Osteopontin, WNT3A, and ABCB5 Biomarkers Expression in Osteosarcoma Patients.

Objective This study aimed to correlate the expression, by immunohistochemistry, of the proteins OPN, ABCB5, and WNT3A from anatomopathological materials obtained from paraffin blocks, slides, or both, from patients with osteosarcoma (OS), analyzing epidemiological characteristics, as well as their presence and influence on the evolution and progression of the disease. Methods After the initial case selection, we searched for the respective paraffin blocks and took only those with sufficient tumor mass to allow additional sections with no complete loss of biological material. The sarcoma area identification in representative paraffin blocks used multisample blocks (tissue microarray [TMA]) created on a BenchMark ULTRA (Roche Diagnostics Corporation, Indianapolis, IN, USA) instrument. Then, we analyzed the association between the expression of ABCB5, WNT3A, and osteopontin (OPN) markers with the variables age, location, and tissue type (Fisher exact test/Chi-squared test). Results The average age of the patients was 23 years, and the rate of males and females was the same. We analyzed 40 slides from 28 OS patients seen from 2005 to 2017. Their follow-up time was 80.0 months, and the 5-year survival rate was 46.7%. Most metastases occurred in lung tissue (92.9%). Proteins ABCB5, OPN, and WNT3A did not present statistical significance when compared with age group, neo-adjuvant, adjuvant, or both, chemotherapy, location, survival, or death. Osteopontin was negative in all samples. WNT3A expression occurred in patients who died early. Conclusion In an immunohistochemical study, ABCB5, OPN, and WNT3A did not have statistical significance. In the parameters analyzed, they did not seem to be a predictive or aggressive factor for OS.

Basal or stimulated thyroglobulin in evaluating response to treatment in papillary thyroid carcinoma? A retrospective cohort study.

OBJECTIVE: It is not clear whether response to initial treatment in papillary thyroid carcinoma (PTC) patients is best evaluated by measuring thyroglobulin (Tg) in the presence of levothyroxine (BTg) or when stimulated by elevated TSH (STg). The aim of this study was to evaluate whether response to therapy 1 year after initial treatment changes with the use of STg in relation to BTg in PTC patients treated with total thyroidectomy (TT) and radioiodine (131I), and, if observed, to assess which response is better associated with clinical course. SUBJECTS AND METHODS: This is a retrospective study of 148 PTC patients submitted to TT and 131I. We analyzed the response to therapy (excellent, biochemical incomplete, or indeterminate) at 1 year after initial treatment, using BTg or STg, and compared which method was better associated with "excellent response at final evaluation." RESULTS: Twenty-eight patients (20.4%) presented change in response to therapy, with 17 of these (60.7%) presenting a worse response. Response using STg was 1.6 times better associated with proposed outcome [odds ratio (OR) = 4.61; confidence interval 95% (IC95%): 2.13-9.98] than with BTg (OR = 2.84; IC95%: 1.33-6.06). CONCLUSION: Response to therapy at 1 year using STg was altered in approximately 20% of cases and therefore proved to be a better predictor of excellent response in the last evaluation.

Cáncer de mama en el norte del Perú: subtipos moleculares y HER2 low / Breast cancer in northern Peru: molecular subtypes and HER2 low

RESUMEN El objetivo del estudio fue conocer el perfil inmunohistoquímico del cáncer de mama e identificar el subgrupo HER2 low en la macrorregión norte del Perú. Se realizó un estudio transversal con una muestra de 1176 pacientes atendidos en el Instituto Regional de Enfermedades Neoplásicas Norte del Perú desde enero de 2016 a diciembre de 2023. Los datos recolectados (edad, tipo histológico, grado y resultados complementarios), se analizaron con frecuencias y porcentajes. El perfil correspondió a: luminal B (45,6%); luminal A (24,7%); triple negativo (18,2%); y HER2 positivo no luminal (11,5%). Además, HER2 low fueron 215 pacientes (25,1% de los considerados previamente negativos). Este estudio proporciona evidencia que la subtipificación de cáncer de mama ha cambiado, siendo luminal B más frecuente, y es esencial involucrar a políticas de salud para adquirir terapias dirigidas considerando a pacientes HER2 low.

ABSTRACT This study aimed to understand the immunohistochemical profile of breast cancer and to identify the HER2 low subgroup in the northern macro-region of Peru. A cross-sectional study was conducted in 1176 patients from the Regional Institute of Neoplastic Diseases Northern Peru, from January 2016 to December 2023. We analyzed the data (age, histological type, grade and complementary results), with frequencies and percentages. The profile corresponded to: luminal B (45.6%); luminal A (24.7%); triple negative (18.2%); and HER2 positive non luminal (11.5%). In addition, 215 patients presented HER2 low (25.1% of those previously considered negative). This study provides evidence that the subtyping of breast cancer has changed, being luminal B the most frequent. It is essential to involve health policies to acquire targeted therapies considering HER2 low patients.

Osteopontin, WNT3A, and ABCB5 Biomarkers Expression in Osteosarcoma Patients / Expressão dos biomarcadores osteopontin, WNT3A e ABCB5 em pacientes com osteossarcoma

Abstract Objective This study aimed to correlate the expression, by immunohistochemistry, of the proteins OPN, ABCB5, and WNT3A from anatomopathological materials obtained from paraffin blocks, slides, or both, from patients with osteosarcoma (OS), analyzing epidemiological characteristics, as well as their presence and influence on the evolution and progression of the disease. Methods After the initial case selection, we searched for the respective paraffin blocks and took only those with sufficient tumor mass to allow additional sections with no complete loss of biological material. The sarcoma area identification in representative paraffin blocks used multisample blocks (tissue microarray [TMA]) created on a BenchMark ULTRA (Roche Diagnostics Corporation, Indianapolis, IN, USA) instrument. Then, we analyzed the association between the expression of ABCB5, WNT3A, and osteopontin (OPN) markers with the variables age, location, and tissue type (Fisher exact test/Chi-squared test). Results The average age of the patients was 23 years, and the rate of males and females was the same. We analyzed 40 slides from 28 OS patients seen from 2005 to 2017. Their follow-up time was 80.0 months, and the 5-year survival rate was 46.7%. Most metastases occurred in lung tissue (92.9%). Proteins ABCB5, OPN, and WNT3A did not present statistical significance when compared with age group, neo-adjuvant, adjuvant, or both, chemotherapy, location, survival, or death. Osteopontin was negative in all samples. WNT3A expression occurred in patients who died early. Conclusion In an immunohistochemical study, ABCB5, OPN, and WNT3A did not have statistical significance. In the parameters analyzed, they did not seem to be a predictive or aggressive factor for OS.

