La elevación de los índices preoperatorios de neutrófilos/linfocitos y de plaquetas/linfocitos se asocia a una mayor agresividad local en los tumores renales / Elevation of Preoperative Neutrophil-Lymphocyte ratio and Platelet-Lymphocyte ratio is associated with a Higher Tumor Aggressiveness in Kidney Cancer

Introducción: Existe evidencia de que los índices de neutrófilos/linfocitos (INL) y plaquetas/linfocitos (IPL) se asocian a un peor pronóstico oncológico en distintas enfermedades neoplásicas. El objetivo de este trabajo es analizar la asociación entre el INL y el IPL preoperatorio y la agresividad local del tumor en el carcinoma de células renales (CCR). Materiales y métodos: Se analizaron el INL y el IPL de 353 pacientes que fueron tratados por CCR, sin enfermedad a distancia, entre enero de 2010 y julio de 2013. Se utilizó la regresión de Cox para estimar la asociación entre ambos índices y el estadío patológico, el grado histológico de Fuhrman/ISUP (International Society of Urological Pathology) y la progresión de la enfermedad. Resultados: La mitad de los pacientes presentó grado ISUP III o IV; 24 pacientes presentaron estadío patológico pT3a o superior. En total, 12 pacientes presentaron recidiva local y 19 presentaron metástasis. En el análisis multivariado, un mayor INL o IPL se asoció a un mayor grado ISUP y estadío patológico avanzado. Las medias de INL e IPL fueron significativamente superiores en los pacientes con grado Fuhrman/ ISUP IV y estadío pT3a o superior (p<0,05). El grado ISUP IV y el estadío pT3b se asociaron significativamente a la progresión de la enfermedad, mientras que el INL y el IPL no lo hicieron. Conclusión: La elevación de INL e IPL se asocia a una mayor agresividad local en el CCR, lo que se manifiesta por tumores con un mayor grado de Fuhrman/ISUP o un estadío localmente avanzado. Evaluar estos cocientes antes de la nefrectomía puede brindarle al cirujano un elemento más para conocer el tipo de tumor al que se enfrenta y programar una estrategia acorde.(AU)

Introduction: Neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) are associated with tumor progression and worse oncologic outcomes in different neoplastic diseases. The aim of this study is to analyze the association between preoperative NLR and PLR and local tumor aggressiveness in renal cell carcinomas (RCC). Materials and methods: Pre-treatment NLR and PLR were analyzed in 353 patients who underwent treatment for non-metastatic RCC. Cox regression was used to estimate the association between NLR and PLR with pathological stage (pT), International Society of Urological Pathology (ISUP) grade, and disease progression. Results: ISUP grades III or IV were found in 50% of patients; 24 patients had pT3a stage or higher. After the surgery, 12 patients presented a local relapse, and 19 presented metastases. On multivariable analysis, higher NLR and PLR were significantly associated with a higher ISUP grade and advanced pT stage. Mean NLR and PLR were significantly higher in patients with Fuhrman/ISUP grade IV and pT3a or higher stage (p<0.05). ISUP grade IV and stage pT3b or higher both were associated with disease progression, while NLR and PLR weren't. Conclusion: Elevation of preoperative NLR and PLR is associated with a higher tumor aggressiveness in RCC. Higher ratios are significantly associated with ISUP grade IV and locally advanced stage (pT3b or higher). The preoperative evaluation of these ratios may give the surgeon another element to evaluate the type of tumor he is facing and adopt the best strategy. (AU)

Clinical Significance of Aberrant Wnt7a Promoter Methylation in Human Non-Small Cell Lung Cancer in Koreans

The Wnt signaling pathway has regulatory roles in cell proliferation, differentiation, and polarity. Aberrant Wnt pathway regulation can lead to abnormal cell proliferation and cancer, and loss of Wnt7a expression has been demonstrated in lung cancer cell lines. E-cadherin keeps intercellular integrity and prevents metastasis. Therefore, E-cadherin has been known as a prognostic factor in cancer. In the present study, we investigated the E-cadherin expression status by immunohistochemical stain and the Wnt7a promoter methylation status in human non-small cell lung carcinoma (NSCLC) by methylation-specific PCR. We also analyzed their correlations with clinicopathological factors. Methylation of the Wnt7a gene promoter was detected in the lung tissues of 32 of 121 (26.4%) patients with NSCLC. Wnt7a promoter methylation was correlated with advanced tumor stage (P = 0.036) and distant metastasis (P = 0.037). In addition, Wnt7a promoter methylation showed correlation with loss of E-cadherin expression (P < 0.001). However, Wnt7a promoter methylation was not closely related with gender, age, histological type, or smoking habit. Even though Wnt7a methylation could not show significant correlation with the long term survival of the patients with limited follow up data, these findings suggest that loss of the Wnt7a gene induced by promoter methylation might be another prognostic factor for NSCLC and that restoration of Wnt7a may be a promising treatment for NSCLC.

