Weighted gene co-expression network analysis for data mining of breast cancer biomarkers / 第二军医大学学报

Objective: To explore the disease targets of breast cancer related to age at diagnosis and tumor stage by weighted gene co-expression network analysis (WGCNA) from public database The Cancer Genome Atlas (TCGA). Methods: We obtained the breast cancer gene chip expression data and corresponding clinical data of 53 Asians and 126 Africans from TCGA database. R software WGCNA package was used to construct the co-expression network of the two populations, and the significant modules related to age at diagnosis and cancer stage were obtained. Online website DAVID was used for function enrichment and online website UALCAN for survival analysis. Results: WGCNA yielded 11 modules significantly related to cancer stage and age at diagnosis. Forty-two candidate genes were obtained after 11 modules were intersected. Gene ontology (GO) enrichment analysis was carried out using online website DAVID and these genes were mainly involved in protein binding function. Nine of the 42 candidate genes were identified as hub genes by WGCNA, the 9 genes were used in UALCAN for differential analysis and survival analysis, and 2 candidate biomarkers (ERLIN2 and ASH2L) were screened out. The expression of the 2 genes in normal tissues and breast cancer tissues was significantly different (P<0.01), and the expression level significantly influenced the survival of breast cancer patients (P<0.05). Conclusion: Data mining from public databases for biomarkers or therapeutic targets is a cost-effective research method. In this study ERLIN2 and ASH2L have been found to be candidate biomarkers for breast cancer through data mining, which needs large sample study and mechanism exploration.

Effect of ambient temperature on determination of carbohydrate antigen 242 by Luminex flow cytometry fluorescence immunoassay / 第二军医大学学报

[Abstract] Objective To analyze the difference of the carbohydrate antigen 242 (CA242) results measured by Luminex flow cytometry fluorescence immunoassay with different calibrations and different ambient temperatures, so as to evaluate the effect of ambient temperature on the measurement results. Methods Two CA242 samples with different concentrations (median- and high-value) were selected and the determination was repeated at 11 temperature points (18.3, 20.1, 21.5, 22.2, 24.1, 25.0, 25.4, 26.5, 27.4, 28.5, and 30.0 ℃) for 5 times by Luminex flow cytometry fluorescence immunoassay. The average value of the detection result at the calibration temperature (25 ℃) was taken as the reference value, and the biases of the detection results at different ambient temperatures were calculated. Forty-nine CA242 specimens covering high-, median- and low-values were examined at 20, 25 and 30 ℃ by Luminex flow cytometry fluorescence immunoassay, and the results were compared and correlation analysis was carried out. Results The biases of the median- and high-value samples at 18.3 ℃ were －35.6% and －29.4%, respectively. The difference between the measurement results at 20 ℃ and 25 ℃ was significant for the 49 specimens (P0.001), and there was a linear correlation between them (Y＝0.676 9X＋0.374 7, R2＝0.990 5). The difference of measurement results was significant between 30 ℃ and 25 ℃ (P0.001), and there was a linear correlation between them (Y＝0.896 6X＋0.227 0, R2＝0.999 4). Conclusion Too low or too high ambient temperature has a negative effect on the determination of CA242 by Luminex flow cytometry fluorescence immunoassay. The ambient temperature should be kept relatively constant and controlled within the range of calibration temperature ±4 ℃.

ASSOCIATION BETWEEN MURINE DOUBLE MINUTE 2 - T309G polymorphism and recurrence of hepatocellular carcinoma after surgical treatment

Background - Discovery and incorporation of biomarker panels to cancer studies enabled the understanding of genetic variation and its interference in carcinogenesis at molecular level. The potential association between single nucleotide polymorphism (SNP) 309 and increased development of tumors, such as hepatocellular carcinoma, has been subject to several studies. This is the first study on this association conducted in Brazil. Methods - 62 cases of cirrhotic patients with hepatocellular carcinoma surgically treated by partial hepatectomy (HPT) or by liver transplantation (LTX) from 2000 to 2009 at Santa Casa Hospital Complex, in the city of Porto Alegre, were retrospectively analyzed. Tumor samples from surgical specimen were collected and prepared for study in paraffin blocks. Results - Overall survival was 26.7 months in the HPT group and 62.4 months in the LTX group (P <0.01). Overall tumor recurrence was 66.7% in the HPT group (10/15) and 17% in the LTX group (8/47) (X²=13.602, P <0.01). Alpha-fetoprotein levels >200ng/mL, microvascular invasion and histological grade were associated with tumor recurrence (P <0.01). Recurrence rates in each surgical group and analysis of factors associated with tumor recurrence, when stratified for each genotypic pattern, were both not statistically significant. Conclusion - G/G genotype was not associated with tumor recurrence after surgical treatment and it did not show any correlation with other prognostic factors.