Resumo Objetivo Correlacionar a expressão, por imunoistoquímica, das proteínas OPN, ABCB5 e WNT3A de material anatomopatológico, obtido de blocos de parafina e/ou lâminas, em pacientes com osteossarcoma (OS), analisando as características epidemiológicas, sua presença e influência na evolução e progressão da doença. Métodos Após a seleção inicial dos casos, ocorreu a busca dos respectivos blocos de parafina, dentre os quais foram selecionados somente aqueles que possuíam massa tumoral suficiente para serem realizados cortes adicionais sem que todo o material biológico fosse utilizado. Foram identificadas áreas do sarcoma nos blocos de parafina representativos para a confecção de blocos multiamostrais (microarranjo de tecidos, ou tissue microarray [TMA], em inglês), realizada em instrumento BenchMark ULTRA (Roche Diagnostics Corporation, Indianapolis, IN, USA). Foi então analisada a associação entre a expressão dos marcadores ABCB5, WNT3A e OPN com as variáveis idade, localização e tipo de tecido (teste exato de Fisher/Qui-quadrado). Resultados A média de idade foi de 23 anos, e a incidência de pacientes dos sexos masculino e feminino foi a mesma; foram analisadas 40 lâminas de 28 pacientes com OS, entre 2005 e 2017, com tempo de segmento de 80,0 meses, e o tempo de sobrevida foi de 46,7% em 5 anos. Metástases ocorreram em tecido pulmonar (92,9%). Quanto aos marcadores ABCB5, OPN e WNT3A, não apresentaram significância estatísticas quando comparados com faixa etária, neo-adjuvância e/ou adjuvância quimioterápica, localização, sobrevida ou óbito. O OPN mostrou-se negativo em todas as amostras. E o WNT3A expressou-se nos pacientes com óbitos precoces. Conclusão As proteínas ABCB5, OPN e WNT3A, em estudo imunoistoquímico, não se mostraram presentes com significância estatística. Nos parâmetros analisados, não surgem como sendo fatores preditivos ou de agressividade para o OS.

Niveles de β2microglobulina, variables clínicas y sociodemográficas en pacientes con síndrome linfoproliferativo crónico de reciente diagnóstico

Fundamento: la β2microglobulina está reconocida como marcador tumoral para diferentes propósitos en hematopatías malignas de estirpe linfoide; sin embargo, no hay antecedentes de su utilización en la provincia de Cienfuegos. Objetivo describir las características sociodemográficas, clínicas y la distribución de los niveles séricos de β2microglobulina en pacientes con síndrome linfoproliferativo crónico y su relación con los estadios clínicos y la respuesta al tratamiento de primera línea. Métodos: estudio observacional descriptivo transversal. La serie se conformó con todos los pacientes adultos con diagnóstico reciente (sin comenzar terapia antitumoral específica) de mieloma múltiple, leucemia linfoide crónica, linfoma no Hodgkin y linfoma Hodgkin, ingresados en el Servicio de Hematología del Hospital General Universitario Dr. Gustavo Aldereguìa Lima, durante el año 2020. La información se obtuvo mediante revisión documental de historias clínicas y ensayos de laboratorio. Se analizaron las variables: sexo, edad, color de la piel, niveles de β2microglobulina, tipo de enfermedad, estadios clínicos y respuesta al tratamiento. Resultados: el 84 % de la serie presentó niveles elevados del analito, más acentuado en el mieloma. Se constató relación entre los niveles estratificados de β2microglobulina con los estadios clínicos y la respuesta al tratamiento de primera línea. Conclusiones: las características sociodemográficas y las variables clínicas observadas no difieren de forma sustantiva con lo reportado. La distribución de los niveles de la β2microglobulina es sugerente de una relación directa entre los estadios clínicos e inversa con la respuesta al tratamiento.

Background: β2microglobulin is recognized as a tumor marker for different purposes in malignant hematopathies of lymphoid lineage; however, there is no history of its use in the Cienfuegos province. Objective: to describe the sociodemographic and clinical characteristics and the distribution of serum β2microglobulin levels in patients with chronic lymphoproliferative syndrome and their relationship with clinical stages and response to first-line treatment. Methods: cross-sectional descriptive observational study. The series was made up of all adult patients (universe 50) recently diagnosed (without starting specific antitumor therapy) of multiple myeloma, chronic lymphoid leukemia, non-Hodgkin lymphoma and Hodgkin lymphoma, admitted to the Hematology Service of the Dr. Gustavo Aldereguìa Lima General University Hospital, during the year 2020. The information was obtained through documentary review of medical records and laboratory tests. The analyzed variables were: sex, age, skin color, β2microglobulin levels, type of disease, clinical stages and response to treatment. Results: 84% of the series presented high levels of the analyte, more accentuated in myeloma. A relationship was found between the stratified levels of β2microglobulin with the clinical stages and the response to first-line treatment. Conclusions: the sociodemographic characteristics and the clinical variables observed do not differ substantially from what was reported. The distribution of β2microglobulin levels is suggestive of a direct relationship between clinical stages and an inverse relationship with response to treatment.

PD-L1 gene amplification and focality: relationship with protein expression.

