 expression (p = 0.4136) was observed. Conclusion: HER2/neu increased expression was identified in high-grade prostatic intraepithelial neoplasia and acinar adenocarcinoma of the prostate.
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Background: Prostate carcinoma is the second leading cause of cancer and the fifth cause of cancer death in men worldwide. Objective: To know high-grade prostatic intraepithelial neoplasia and prostate acinar adenocarcinoma immunohistochemical profiles. Material and methods: Observational, analytical, cross-sectional, retrospective study of specimens obtained by cutting needle biopsy and prostate resection from subjects diagnosed with acinar adenocarcinoma of the prostate and high-grade prostatic intraepithelial neoplasia between January 2015 and December 2020. Tissue microarrays were performed and, subsequently, immunohistochemical studies for BCL2, EGFR, p53, Her2/neu and Ki67. Descriptive statistics were used to analyze clinicopathological factors. Qualitative variables were compared with Fisher's exact test. Results: Twenty-three patients were studied; eight (34%) with angiolymphatic invasion, 14 (60.8%) with perineural invasion, five (21.2%) with prostatitis, and four (17.3%) with fibroadenomatous hyperplasia. HER2/neu (p = 0.1023), p53 (p = 1) and BCL2 expression (p = 0.4136) was observed. Conclusion: HER2/neu increased expression was identified in high-grade prostatic intraepithelial neoplasia and acinar adenocarcinoma of the prostate.
Antecedentes: En el mundo, el carcinoma de próstata constituye la segunda causa de cáncer y la quinta causa de muerte por cáncer en hombres. Objetivo: Conocer el perfil inmunohistoquímico de la neoplasia intraepitelial prostática de alto grado y del adenocarcinoma acinar de próstata. Material y métodos: Estudio observacional, analítico, transversal y retrospectivo de especímenes obtenidos por biopsia con aguja cortante y resección de próstata debido a diagnóstico de adenocarcinoma acinar de próstata y neoplasia intraepitelial de alto grado, entre enero de 2015 y diciembre de 2020. Se realizaron microarreglos tisulares y, posteriormente, estudios de inmunohistoquímica para BCL2, EGFR, p53, Her2/neu y Ki67. Se realizó estadística descriptiva para analizar los factores clinicopatológicos; las variables cualitativas se compararon con prueba exacta de Fisher. Resultados: Se estudiaron 23 pacientes, ocho (34 %) con invasión angiolinfática, 14 (60.8 %) con invasión perineural, cinco (21.2 %) con prostatitis y cuatro (17.3 %) con hiperplasia fibroadenomatosa. Se observó expresión de HER2/neu (p = 0.1023), p53 (p = 1) y BCL2 (p = 0.4136). Conclusión: Se identificó mayor expresión de HER2/neu en la neoplasia intraepitelial prostática de alto grado y el adenocarcinoma acinar de próstata.
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Resumen Introducción: Variantes génicas relacionadas con la vía de señalización de las proteínas morfogenéticas óseas (BMP2, BMP4, GREM1, SMAD7) se han asociado a cáncer colorrectal, principalmente en poblaciones caucásicas. Objetivo: Describir la asociación de variantes en miembros de la vía BMP en población mexicana, caracterizada por su ancestría indoamericana y caucásica. Métodos: Se realizó el genotipado de 1000 casos de cáncer colorrectal y 1043 individuos de control reclutados en la Ciudad de México, Monterrey y Torreón mediante la plataforma Sequenom. Con análisis univariados y multivariados se estudiaron las asociaciones entre cáncer colorrectal y variantes. Resultados: Las variantes rs4444235, rs12953717 y rs4939827 replicaron la asociación con la neoplasia (p ≤ 0.05). La ascendencia caucásica mostró asociación con el tumor. Conclusiones: El estudio mostró las asociaciones entre cáncer colorrectal y las variantes SMAD7 y BMP4, así como con el componente caucásico de la mezcla étnica.
Abstract Introduction: Genetic variants related to bone morphogenetic proteins (BMP2, BMP4, GREM1, SMAD7) signaling pathway have been associated with colorectal cancer, mainly in Caucasian populations. Objective: To describe the association of variants in members of the BMP signaling pathway in a Mexican population, characterized by its indigenous American and Caucasian ancestry. Methods: Genotyping of 1,000 colorectal cancer cases and 1,043 control individuals recruited in Mexico City, Monterrey, and Torreón was carried out using the Sequenom platform. Associations between colorectal cancer and variants were studied with univariate and multivariate analyses. Results: Variants rs4444235, rs12953717 and rs4939827 replicated the association with the neoplasm (p ≤ 0.05). Caucasian ancestry showed association with the tumor. Conclusions: The study replicated the associations between colorectal cancer and SMAD7 and BMP4 variants, with an association being observed with the Caucasian component of the ethnic mix.