Contexto - A descoberta e incorporação de painéis de biomarcadores aos estudos do câncer permitiram o conhecimento de variações genéticas e sua interferência no processo de carcinogênese. A possibilidade de associação do polimorfismo de nucleotídeo simples T309G do gene MDM2 com o aumento da formação de tumores, dentre eles o hepatocarcinoma, tem sido alvo de diversos estudos. Objetivo - Analisar a influência do polimorfismo T309G do gene MDM2 na recidiva tumoral de pacientes cirróticos com hepatocarcinoma submetidos a tratamento cirúrgico. Métodos - Foram analisados retrospectivamente pacientes cirróticos com carcinoma hepatocelular submetidos a tratamento cirúrgico (hepatectomia parcial ou transplante hepático) no período de 2000 a 2009, na Santa Casa Hospital Complex in Porto Alegre, South Brazil. Foram coletadas amostras de fragmentos tumorais da peça operatória (fígado explantado ou segmento hepático), as quais foram preparadas para estudo em bloco parafinado. Resultados - A sobrevida global foi de 26,7 meses para o grupo hepatectomias e 62,4 meses para o grupo transplante hepático (P <0,01), havendo 66,7% de recidiva global no grupo hepatectomias (10/15), e 17% no grupo transplante hepático (8/47) (X²=13,602, P <0.01). Níveis de AFP>200ng/mL correlacionaram-se com a recidiva tumoral em ambos os subgrupos cirúrgicos. Observou-se que 83,3% dos pacientes com recidiva também apresentaram invasão microvascular ao exame anátomo-patológico (P <0,01). Não houve significância estatística quando a recidiva neoplásica foi avaliada para os diferentes genótipos e analisada para cada subgrupo cirúrgico. A análise dos fatores prognósticos relacionados à recidiva do hepatocarcinoma, quando estratificada para cada padrão genotípico, também não se mostrou significante. Conclusão - O nosso estudo revelou que o genótipo G/G não esteve associado à recidiva tumoral após o tratamento cirúrgico, seja nas hepatectomias parciais ou transplante hepático. Além disso, a presença desse genótipo não mostrou correlação com os fatores prognósticos estudados.

Cancer stem cells: a new approach to tumor development / Células-tronco de câncer: um nova abordagem do desenvolvimento tumoral

Many theories have been proposed to explain the origins of cancer. Currently, evidences show that not every tumor cell is capable of initiating a tumor. Only a small part of the cancer cells, called cancer stem cells (CSCs), can generate a tumor identical to the original one, when removed from human tumors and transplanted into immunosuppressed mice. The name given to these cells comes from the resemblance to normal stem cells, except for the fact that their ability to divide is infinite. These cells are also affected by their microenvironment. Many of the signaling pathways, such as Wnt, Notch and Hedgehog, are altered in this tumoral subpopulation, which also contributes to abnormal proliferation. Researchers have found several markers for CSCs; however, much remains to be studied, or perhaps a universal marker does not even exist, since they vary among tumor types and even from patient to patient. It was also found that cancer stem cells are resistant to radiotherapy and chemotherapy. This may explain the re-emergence of the disease, since they are not completely eliminated and minimal amounts of CSCs can repopulate a tumor. Once the diagnosis in the early stages greatly increases the chances of curing cancer, identifying CSCs in tumors is a goal for the development of more effective treatments. The objective of this article is to discuss the origin of cancer according to the theory of stem cell cancer, as well as its markers and therapies used for treatment.