PD-L1 (CD274) amplification occurs in a small subset of malignancies and may predict anti-PD-1/PD-L1 immunotherapy responsiveness. We hypothesized that both copy number (CN) and focality of cancer-related PD-L1 amplifications impact protein expression, and, thus, analyzed solid tumors that underwent comprehensive genomic profiling between March 2016 and February 2022 at Foundation Medicine. PD-L1 CN alterations were detected using a comparative genomic hybridization-like method. PD-L1 CN changes were correlated with PD-L1 protein expression (DAKO 22C3 antibody) by immunohistochemistry (IHC). Overall, 60,793 samples were analyzed (most frequent histologies: lung adenocarcinoma (20%), colon adenocarcinoma (12%), lung squamous carcinoma (8%)). Using a definition of CD274 CN ≥ specimen ploidy +4 (6 copies), 1.21% of tumors (738/60,793) were PD-L1 amplified. Focality category distribution was as follows: <0.1 mB (n=18 (2.4%)), ≥0.1 to <4 mB (n=230 (31.1%)), ≥4 to <20 mB (n=310 (42%)), ≥20mB (n=180 (24.4%)). Lower levels of PD-L1 amplification (below specimen ploidy +4) were more frequently non-focal amplifications compared to higher levels. In addition, more focal amplification (<0.1 mB) correlated with higher PD-L1 IHC expression. Median tumor proportion score (TPS) for samples with PD-L1 amplification (ploidy ≥+4) according to focality were 87.5% (<0.1 mB), 80% (≥0.1 to <4 mB), 40% (≥4 to <20 mB), 1% (≥20mB). In specimens with PD-L1 ploidy less than +4, but highly focal (<0.1 mB), the 75th percentile of PD-L1 expression by TPS was 80%. Conversely, non-focal (≥20 mB) PD-L1 amplification (ploidy ≥+4) can present high PD-L1 expression (TPS≥50%), albeit infrequently (0.09% of our cohort). In conclusion, PD-L1 expression measured by IHC is influenced by PD-L1 amplification level and focality. Further correlation between amplification, focality, protein expression and therapeutic outcome for PD-L1 and other targetable genes warrants exploration.

Identification of novel biomarkers with potential for diagnosis and prognosis of gastric cancer: a bioinformatics approach

INTRODUCTION: Gastric cancer (GC) is the fifth most diagnosed neoplasia and the third leading cause of cancer-related deaths. A substantial number of patients exhibit an advanced GC stage once diagnosed. Therefore, the search for biomarkers contributes to the improvement and development of therapies. OBJECTIVE: This study aimed to identify potential GC biomarkers making use of in silico tools. METHODS: Gastric tissue microarray data available in Gene Expression Omnibus and The Cancer Genome Atlas Program was extracted. We applied statistical tests in the search for differentially expressed genes between tumoral and non-tumoral adjacent tissue samples. The selected genes were submitted to an in-house tool for analyses of functional enrichment, survival rate, histological and molecular classifications, and clinical follow-up data. A decision tree analysis was performed to evaluate the predictive power of the potential biomarkers. RESULTS: In total, 39 differentially expressed genes were found, mostly involved in extracellular structure organization, extracellular matrix organization, and angiogenesis. The genes SLC7A8, LY6E, and SIDT2 showed potential as diagnostic biomarkers considering the differential expression results coupled with the high predictive power of the decision tree models. Moreover, GC samples showed lower SLC7A8 and SIDT2 expression, whereas LY6E was higher. SIDT2 demonstrated a potential prognostic role for the diffuse type of GC, given the higher patient survival rate for lower gene expression. CONCLUSION: Our study outlines novel biomarkers for GC that may have a key role in tumor progression. Nevertheless, complementary in vitro analyses are still needed to further support their potential.

Expressão de enzimas modificadoras de MRNA no carcinoma renal de células claras e no carcinoma de mama / Expression of MRNA-modifying enzymes in clear cell renal cell carcinoma and breast cancer

Após a transcrição, as moléculas de RNA podem ser alteradas por uma infinidade de modificações químicas distintas que ocorrem de maneira dinâmica, constituindo o epitranscriptoma. A primeira modificação de mRNA identificada foi a N6-metiladenosina (m6A), afetando quase todas as etapas do metabolismo do RNA, desde o processamento no núcleo até a tradução e decaimento no citoplasma, alterando assim os níveis de expressão gênica. A m6A é controlada por três grupos de proteínas, writers, readers e erasers. Na literatura estudos relatam que as proteínas que regulam a m6A possam estar mutadas e / ou exibir expressão alterada através de uma variedade de tipos de tumores, mais notavelmente o carcinoma de mama e o CRCC. Neste projeto, tivemos como objetivo determinar os níveis de expressão das enzimas modificadoras de mRNA, e suas correlações com dados clínicos e anatomopatológicos para CRCC e carcinoma de mama, o que pode nos ajudar a ampliar o conhecimento sobre os mecanismos moleculares associados a estas doenças. Em nossa coorte dos pacientes com CRCC, detectamos que a baixa expressão da writer RBM15B, se associa com variáveis relacionadas a progressão tumoral e apresenta pior SR e aumento de risco do paciente recidivar. A baixa expressão da FTO e alta da METTL14, se associam aos estágios mais agressivos de CRCC, podendo serem possíveis marcadores de prognóstico. No carcinoma de mama, os pacientes com expressão baixa da METTL14, apresentaram associação com pior prognóstico para esta doença, especificamente no subtipo molecular TN e aumento de risco em (RR = 4,772; p= 0,01), para óbito global. Sendo assim, acreditamos que interferência no mecanismo de controle da m6A no mRNA desencadeada por alterações de expressão destas proteínas, podem estar ligadas a alterações biológicas levando ao processo de tumorigênese