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INTRODUCTION: Genetic variants related to bone morphogenetic proteins (BMP2, BMP4, GREM1, SMAD7) signaling pathway have been associated with colorectal cancer, mainly in Caucasian populations. OBJECTIVE: To describe the association of variants in members of the BMP signaling pathway in a Mexican population, characterized by its indigenous American and Caucasian ancestry. METHODS: Genotyping of 1,000 colorectal cancer cases and 1,043 control individuals recruited in Mexico City, Monterrey, and Torreón was carried out using the Sequenom platform. Associations between colorectal cancer and variants were studied with univariate and multivariate analyses. RESULTS: Variants rs4444235, rs12953717 and rs4939827 replicated the association with the neoplasm (p ≤ 0.05). Caucasian ancestry showed association with the tumor. CONCLUSIONS: The study replicated the associations between colorectal cancer and SMAD7 and BMP4 variants, with an association being observed with the Caucasian component of the ethnic mix.
INTRODUCCIÓN: Variantes génicas relacionadas con la vía de señalización de las proteínas morfogenéticas óseas (BMP2, BMP4, GREM1, SMAD7) se han asociado a cáncer colorrectal, principalmente en poblaciones caucásicas. OBJETIVO: Describir la asociación de variantes en miembros de la vía BMP en población mexicana, caracterizada por su ancestría indoamericana y caucásica. MÉTODOS: Se realizó el genotipado de 1000 casos de cáncer colorrectal y 1043 individuos de control reclutados en la Ciudad de México, Monterrey y Torreón mediante la plataforma Sequenom. Con análisis univariados y multivariados se estudiaron las asociaciones entre cáncer colorrectal y variantes. RESULTADOS: Las variantes rs4444235, rs12953717 y rs4939827 replicaron la asociación con la neoplasia (p ≤ 0.05). La ascendencia caucásica mostró asociación con el tumor. CONCLUSIONES: El estudio mostró las asociaciones entre cáncer colorrectal y las variantes SMAD7 y BMP4, así como con el componente caucásico de la mezcla étnica.
Assuntos
Proteínas Morfogenéticas Ósseas , Neoplasias Colorretais , Predisposição Genética para Doença , Humanos , Estudos de Casos e Controles , Neoplasias Colorretais/genética , Neoplasias Colorretais/epidemiologia , Estudo de Associação Genômica Ampla , México , Polimorfismo de Nucleotídeo Único , Transdução de Sinais , Proteínas Morfogenéticas Ósseas/genéticaRESUMO
Various cell types participate in the tumor process, in which the mast cells have been described; however, the role they play in colorectal adenocarcinoma has not yet been fully understood. Therefore, the present work aimed to compare employing histochemistry and immunohistochemistry, the number of mast cells and the content of some cytoplasmic granules in moderately differentiated non-metastatic and metastatic colorectal adenocarcinoma, analyzing tissue samples from patients. Histochemical techniques with Toluidine Blue (TBO), Periodic Schiff Acid (PAS), Alcian Blue/Periodic Acid-Schiff (PAB) and Alcian Blue/Safranin (ABS); as well as immunohistochemical reactions with anti-antibodies anti-Tryptase and anti-Chymase were applied to quantify total mast cells and content of some cytoplasmic granules. Statistical analysis was performed using SPSS V22.0 software (pâ¯≤â¯0.05). The degree of positivity of the reaction and degranulation of mast cells was reported in percentages. In our results, we observed that there are differences in the quantity and histochemical composition of the granules of mast cells (metastatic group PAS and ABS comparing the TBO reaction), as well as in the immunohistochemical composition between Tryptase and Chymase and the number of degranulated cells in both study groups (74 % degranulated mast cells in the metastatic group, 66 % integrate mast cells in the non-metastatic group). Therefore, we consider that the differences may be some of the probable factors that lead to metastasis of colorectal adenocarcinoma.