Diversas teorias buscam explicar a origem do câncer. Atualmente, há evidências de que nem todas as células tumorais têm poder de iniciar um tumor. Apenas uma pequena parte das células cancerígenas, chamadas de células-tronco de câncer (do inglês cancer stem cells - CSC), é capaz de iniciar um tumor idêntico ao original quando retirada de tumores humanos e enxertada em camundongos imunossuprimidos. Essas células foram assim denominadas por suas semelhanças com células-tronco normais, exceto pelo fato de que sua capacidade de dividir-se é infinita. Essas células também recebem influência de seu microambiente. Várias vias de sinalização, como WNT, NOTCH e Hedgehog, estão alteradas nessa subpopulação tumoral, contribuindo também para a desregulação de sua proliferação. Pesquisadores descobriram vários marcadores para as CSC, porém ainda há muito a ser pesquisado, ou talvez nem exista um marcador universal, já que eles variam entre cada tipo de tumor e até de paciente para paciente. Foi constatado também que as CSC são resistentes à radioterapia e à quimioterapia, podendo explicar o reaparecimento da doença, visto que, além de não eliminá-la completamente, quantidades mínimas das CSC podem repovoar um tumor. Como o diagnóstico em estágios iniciais aumenta muito as chances de cura do câncer, a identificação das CSC em meio a um tumor é alvo para o desenvolvimento de tratamentos mais eficazes. O objetivo deste artigo é discutir a origem do câncer segundo a teoria das CSC, bem como seus marcadores e as terapias utilizadas em seu tratamento.

Tumores germinales gonadales en niños: experiencia de 20 años en un centro de referencia pediátrico / Gonadal germ cell tumors in children: experience of 20 years in a pediatric referral center

Antecedentes. Los tumores de células germinales son un grupo heterogéneo de neoplasias que corresponden al 1-3% de los tumores en pediatría. Por lo general, se manifiestan clínicamente con masa testicular o dolor abdominal. Objetivo. Describir las características de los pacientes con tumores germinales gonadales en un centro de referencia de cáncer pediátrico en Colombia. Materiales y métodos. Este artículo hace una revisión retrospectiva recopilando 20 años de experiencia en el diagnóstico y manejo de estos tumores en la Fundación Hospital de la Misericordia. Resultados. Se encontraron 79 pacientes, 35 hombres y 44 mujeres, con un promedio de edad, al diagnóstico, de 6 años. El teratoma fue la neoplasia más frecuente en el sexo femenino y el tumor del seno endodérmico en el masculino. El 70,9% de los pacientes se diagnosticaron en estadio I; se tienen datos de marcadores tumorales en 84,8%. El 98,7% se manejaron con cirugía y 58,2% recibieron además quimioterapia, especialmente protocolo BEP. 96% alcanzaron remisión de la enfermedad, 3 pacientes fallecieron. Conclusiones. El estudio demuestra buenos resultados en el manejo de los tumores germinales gonadales con el protocolo establecido de manejo quirúrgico y quimioterapia, se encontró una baja tasa de recurrencia en el periodo evaluado y alto porcentaje de niños libres de enfermedad.

Background. Germ cell tumors are a heterogeneous group of neoplasms corresponding to 1-3% of pediatric tumors. They usually manifest clinically as testicular mass or abdominal pain. Objective. To make a description of gonadal germ cell tumor types in pediatric referral center in Colombia. Materials and methods. This article takes a retrospective review compiling 20 years of experience in diagnosis and management of these tumors in the Fundación Hospital de La Misericordia. Results. We found 79 patients, 35 men and 44 women, with an average age at diagnosis of 6 years. The teratoma was the most common neoplasia in females and endodermal sinus tumor in men. 70.9% of patients were diagnosed with stage I. In 84,8% measuring tumor markers were obtained. 98.7% were managed with surgery and 58.2% also received chemotherapy, especially BEP protocol. 96% achieved disease remission, 3 patients died. Conclusions. The study shows good results in the management of gonadal germ cell tumors with the established protocol and low recurrence rate in the evaluated period and high rates of children free of disease, were found a low rate of recurrence in the assessment period and high percentage of free of disease.