After transcription, RNA molecules can be altered by a multitude of different chemical modifications that occur dynamically, constituting the epitranscriptome. The first mRNA modification identified was N6-methyladenosine (m6A), affects almost all steps of RNA metabolism, from processing in the nucleus to translation and decay in the cytoplasm, thus altering gene expression levels. m6A is controlled by three groups of proteins, writers, readers and erasers. Studies in the literature report that proteins that regulate m6A may be mutated and/or exhibit altered expression across a variety of tumor types, most notably breast cancer and ccRCC. In this project, we aimed to determine the expression levels of mRNA-modifying enzymes, and their correlations with clinical and anatomopathological data for ccRCC and breast cancer, which can help to expand our knowledge about the molecular mechanisms associated with these diseases. In our cohort of patients with ccRCC, we detected that the low expression of writer RBM15B is associated with characteristics related to tumor progression showing worse Relapse-Free survival and increased recurrence risk. Low expression of FTO and high expression of METTL14 are associated with more aggressive stages of ccRCC and may be possible prognostic markers. In breast cancer, patients with low METTL14 expression were associated with a worse prognosis, specifically in the TN molecular subtype, with increased death risk (RR = 4.772; p= 0.01). Therefore, we believe that interference in the m6A control mechanism in the mRNA triggered by changes in the expression of these proteins may be linked to biological alterations leading to the process of tumorigenesis

Can we use Ki67 expression to predict prostate cancer aggressiveness? / Podemos usar a expressão de Ki67 para prever a agressividade do câncer de próstata?

ABSTRACT Introduction: specialists have an urge for biomarkers that can discriminate indolent prostate cancer from aggressive tumors. Ki67 is a proliferation marker, and its expression is associated with the aggressiveness of several cancers. Objective: analyze the expression of Ki67 in prostate cancer samples correlating with the aggressiveness of the disease. Methods: Ki67 mRNA levels were determined utilizing data from a TCGA cohort (Tumor(n)=492 and control(n)=52). The protein expression was determined on 94 biopsies from patients by immunohistochemical assay. Results: in mRNA, the Ki67 upregulation is associated with cancer tissue (p<0.0001) and worst disease-free survival (p=0.035). The protein upregulation is associated with increase of the ISUP score (p<0.0001), cancer stage (p=0.05), biochemical recurrence (p=0.0006) and metastasis (p<0.0001). We also show a positive correlation between Ki67 expression and ISUP score (r=0.5112, p<0.0001) and disease risk stratification (r=0.3388, p=0.0009). Ki67 expression is a factor independently associated with biochemical recurrence (p=0.002) and metastasis (p<0.0001). Finally, the patients with high Ki67expression shows better survival regarding biochemical recurrence (p=0.008) and metastasis (p=0.056). Patients with high Ki67 expression are 2.62 times more likely to develop biochemical recurrence (p=0.036). Conclusion: Ki67 upregulation is associated with prostate cancer aggressiveness.

RESUMO Introdução: especialistas precisam biomarcadores que podem discriminar o câncer de próstata indolente de tumores agressivos. Ki67 é um marcador de proliferação, e sua expressão está associada à agressividade de vários tumores. Objetivo: analisar a expressão do Ki67 em amostras de câncer de próstata correlacionando com a agressividade da doença. Métodos: os níveis de mRNA de Ki67 foram determinados utilizando dados de uma coorte de TCGA (Tumor(n)=492 e controle(n)=52). A expressão da proteína foi determinada em 94 biópsias de pacientes por ensaio imuno-histoquímica. Resultados: no mRNA, a superexpressão Ki67 está associada ao tecido canceroso (p<0,0001) e à pior sobrevida livre de doença (p=0,035). A superexpressão proteica está associada ao aumento do escore ISUP (p<0,0001), estágio de câncer (p=0,05), recorrência bioquímica (p=0,0006) e metástase (p<0,0001). Também mostramos uma correlação positiva entre a expressão Ki67 e o escore ISUP (r=0,5112, p<0,0001) e a estratificação de risco de doença (r=0,3388, p=0,0009). A expressão Ki67 é um fator independentemente associado à recorrência bioquímica (p=0,002) e metástase (p<0,0001). Finalmente, os pacientes com alta expressão de Ki67 expression mostram melhor sobrevivência em relação à recorrência bioquímica (p=0,008) e metástase (p=0,056). Os pacientes com alta expressão de Ki67 são 2,62 vezes mais propensos a desenvolver recorrência bioquímica (p=0,036). Conclusão: a superexpressão Ki67 está associada à agressividade do câncer de próstata.

Las enzimas metalo-óxidorreductasas: posibles biomarcadores de tumores ginecológicos

RESUMEN La incidencia de tumores epiteliales ginecológicos y su diagnóstico en etapas avanzadas ocasionan daños físicos, impactan en la salud reproductiva y producen afectaciones psicológicas en las mujeres. Reducir el tiempo de su detección constituye un gran reto para la Salud Pública. El conocimiento y validación de diversos métodos enzimáticos de estudio, aplicados a la patología tumoral, permitirá la integración de cada resultado al entramado de reacciones, mecanismos de reconocimiento molecular y celular, así como de las vías de señalización, útiles para la comprensión de la enfermedad y sus mecanismos diagnósticos y terapéuticos. La determinación de la actividad de las enzimas metalo-óxidorreductasas en suero es una tentativa para la implementación de biomarcadores líquidos para el diagnóstico temprano y el pronóstico de tumores ginecológicos. El objetivo del presente trabajo es la recopilación de información actualizada acerca de los biomarcadores enzimáticos para la predicción, diagnóstico y seguimiento de los tumores epiteliales ginecológicos.

ABSTRACT The incidence of gynecological epithelial tumors and their diagnosis in advanced stages cause physical damage, impact on reproductive health and produce psychological effects in women. Reducing the time of its detection constitutes a great challenge for public health. The knowledge and validation of various enzymatic study methods, applied to tumor pathology, will allow the integration of each result into the network of reactions, molecular and cellular recognition mechanisms, as well as signaling pathways, useful for understanding the disease and its diagnostic and therapeutic mechanisms. The determination of the activity of metallo-oxidoreductases enzymes in serum is an attempt to implement liquid biomarkers for the early diagnosis and prognosis of gynecological tumors. The aim of the research is the compilation of updated information about enzyme biomarkers for the prediction, diagnosis and follow-up of gynecological epithelial tumors.