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Quimases/metabolismo , Neoplasias Colorretais/metabolismo , Mastócitos/metabolismo , Triptases/metabolismo , Quimases/análise , Neoplasias Colorretais/patologia , Histocitoquímica/métodos , Humanos , Imuno-Histoquímica/métodos , Coloração e Rotulagem/métodos , Cloreto de Tolônio/análise , Cloreto de Tolônio/metabolismoRESUMO
BACKGROUND: Germline mutations in E-cadherin (CDH1) gene are associated with autosomal-dominantly inherited cancer syndrome characterized by diffuse gastric cancer, lobular breast cancer, and in some families, cleft lip/palate. However, there may be generations in which these neoplasms do not occur at all in a family and later on, one or another carcinoma arises, which makes it difficult for physicians to think about hereditary origin. METHODS: We report the first Mexican family with CDH1 mutation (variant c.377del). RESULTS: An asymptomatic young woman underwent a search for mutations in susceptibility genes for breast cancer due to the history of this neoplasm in her mother and maternal aunt. A CDH1 mutation was detected. After an endoscopy, a diffuse gastric carcinoma was found. Later on, three generations of this family were studied. The findings are presented. CONCLUSION: Medical communities should be aware of the contribution of this gene in the development of hereditary diffuse gastric carcinoma (HDGC) and breast cancer.
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Antígenos CD/genética , Neoplasias da Mama/genética , Caderinas/genética , Carcinoma/genética , Deleção de Genes , Neoplasias Gástricas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Carcinoma/patologia , Feminino , Humanos , Masculino , México , Pessoa de Meia-Idade , Linhagem , Neoplasias Gástricas/patologiaRESUMO
ANTECEDENTES: El cáncer de laringe representa el 21.7% de las neoplasias malignas de vías aerodigestivas superiores. La prevalencia del virus del papiloma humano (VPH) en el cáncer de laringe oscila entre el 0 y el 80%. MÉTODO: Se incluyeron 112 muestras de tejido laríngeo de pacientes con cáncer de laringe. Se amplificó el ADN y se analizó la presencia y el genotipo del VPH mediante hibridación reversa (INNO-LiPA®). Se realizaron pruebas de ji cuadrada, Fisher y t de Student no pareada. RESULTADOS: Se incluyeron muestras de 107 hombres (95.5%) y 5 mujeres (4.5%), con una edad de 65.3 ± 10.1 años, con antecedente de tabaquismo 108 (96.4%), alcoholismo 9 (8.0%) y carcinoma epidermoide moderadamente diferenciado queratinizante 96 (85.7%). Se identificó VPH en 60 (53.5%), VPH-11 en 51 (45.5%), VPH-52 en 27 (24.1%), VPH-16 en 9 (8.0%), VPH-45 en 3 (2.6%) y coinfección por más de un genotipo en 31 (27.6%). No hubo diferencia entre pacientes con y sin infección por VPH en cuanto a edad, sexo, localización, diagnóstico histopatológico, tabaquismo ni alcoholismo (p > 0.05). CONCLUSIONES: La prevalencia de infección por VPH en el cáncer de laringe fue del 53.5%, con coinfección por más de un genotipo en el 27.6%. El genotipo más frecuente fue el VPH-11, tipo de bajo riesgo, seguido por el VPH-52, de alto riesgo oncogénico. BACKGROUND: Laryngeal cancer represents 21.7% of malignancies of the upper aerodigestive tract. The prevalence of the Human Papillomavirus (HPV) in laryngeal cancer ranges 0 to 80%. METHODS: We included 112 laryngeal tissue samples obtained from patients with laryngeal cancer. DNA was extracted and amplified by PCR. HPV presence and genotype were analyzed by the reverse hybridization INNO-LiPA® assay. Chi-square, Fisher's and unpaired Student t tests were used. RESULTS: Samples from 107 male (95.5%) and 5 female patients (4.5%) were evaluated, aged 65.3±10.1 years, 108 with smoking history (96.4%), 9 with alcoholism history (8.0%), and in 96 the histological diagnosis was moderately differentiated keratinizing squamous cell carcinoma (85.7%). HPV was detected in 60 samples (53.5%), HPV-11 in 51 (45.5%), HPV-52 in 27 (24.1%), HPV-16 in 9 (8.0%), HPV-45 in 3 (2.6%), and coinfection by more than one genotype in 31 (27.6%). There was no difference between patients with and without HPV infection with respect to age, sex, tumor location and histology, smoking and alcoholism history (p>0.05). CONCLUSIONS: The prevalence of HPV infection in laryngeal cancer was 53.5% with coinfection with more than one genotype in 27.6%. The most frequent genotype was HPV-11, an oncogenic low-risk genotype, followed by HPV-52, a high-risk genotype.