Breast Cancer Subtype as a Predictor of Lymph Node Metastasis according to the SEER Registry / 한국유방암학회지

PURPOSE: Breast cancer subtype correlates with response to systemic therapy and overall survival (OS), but its impact on lymphatic spread is incompletely understood. In this study, we used the Surveillance, Epidemiology, and End Results registry to assess whether the subtype can predict the presence of nodal metastasis or advanced nodal stage in breast cancer. METHODS: A total of 7,274 eligible patients diagnosed with T1-3 infiltrating ductal carcinoma with known estrogen or progesterone hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status, who underwent surgical excision of the primary tumor and pathologic lymph node evaluation, were included in this analysis. Patients were categorized into four breast cancer subtypes: HR+/HER2-; HR+/HER2+; HR-/HER2+; and HR-/HER2-. Binary logistic regression analysis was used to determine whether breast cancer subtype, tumor size, tumor grade, patient race, and patient age at diagnosis are independently predictive of lymph node positivity or advanced nodal stage. The Pearson chi-square test was used to determine whether progesterone receptor (PR) status had an impact on the incidence of lymph node positivity in estrogen receptor (ER) positive patients. RESULTS: Independent predictors of nodal positivity included breast cancer subtype (p=0.040), tumor size (p<0.001), tumor grade (p<0.001), and patient age (p<0.001), whereas only tumor size (p<0.001), grade (p=0.001), and patient age (p=0.005) predicted advanced nodal stage. Triple-negative cancers had a significantly lower risk of nodal positivity than the HR+/HER2- subtype (odds ratio, 0.686; p=0.004), but no other significant differences between subtypes were observed. There was also no difference in lymph node positivity between PR+ and PR- tumors amongst ER+/HER2- (p=0.228) or ER+/HER2+ tumors (p=0.713). CONCLUSION: The HR+/HER2-breast cancer subtype has a higher rate of lymph node involvement at diagnosis than the triple-negative subtype. These findings may play a role in guiding regional management considerations if confirmed in further studies.

p27 Loss Is Associated with Poor Prognosis in Gastroenteropancreatic Neuroendocrine Tumors / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) represent a heterogeneous disease group originating from the neuroendocrine cells. Identification of prognostic markers, related to neuroendocrine tissue-selective tumorigenesis, is necessary to find therapeutic targets. MATERIALS AND METHODS: A total of 327 patients with GEP-NETs were included in this study; there were 49 gastric, 29 duodenal, 49 pancreatic, 12 hepatobiliary, 33 appendiceal, 5 proximal colon, and 150 distal colon cases. We performed immunostaining with the tissue microarray method for menin, p27, and p18. RESULTS: We observed negative staining for menin, p27, and p18 in 34%, 21%, and 56% of GEP-NETs, respectively. The loss of p27, but not menin, was positively correlated with the grade of Ki-67. Menin-/p27-, menin-/p27+, menin+/p27-, and menin+/p27+ phenotype groups included 13%, 22%, 8%, and 57% of patients, respectively. A dichotomized comparison showed that menin- or p27- tumors were significantly associated with foregut and midgut localizations, high World Health Organization (WHO) grade, lymph node metastasis, and more advanced stage as compared to menin+/p27+ patients. Kaplan-Meier analysis for the overall survival showed that p27 loss was significantly associated with decreased survival. Multivariate analysis showed that p27 loss is an independent factor for poor overall survival. CONCLUSION: Our results revealed that the loss of p27 is associated with poor prognosis and the menin-p27 pathway is important in the tumorigenesis of GEP-NETs.

APC protein immunoexpression in colorectal adenoma and adenocarcinoma / Imunoexpressão da proteína APC nos tecidos de adenoma e de adenocarcinoma colorretais