Imunoexpressão da proteína ING3 em Queilites Actínicas e carcinomas de células escamosas de lábio inferior / Immunoexpression of ING3 protein in actinic cheilitis and squamous cell carcinomas of the lower lip

A família de inibidores de crescimento (inhibitor of growth - ING) corresponde a um grupo de genes supressores tumorais cuja expressão se apresenta alterada ou ausente em diversos tipos de câncer. Os produtos destes genes estão relacionados, principalmente, a processos celulares indispensáveis na carcinogênese, como remodelação da cromatina, proliferação celular, replicação e reparo do DNA. Este estudo avaliou a expressão imuno-histoquímica da proteína ING3 em 45 espécimes de queilite actínica (QA) e 48 espécimes de carcinoma de células escamosas de lábio inferior (CCELI). A expressão da proteína foi comparada entre os dois grupos de amostras, bem como com os parâmetros clínico-patológicos das lesões estudadas, através dos testes estatísticos Exato de Fisher, Kruskal-Wallis (KW), Mann-Whitney (U) e teste de correlação de Spearman. Um nível de significância de 5% foi adotado para todos os testes, sendo considerados significativos os valores de p ≤ 0,05. Não foram encontradas associações estatisticamente significativas entre as variáveis morfológicas de CCELI e tamanho do tumor, envolvimento linfonodal, estadiamento clínico, recorrência local e metástase linfonodal após tratamento (p>0,05). Óbitos foram significativamente mais frequentes em tumores de alto escore de risco histopatológico (p<0,05). Nas QAs, diferenças significativas na expressão de ING3 núcleo-citoplasmática, e restrita ao citoplasma, com a gradação de Kujan et al. (2006) foram encontradas (p<0,05). Nos CCELIs, não houve diferença estatisticamente significativa ao comparar as expressões de ING3 (núcleo-citoplasmática e restrita ao citoplasma) com os parâmetros clínicos e morfológicos (p>0,05). A expressão de ING3 núcleo-citoplasmática foi significativamente menor em CCELI quando comparada aos casos de QA (p<0,05) e a expressão restrita ao citoplasma foi significativamente maior nos CCELIs (p<0,05). Nossos resultados sugerem que há notável diminuição da expressão nuclear de ING3 conforme a progressão maligna, indicando função supressora tumoral prejudicada desta proteína em QAs e CCELIs. Entretanto, acredita-se que, na carcinogênese labial, ING3 caracteriza-se melhor como um marcador preditor de transformação maligna, do que um biomarcador de comportamento biológico tumoral (AU).

The family of inhibitors of growth (ING) corresponds to a group of tumor suppressor genes whose expression is altered or absent in several types of cancer. The products of these genes are mainly related to cellular processes indispensable in carcinogenesis, including cell proliferation, DNA replication and repair. This study evaluated the immunohistochemical expression of ING3 protein in 45 actinic cheilitis (AC) and 48 lower lip squamous cell carcinoma (CCELI) specimens. Protein expression was compared between the two groups of samples, as well as with the clinicopathological parameters of studied lesions, using Fisher's exact tests, Kruskal-Wallis (KW), Mann-Whitney (U) and correlation test of Spearman. A significance level of 5% was adopted for all tests, with values of p ≤ 0.05 being considered significant. No statistically significant associations were found between morphological variables of CCELI and tumor size, lymph node involvement, clinical staging, local recurrence and lymph node metastasis after treatment (p>0.05). Deaths were significantly more frequent in tumors with a high histopathological risk score (p<0.05). In ACs, significant differences in nuclear-cytoplasmic and restricted to the cytoplasm expression of ING3, with gradation of Kujan et al. (2006) were found (p<0.05). In CCELIs, there was no statistically significant difference when comparing ING3 expressions (nucleocytoplasmic and cytoplasmic restricted) with clinical and morphological parameters (p>0.05). Nucleocytoplasmic ING3 expression was significantly lower in CCELI when compared to AC cases (p<0.05) and cytoplasm-restricted expression was significantly higher in CCELIs (p<0.05). Our results suggest that there is a remarkable decrease in ING3 nuclear expression according to malignant progression, indicating an impaired tumor suppressor function of this protein in AC and CCELI. However, it is believed that, in lip carcinogenesis, ING3 is better characterized as predictive marker of malignant transformation, rather than a biomarker of tumor biological behavior (AU).

Tumores Neuroendocrinos: un desafío transversal / Update on neuroendocrine tumors

Neuroendocrine Tumors (NETs) encompass a wide variety of tumors arising from neuroendocrine cells, which produce bioactive substances. The incidence of NETs increased significantly lately, becoming one of the most common tumors of the digestive tract. Their clinical presentation is as diverse as their capacity for hormone production. Carcinoid syndrome is the most common hormonal syndrome produced by NETs and is characterized by diarrhea, flushing and cardiac valvular lesions. New research brought multiple changes in the classification of these neoplasms and a new understanding about their diagnosis and treatment, promoting a multidisciplinary approach. Somatostatin analogues, radiation, biological, and cytotoxic drugs have improved the prognosis of these patients, which entails a great challenge for healthcare providers.

Tumores ováricos en pediatría: revisión de los casos en un servicio de pediatría durante 10 años / Pediatric ovarian tumors: a 10-year review in a pediatric service

Los tumores ováricos, a diferencia de lo que sucede en la edad adulta, son infrecuentes en la población pediátrica. Predomina la estirpe germinal, con altas tasas de supervivencia. El objetivo de este estudio es presentar la epidemiología, clínica, diagnóstico y tratamiento de las pacientes de 0-15 años con diagnóstico, entre 2007 y 2017, de tumor ovárico en nuestro centro. Fueron 8 los casos encontrados de 171 tumores diagnosticados (el 4,7 %), con edad media de presentación de 12,5 años. Predominaban, al momento del debut, alteraciones menstruales, dolor abdominal y aumento de perímetro abdominal. Fueron de tipo germinal 6/8, y el teratoma maduro fue el más frecuente. Todas se diagnosticaron con ecografía abdominal, y se confirmó el diagnóstico en 7/8 con resonancia magnética. Se intervinieron todos los casos; predominó la salpingo-ooforectomía, y una paciente precisó quimioterapia adyuvante. La supervivencia libre de enfermedad fue del 100 %.

Unlike adults, ovarian tumors are infrequent in the pediatric population, predominating the germ line at this age, with high survival rates. The objective is to present the epidemiological, clinical, diagnosis and therapeutic characteristics of 0 to 15-year-old patients diagnosed with ovarian tumor in our center between 2007 and 2017.Eight cases out of 171 diagnosed tumors (4.7 %) were found, with a mean age of presentation of 12.5 years. At the moment of diagnosis, menstrual disturbances, abdominal pain and an increase in abdominal circumference predominated. Six out of eight were germ cell tumors, being the mature teratoma the most frequent one. All cases were diagnosed with abdominal ultrasound scan, confirmed in 7/8 cases with magnetic resonance imaging. All cases underwent surgery, predominating salpingo-oophorectomy with one patient requiring adjuvant chemotherapy. Disease-free survival was 100 %.

Analysis of RPL37A, MTSS1, and HTRA1 expression as potential markers for pathologic complete response and survival.

BACKGROUND: Non-metastatic locally advanced breast carcinoma (LABC) treatment involves neoadjuvant chemotherapy (NCT). We evaluated the association of clinical-pathological data and immunoexpression of hormone receptors, HER2 and Ki67, and new biomarkers, RPL37A, MTSS1 and HTRA1, with pathological complete response (PCR) or tumour resistance (stable disease or disease progression), disease-free survival (DFS) and cancer-specific survival (CSS). METHODS: This is a retrospective study of 333 patients with LABC who underwent NCT. Expression of MTSS1, RPL37A and HTRA1/PRSS11 was evaluated by immunohistochemistry in TMA slides. Cutoff values were established for low and high tumour expression. ROC plotter evaluated response to NCT. Chi-square test for factors related to PCR, and Kaplan-Meier test and Cox model for factors related to DFS and CSS were prformed. RESULTS: The mean follow-up was 70.0 months and PCR rate was 15.6%. At 120 months, DFS rate was 32.5% and CSS rate was 67.1%. In multivariate analysis, there was an association between: (1) necrosis presence, intense inflammatory infiltrate, ER absence, HER2 molecular subtype and high RPL3A expression with increased odds of PCR; (2) lymph node involvement (LNI), high Ki67, low RPL37A and high HTRA1 expression with increased risk for NCT non-response; (3) LNI, high proliferation, necrosis absence, low RPL37A and high HTRA1 expression with increased recurrence risk; (4) advanced LNI, ER negative tumours, high HTRA1, low RPL37A expression and desmoplasia presence with higher risk of cancer death. CONCLUSION: RPL37A is a potential biomarker for response to NCT and for prognosis. Additional studies evaluating HTRA1 and MTSS1 prognostic value are needed.

Are stem cell marker expression and cd133 analysis relevant to differentiate colorectal cancer? / A expressão de marcadores de células-tronco e a análise do cd133 são relevantes na diferenciação do câncer colorretal?

ABSTRACT Background: CD133 and AXL have been described as cancer stem cell markers, and c-MYC as a key regulatory cellular mechanism in colorectal cancer (CRC). Aim: Evaluate the prognostic role of the biomarkers CD133, AXL and c-MYC and their association with clinicopathologic characteristics in colorectal adenocarcinomas and adenomas. Methods: A total of 156 patients with UICC stage I-IV adenocarcinomas (n=122) and adenomas (n=34) were analyzed. Tissue microarrays (TMA) from primary tumors and polyps for CD133, c-MYC and AXL expression were performed and analyzed for their significance with clinicopathologic characteristics. Results: Poorly differentiated adenocarcinomas and disease progression were independent risk factors for poor overall survival. The median overall survival time was 30 months. Positive CD133 expression (35.9% of all cases), particularly of right-sided CRCs (44.8% of the CD133+ cases), was negatively correlated with death in the univariate analysis, which did not reach significance in the multivariate analysis. c-MYC (15.4% of all cases) was predominantly expressed in advanced-stage patients with distant (non-pulmonary/non-hepatic) metastasis. AXL expression was found only occasionally, and predominantly dominated in adenomas, with less penetrance in high-grade dysplasia. Conclusions: CD133 expression was not associated with inferior overall survival in CRC. While AXL showed inconclusive results, c-MYC expression in primary CRCs was associated with distant metastasis.

RESUMO Racional: CD133 e AXL são descritos na literatura como marcadores de células-tronco tumorais, e c-MYC cumpre papel chave como mecanismo de regulação celular no câncer colorretal (CCR). Objetivo: Avaliar o papel prognóstico dos biomarcadores CD133, AXL e c-MYC e sua associação com características clinicopatológicas de adenocarcinomas e adenomas colorretais. Métodos: Um total de 156 pacientes com adenocarcinomas de estádio UICC I-IV (n=122) e adenomas (n=34) colorretais foram avaliados. Microarranjos teciduais (TMA) dos tumores primários e adenomas foram realizados em busca de expressão de CD133, c-MYC e AXL, com posterior análise de relação significativa com características clinicopatológicas. Resultados: Adenocarcinomas pobremente diferenciados e progressão de doença foram fatores de risco independentes para má sobrevida global. A taxa mediana de sobrevida global foi de 30 meses. Expressão positiva de CD133 (35,9% dos casos), particularmente em cânceres de cólon direito (44,8% dos casos CD133+), correlacionou-se negativamente com óbito na análise univariada, sem significância estatística na análise multivariada. c-MYC (15,4% dos casos) teve predomínio de expressão em pacientes com estádio avançado com metástases distantes (não-pulmonares/não-hepáticas). Expressão de AXL foi pouco encontrada, com predomínio em adenomas, com menor penetrância em displasia de alto grau. Conclusão: Expressão de CD133 não se associou com sobrevida global inferior em CCR. Enquanto AXL demonstrou resultados inconclusivos, expressão de c-MYC em tumores primários se associou-se à metástases à distância.