BACKGROUND: activation of the Wnt pathway by mutated APC gene is considered the initial event in colorectal carcinogenesis. The identification of these mutations can improve the specific treatment of the adenocarcinoma. OBJECTIVE: detect and evaluate wild-type APC protein in tissue from colorectal adenoma, adenocarcinoma and adjacent mucosa. METHODS: 42 patients that underwent surgery for adenocarcinoma and 53 patients with resected adenomas were studied. Tissue samples from the adenocarcinoma were obtained from the tumor and from adjacent non-neoplastic mucosa located 10 cm from the proximal margin of the tumor. Adenoma tissue was obtained from representative areas. Blocks of tissue microarray (TMA) were submitted to immunohistochemistry with anti-APC, with readings of positivity and intensity of immunostaining and the score of immune expression of APC protein was obtained. RESULTS: the APC protein immune expression score showed a significantly lower expression of APC protein in the adenoma when compared with the adenocarcinoma (p < 0.0001) and adjacent mucosa (p < 0.0001). The APC protein immune expression score in the colorectal mucosa and adjacent to the adenocarcinoma showed no significant difference (p = 0.24). CONCLUSIONS: the finding of decreased expression of APC protein in adenoma tissue may indicate that the mutated APC gene may contribute to the changes in the adenoma-carcinoma process of carcinogenesis sequence. The strong expression of protein APC in tissues from the carcinoma and adjacent mucosa suggests that in most patients in this series, the mutation of the APC gene did not participate in the oncogenesis mechanism. (AU)

RACIONAL: a ativação da via Wnt pelo gene APC mutado é considerado evento inicial da carcinogênese colorretal. A identificação dessas mutações pode tornar o tratamento do adenocarcinoma mais específico. OBJETIVO: detectar e avaliar a proteína APC não mutada em tecidos de adenoma, adenocarcinoma e mucosa adjacente. MÉTODO: estudados 42 doentes operados de adenocarcinoma e 53 com adenomas ressecados. Tecidos de adenocarcinoma foram obtidas da neoplasia e da mucosa adjacente não neoplásica situadas a 10 cm da margem proximal do tumor. Tecidos do adenoma foram obtidas de área representativa. Blocos de tissue microarray (TMA) foram submetidos a imuno-histoquímica com anticorpo anti-APC. Avaliadas a positividade e intensidade da expressão e obtidos escores da imunoexpressão da proteína APC. RESULTADOS: o escore da imunoexpressão da proteína APC no adenoma foi significantemente menor do que no adenocarcinoma (p < 0,0001) e na mucosa adjacente (p < 0,0001). O escore da imunoexpressão da proteína APC na mucosa adjacente e no adenocarcinoma não mostraram diferença significante (p = 0,24). CONCLUSÕES: a menor expressão da proteína APC no adenoma pode indicar que o gene APC mutado participa das alterações do processo adenoma-carcinoma. A forte expressão da proteína APC no CCR e na mucosa adjacente sugerem que a mutação do gene APC não participou da oncogênese. (AU)

Application of bayesian classifier tn diagnosis of lung cancer by multiple autoantibody biomarkers / 第二军医大学学报

Objective To establish a Bayesian classifier-based lung cancer prediction model, and to discuss its predictive efficiency. Methods Using the reaction data of previously screened 6 phage peptide clones with the sera of 90 lung cancer patients and 90 healthy controls, we established a Bayesian classifier-based lung cancer prediction model, with the data analyzed by BinReg 2.0 software. The predictive efficiencies of different models (Bayesian classifier-based prediction model, Logistic regression, principal component regression, and support vector machine) were evaluated by receiver operating characteristic (ROC) curves. Results The sensitivity and specificity of Bayesian classifier-based lung cancer prediction model were 92.00% and 96.00% respectively. And the model satisfactorily distinguished lung cancer patients and healthy controls. Conclusion Our Bayesian classifier-based lung cancer prediction model can accurately predict the risk of lung cancer.