A systematic review on the expression of bcl-2 in the nonsyndromic odontogenic keratocyst: should it be considered a cyst or a tumor?

The purpose of this study is to find out if the biological behavior and the capacity of the odontogenic keratocyst (OKC) in maintaining pathologic cells alive are more similar to the dentigerous cyst or to the ameloblastoma by assessing bcl-2. We searched MEDLINE, Web of Science, and Scopus for immunohistochemical studies reporting OKCs, dentigerous cysts, and ameloblastomas. Risk difference between the lesions expressing bcl-2 was the effect measure and a P value < 0.05 was considered to provide evidence to the effect estimates. OKCs have an estimated difference of 91% in the probability to express the bcl-2 over dentigerous cysts, but there is no difference in the expression of bcl-2 between OKCs and ameloblastomas. The present study demonstrated a great risk difference in the expression of bcl-2 between OKCs and dentigerous cysts and no risk difference between OKCs and ameloblastomas. OKC's growth may indirectly be attributed to the anti-apoptotic effect of bcl-2 in the cystic epithelium and not only to the increase of its intraluminal pressure. Therefore, the classification of this lesion into keratocystic odontogenic tumor should be carefully reconsidered.

Detection of COX-2 in liquid biopsy in patients with breast cancer.

AIMS: To determine the expression of the cyclooxygenase-2 (COX-2) gene in patients with breast cancer attended at the Centro Universitário Saúde ABC/Faculdade de Medicina do ABC (CUS-ABC/FMABC) outpatient clinic. Breast cancer is the most common cancer in women worldwide. More than two million new cases are reported annually. An overexpression of COX-2 has been observed in many cancers. COX-2 is related to parameters of cancer aggressiveness, including tumour size, positive nodal state and lower survival, and to angiogenesis and resistance to apoptosis. METHODS: 15 mL of peripheral blood was obtained from 34 patients and 21 healthy women. The extracellular RNA of QIAamp RNA was submitted to an RNA sequestration kit for RNA reverse transcriptase. Quantitative real-time PCR was performed using COX-2-specific oligonucleotides and the endogenous Glyceraldehyde-3-Phosphate Dehydrogenase gene. RESULTS: The mean remission time was 53 years. The mean progression time was 33 months. The difference observed between the patient and control groups in median COX-2 expression (p<0.001) was significant. CONCLUSIONS: Patients with breast cancer showed a higher mean COX-2 expression in peripheral blood samples at diagnosis than the control group. Since this information could prove important in the diagnosis and prognosis of breast cancer, further research is required on larger patient samples.

The use of biomarkers in breast cancer. / El uso de biomarcadores en cáncer de mama.

Advances in the understanding of molecular biology of cancer have allowed that in the last 30 years some biomarkers in cancer have managed to be transferred from the laboratory to clinical practice and have been established as extremely important tools in the management of breast cancer patients. In this review are presented some biomarkers that are routinely used in clinical oncology practice and have a well-established clinical value to direct treatment and establish prognosis in patients with breast cancer, such as ER-alpha (estrogen receptor alpha), PR (progesterone receptor), HER2 (Human Epidermal Growth Factor Receptor 2), Ki-67 (Marker Of Proliferation Ki-67), and other biomarkers, such as multigenic signatures, which are used more and more frequently, due to the clinical value shown in various randomized clinical trials and for being increasingly accessible in daily clinical practice. Given the considerable importance of breast cancer in public health, it is necessary to be updated with respect to current biomarkers that have a use in clinical practice and that can serve as tools to provide patients with a more personalized treatment, as well as to know their prognosis.

Los avances en el entendimiento de la biología molecular del cáncer han permitido que en los últimos 30 años algunos biomarcadores en cáncer hayan logrado ser trasladados del laboratorio a la práctica clínica y se hayan ido estableciendo como herramientas sumamente importantes en el manejo de las pacientes con cáncer de mama. En esta revisión se presentan algunos biomarcadores de uso rutinario en la práctica clínica oncológica que tienen un valor clínico bien establecido para dirigir el tratamiento y establecer el pronóstico en pacientes con cáncer de mama, como el ER-alfa (receptor de estrógenos alfa), el PR (receptor de progesterona), el HER2 (receptor 2 del factor de crecimiento epidérmico humano), el Ki-67 (marcador de proliferación Ki-67) y otros biomarcadores, como las firmas multigénicas, las cuales son usadas cada vez con más frecuencia, debido al valor clínico mostrado en diversos ensayos clínicos aleatorizados y por ser cada vez más accesibles en la práctica clínica diaria. Dada la considerable importancia del cáncer de mama en la salud pública, es necesario estar actualizados con respecto a estos biomarcadores de uso clínico, los cuales nos pueden permitir brindarles a las pacientes un tratamiento más personalizado, así como conocer su pronóstico.