Prognostic Value of Different Patterns of Squamous Cell Carcinoma Antigen Level for the Recurrent Cervical Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: In some unusual cases, in patients with cervical cancer, an elevation of squamous cell carcinoma antigen (SCC-Ag) was not observed at diagnosis but was observed on recurrence, or vice versa. The objective of this study was to identify patient-, disease-, and treatment-related factors associated with this unusual level of SCC-Ag, and to determine whether SCC-Ag is a useful tumor marker in such patients. MATERIALS AND METHODS: Among 129 patients with recurrence, 14 who showed a normal SCC-Ag level at diagnosis but an elevated level at recurrence were classified as group I; 22 patients with an elevated SCC-Ag level at diagnosis but not at recurrence were classified as group II; and 76 patients with an elevated SCC-Ag level at both diagnosis and recurrence were classified as group III. RESULTS: In univariate analysis, unusual SCC-Ag showed statistically significant relationships with pathology and biochemical response to treatment. However, in the multivariate analysis, none of the clinicopathologic factors showed a statistical relationship with unusual levels of SCC-Ag. The 5-year disease-free survival rates for groups I, II, and III were 7.1%, 9.1%, and 0% (p=0.418), and the 5-year overall survival rates were 34.3%, 58.4%, and 33.3% (p=0.142), respectively. CONCLUSION: The value of SCC-Ag has been confirmed in all patients; thus, check of SCC-Ag level at follow-up should be considered. Although no statistically significant differences were observed among the groups, we conclude that patients with a high initial SCC-Ag and elevated SCC-Ag at relapse have poor prognosis due to high SCC-Ag level.

Thrombopoietin: a novel candidate tumor marker for the diagnosis of ovarian cancer / 부인종양

OBJECTIVE: To investigate the decisive role of preoperative serum thrombopoietin levels in the discrimination of benign and malignant ovarian pathologies and its value in the evaluation of treatment response. METHODS: Fifty patients with diagnoses of adnexal masses (25 benign, 25 malignant) were included in the study. Blood samples were collected from all cases preoperatively. Age, menopausal status, adnexal mass size, preoperative CA-125 level, platelet count, the stage of the disease (FIGO stage), tumor grade, histologic subgroup, the residual tumor mass, ascites cytology, surgical procedures, and postoperative treatments were recorded for the malignant group. Response to treatment was evaluated based on the revised RECIST guideline. RESULTS: The preoperative serum thrombopoietin levels of the malignant cases (median, 98; range, 7 to 768) were significantly higher when compared with those of benign cases (median, 27; range, 13 to 131; p=0.004). The positive predictive value of CA-125 was found to be 79%, when it was used as a single marker; however it had risen to 85% when both CA-125 and thrombopoietin levels were used. There was no significant relationship between preoperative serum thrombopoietin levels and tumor grade, ascites cytology, presence of residual mass, and response to treatment. The preoperative serum thrombopoietin levels were significantly higher in stage III-IV cases and cases with serous histology. The post-treatment serum thrombopoietin levels in the malignant group were significantly lower as compared with the preoperative thrombopoietin levels. CONCLUSION: Thrombopoietin can play an additive role for prediction of ovarian cancer.

Screening of molecular markers for early diagnosis of colorectal cancer by phage-peptide library / 第二军医大学学报

Objective: To establish a colorectal cancer phage-peptide library and to screen for biomarkers for early detection of colorectal cancer. Methods: A T7 phage display peptide library was constructed using 30 surgical colorectal cancer specimens from Changhai Hospital, Second Military Medical University. Protein-A/G was used to enrich IgG from control sera as well as colorectal cancer sera. Five biopanning protocols were carried out for enrichment of colorectal cancer-specific phage clones, and 2 000 phage clones were randomly selected. ELISA was used for further screening of clones of different reactivities between the cancer serum and control serum; and the selected clones were subjected to DNA sequencing and the cloned protein function was forecasted by Chilibot for validation. Results: (1) The titer of the colorectal cancer phage display peptide library was 3.0×106pfu, with a recombination rate of 60% as showed by PCR identification and a storage capacity of 1.8×106 pfu. (2) Of the 18 phage clones selected by ELISA, 12 were cancer-related genes. Conclusion: ELISA for screening the recombinant tumor antigen phage display peptide library can be used to discover new differentially expressed antigens ; and the selected phage clones expressing antigen might be used for early detection of colorectal cancer.

mRNA Expression of S100A8 as a Prognostic Marker for Progression of Non-Muscle-Invasive Bladder Cancer

PURPOSE: S100A8 is a member of the S100 protein family containing 2EF-hand calcium-binding motifs. S100 proteins are involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. Altered expression of this protein is associated with various diseases and cancers. The present study aimed to evaluate whether S100A8 has prognostic value for non-muscle-invasive bladder cancer (NMIBC). MATERIALS AND METHODS: A total of 103 primary NMIBC samples obtained by transurethral resection were evaluated. mRNA levels were examined by real-time reverse transcriptase polymerase chain reaction (RT-PCR) analysis. The results were compared with clinico-pathological parameters. The Kaplan-Meier method was applied to plot the curves for progression-free survival. The multivariate Cox regression model was used to identify the independent prognostic factors for progression. RESULTS: mRNA expression levels of S100A8 were significantly related to the progression of NMIBC. Kaplan-Meier estimates demonstrated significant differences in tumor progression according to the level of S100A8 expression (log-rank test, p<0.001). The multivariate Cox regression model revealed that the S100A8 mRNA expression level (hazard ratio: 12.538; 95% confidence interval: 2.245-70.023, p=0.004) was an independent predictor for disease progression of NMIBC. CONCLUSIONS: Expression levels of S100A8 might be a useful prognostic marker for disease progression of NMIBC.

Differential Expression of Stem Cell Markers and Vascular Endothelial Growth Factor in Human Retinoblastoma Tissue

PURPOSE: To investigate the relationship between vascular endothelial growth factor (VEGF) and the cancer stem cell-vascular niche complex in human retinoblastoma tissue. METHODS: Six human retinoblastoma specimens primarily enucleated for Reese-Ellsworth classification stage 5a were stained to detect cancer stem cell markers, including ABCG2 for the stem cell marker and MCM2 for the neural stem cell marker, as well as to detect VEGF for the angiogenic cytokine. Using immunofluorescence, the expression of these proteins was analyzed, and their relative locations noted. RESULTS: In non-neoplastic retina of tumor-bearing eyes, ABCG2 and MCM2 were sporadically expressed in the ganglion cell layer and the inner nuclear layer, whereas VEGF was sporadically expressed in inner retina where retinal vessels are abundantly distributed. In the tumor, ABCG2 was strongly expressed out of Wintersteiner rosettes, whereas MCM2 and VEGF were strongly stained in the rosettes. Interestingly, the outer portion of the rosettes was positive for MCM2, and the inner portion of the rosettes was positive for VEGF. CONCLUSIONS: Our data demonstrated that MCM2 and VEGF are strongly expressed in the rosettes of the tumor, which were far from the area of ABCG2-positive cells. Although VEGF might not directly contribute to the cancer stem cell-vascular niche complex, it could play some role in the differentiation of tumor cells to build up the rosettes.

Fundamento biológico y aplicación clínica de los marcadores tumorales séricos / Biological basis and clinical application of serum tumor markers

El cáncer es el resultado de la acumulación de alteraciones en moléculas con importante función en procesos celulares como proliferación, apoptosis, muerte celular y reparación génica. Las moléculas, sustancias o procesos alterados pueden constituirse en marcadores o biomarcadores tumorales de gran utilidad clínica en el seguimiento de pacientes oncológicos ya que han demostrado ser idóneos para la valoración del tratamiento y su eficiencia. La determinación de biomarcadores tumorales no ha sido muy exitosa debido a la baja sensibilidad y especificidad de las técnicas usadas y al requerimiento de muestras biológicas en volúmenes grandes o de métodos invasivos para su recolección. Los marcadores tumorales séricos surgen, entonces, como una herramienta útil en la obtención de información sobre el estado de la enfermedad y constituye un reto científico mejorar su aplicabilidad en el diagnóstico temprano, pronóstico, seguimiento de la enfermedad y evaluación de la eficacia terapéutica.

Cancer is the result of the accumulation of changes in molecules with important functions in processes such as cell proliferation, apoptosis, cell death and gene repair. Molecules, substances or altered pathways constitute tumor markers or biomarkers useful in clinical monitoring of cancer patients, because they have demonstrated to be suitable for the valuation of the patient's treatment and it efficiency. Determination of tumor markers has not been very successful due to the low sensitivity and specificity of the techniques used and the requirement of large volumes of biological samples or the use of invasive methods for collecting them. The serum tumor markers arise, as a useful tool to obtain information about the disease progress and constitute as a scientific challenge to improve its applicability in early diagnosis, prognosis, monitoring of the disease and evaluation of therapeutic efficacy.