Tumor de células germinales mixto de ovario y una inusual combinación / Mixed ovarian germ cell tumor, an unusual combination

Resumen ANTECEDENTES: Los tumores de células germinales del ovario son poco frecuentes. Desde el punto de vista clínico y biológico son heterogéneos. Están formados por varios tipos de tumores histopatológicamente diferentes, que derivan de células primitivas y que se anidan de forma ectópica, proliferan y sufren transformación maligna. CASO CLÍNICO: Paciente de 10 años llevada a la consulta debido a la pérdida de peso en un periodo corto, dolor abdominal y aumento del perímetro abdominal. En la exploración se encontró una tumoración abdominopélvica de 20 x 20 cm, fija, pétrea, con un ganglio cervical izquierdo palpable. Los marcadores tumorales reportaron: alfafetoproteína 1104 ng/mL, B-HCG 865.6 mUi/mL. La TAC mostró una lesión que ocupaba el abdomen y la pelvis con densidad heterogénea de 14 x 12 x 10 cm. Se intervino para extirpación del tumor y enseguida se le indicó un esquema de quimiterapia. El reporte de patología reportó ser una tumoración germinal mixta con 5 tipos histológicos, muy agresiva, que terminó con la vida de la paciente 9 meses después. CONCLUSIÓN: Los tumores malignos de las células germinales son extremadamente malignos y de crecimiento rápido, con un pico de incidencia en niñas, adolescentes y mujeres jóvenes. Los síntomas se relacionan con el crecimiento rápido que se caracteriza por dolor pélvico-abdominal relacionado con la distensión capsular, hemorragia o necrosis. La estadificación quirúrgica es el primer paso en el tratamiento del cáncer de células germinales de ovario. La tasa de supervivencia es mayor de 95% en etapa temprana (l-ll), 80% en etapa lll y 60% en etapa lV, por lo que el diagnóstico y tratamiento oportuno son lo más importante.

Abstract BACKGROUND: Ovarian germ cell tumors are rare, clinically and biologically heterogeneous tumors, formed by several types of histopathologically different tumors that derive from primitive cells and that are nested ectopically, proliferate and undergo malignant transformation. CLINICAL CASE: A 10-year-old patient who came to consult for weight loss and abdominal pain as well as an increase in abdominal perimeter of rapid growth. A fixed abdominal tumor of 20 x 20 cm is scanned and found, as well as palpable left cervical lymph node. Tumor markers showing alphafetoprotein were taken. 1104 ng/mL, B-HCG 865.6 mUi/mL. The CT scan showed a lesion that occupies abdomen and pelvis with a heterogeneous density of 14 x 12 x 10 cm. It was decided to intervene surgically and complement with chemotherapy; The pathology report reported being a mixed germ tumor with 5 very aggressive histological types that ended with the patient´s life 9 months later. CONCLUSION: Malignant germ cell tumors are extremely malignant and rapidly growing, with a peak incidence in girls, adolescents and young women. Symptoms are related to rapid growth characterized by pelvic-abdominal pain related to capsular distention, hemorrhage or necrosis. Surgical staging is the first step in the treatment of ovarian germ cell cancer. The survival rate is greater than 95% in early stage (l-ll), 80% in stage lll and 60% in stage lV, so the diagnosis and timely treatment is the most important.

Are stem cell marker expression and cd133 analysis relevant to differentiate colorectal cancer? / A expressão de marcadores de células-tronco e a análise do cd133 são relevantes na diferenciação do câncer colorretal?

ABSTRACT Background: CD133 and AXL have been described as cancer stem cell markers, and c-MYC as a key regulatory cellular mechanism in colorectal cancer (CRC). Aim: Evaluate the prognostic role of the biomarkers CD133, AXL and c-MYC and their association with clinicopathologic characteristics in colorectal adenocarcinomas and adenomas. Methods: A total of 156 patients with UICC stage I-IV adenocarcinomas (n=122) and adenomas (n=34) were analyzed. Tissue microarrays (TMA) from primary tumors and polyps for CD133, c-MYC and AXL expression were performed and analyzed for their significance with clinicopathologic characteristics. Results: Poorly differentiated adenocarcinomas and disease progression were independent risk factors for poor overall survival. The median overall survival time was 30 months. Positive CD133 expression (35.9% of all cases), particularly of right-sided CRCs (44.8% of the CD133+ cases), was negatively correlated with death in the univariate analysis, which did not reach significance in the multivariate analysis. c-MYC (15.4% of all cases) was predominantly expressed in advanced-stage patients with distant (non-pulmonary/non-hepatic) metastasis. AXL expression was found only occasionally, and predominantly dominated in adenomas, with less penetrance in high-grade dysplasia. Conclusions: CD133 expression was not associated with inferior overall survival in CRC. While AXL showed inconclusive results, c-MYC expression in primary CRCs was associated with distant metastasis.

RESUMO Racional: CD133 e AXL são descritos na literatura como marcadores de células-tronco tumorais, e c-MYC cumpre papel chave como mecanismo de regulação celular no câncer colorretal (CCR). Objetivo: Avaliar o papel prognóstico dos biomarcadores CD133, AXL e c-MYC e sua associação com características clinicopatológicas de adenocarcinomas e adenomas colorretais. Métodos: Um total de 156 pacientes com adenocarcinomas de estádio UICC I-IV (n=122) e adenomas (n=34) colorretais foram avaliados. Microarranjos teciduais (TMA) dos tumores primários e adenomas foram realizados em busca de expressão de CD133, c-MYC e AXL, com posterior análise de relação significativa com características clinicopatológicas. Resultados: Adenocarcinomas pobremente diferenciados e progressão de doença foram fatores de risco independentes para má sobrevida global. A taxa mediana de sobrevida global foi de 30 meses. Expressão positiva de CD133 (35,9% dos casos), particularmente em cânceres de cólon direito (44,8% dos casos CD133+), correlacionou-se negativamente com óbito na análise univariada, sem significância estatística na análise multivariada. c-MYC (15,4% dos casos) teve predomínio de expressão em pacientes com estádio avançado com metástases distantes (não-pulmonares/não-hepáticas). Expressão de AXL foi pouco encontrada, com predomínio em adenomas, com menor penetrância em displasia de alto grau. Conclusão: Expressão de CD133 não se associou com sobrevida global inferior em CCR. Enquanto AXL demonstrou resultados inconclusivos, expressão de c-MYC em tumores primários se associou-se à metástases à distância.