Clinical Significance of Aberrant Wnt7a Promoter Methylation in Human Non-Small Cell Lung Cancer in Koreans

The Wnt signaling pathway has regulatory roles in cell proliferation, differentiation, and polarity. Aberrant Wnt pathway regulation can lead to abnormal cell proliferation and cancer, and loss of Wnt7a expression has been demonstrated in lung cancer cell lines. E-cadherin keeps intercellular integrity and prevents metastasis. Therefore, E-cadherin has been known as a prognostic factor in cancer. In the present study, we investigated the E-cadherin expression status by immunohistochemical stain and the Wnt7a promoter methylation status in human non-small cell lung carcinoma (NSCLC) by methylation-specific PCR. We also analyzed their correlations with clinicopathological factors. Methylation of the Wnt7a gene promoter was detected in the lung tissues of 32 of 121 (26.4%) patients with NSCLC. Wnt7a promoter methylation was correlated with advanced tumor stage (P = 0.036) and distant metastasis (P = 0.037). In addition, Wnt7a promoter methylation showed correlation with loss of E-cadherin expression (P < 0.001). However, Wnt7a promoter methylation was not closely related with gender, age, histological type, or smoking habit. Even though Wnt7a methylation could not show significant correlation with the long term survival of the patients with limited follow up data, these findings suggest that loss of the Wnt7a gene induced by promoter methylation might be another prognostic factor for NSCLC and that restoration of Wnt7a may be a promising treatment for NSCLC.

Validation of Immature Granulocyte as a Predictor for the 28-Day Mortality in Patients with Severe Sepsis and Septic Shock

PURPOSE: Recently, several studies for immature granulocyte proportion (IG%) in patients with sepsis have revealed its association with diagnosis and prognosis of patients with sepsis. In this study, we enrolled patients with severe sepsis and septic shock and compared IG% with other biologic markers as a predictor of 28-day mortality. METHODS: This was a retrospective study for patients with severe sepsis and septic shock who were admitted to the emergency department of a tertiary care hospital for four-months. The IG% measured using Sysmex XE-2100 and other inflammatory markers, including C-reactive protein, lactate, and procalcitonin were evaluated and compared for 28-day mortality. RESULTS: A total of 85 patients with septic shock and 45 patients with severe sepsis were enrolled. In the non-survivors group (n=32, 24.6%), APACHE II score (p=0.017), use of continuous renal replacement therapy (CRRT) (p=0.002), and septic shock (p=0.009) were statistically higher compared with thesurvivors group. APACHE II score (Odd ratio [OR] 1.099, p=0.008) and IG% (> or =0.5%) (OR 3.568, p=0.036) predicted the 28-day mortality independently after adjusting SOFA score, septic shock,disseminated intravascular coagulopathy, use of CRRT, and gender. However, IG (> or =0.5%) had low specificity of 33.7% and positive predictive value (PPV) of 30.1% for 28-day mortality. CONCLUSION: IG% could be a useful biologic marker for prediction of 28-day mortality in patients with severe sepsis or septic shock. However, the limitation of low specificity and PPV must be considered in clinical use.

Baixo valor sérico de P1NP: preditor de perda de massa óssea em mulheres na pré-menopausa com Lúpus Eritematoso Sistêmico / Lower P1NP serum levels: a predictive marker of bone loss in premenopausal SLE patients

Objetivos: Determinar a incidência de perda de massa óssea em um ano em pacientes com lúpus na pré-menopausa e o valor preditor dos marcadores do metabolismo ósseo para essa complicação. Métodos: Sessenta e três pacientes foram avaliadas à entrada no estudo e após um ano de seguimento. Variações na densidade mineral óssea (DXA) acima da mínima variação significativa (MVS) foram consideradas significativas, como recomendado pela Sociedade Internacional de Densitometria Clínica (International Society for Clinical Densitometry). Os níveis séricos dos marcadores do metabolismo ósseo foram determinados no início do estudo: propeptídeo N-terminal do pro-colágeno tipo 1 (P1NP) e telopeptídeo C-terminal do colágeno tipo 1 (CTX) por eletroquimioluminescência; osteoprotegerina (OPG) e ligante do receptor ativador do fator nuclear kB (RANKL) por ELISA. Resultados: 36,5% dos pacientes apresentaram perda de massa óssea e 17,5% ganho de massa óssea na coluna lombar e/ou fêmur. Os pacientes foram divididos em três grupos: perda de massa óssea (P), massa óssea estável (E) e ganho de massa óssea (G). Pacientes com P e E tomaram doses cumulativa, média e máxima de glicocorticoide semelhantes durante o estudo, mas pacientes com G receberam doses menores (G vs. P e G vs. E, p < 0,05). Os níveis séricos basais de P1NP foram diferentes nos três grupos (P: 36,95 ± 23,37 vs. E: 54,63 ± 30,82 vs. G: 84,09 ± 43,85 ng/ml, p=0,001). Análises de múltiplas comparações demonstraram diferenças significativas nos níveis de P1NP entre P vs. E, p=0,031; P vs. G, p < 0,001 e E vs. G, p=0,039. Não houve diferença entre os grupos com relação aos níveis de CTX, OPG/RANKL, fatores de risco para osteoporose ou parâmetros relacionados à doença. Após análise multivariada, apenas níveis baixos de P1NP permaneceram como fator de risco independente para perda de massa óssea (p < 0,013)...

Objective: To determine the one-year incidence of bone loss in premenopausal lupus patients and the value of bone markers as predictors of this complication. Methods: Sixty-three premenopausal SLE patients were evaluated at baseline and after one-year of follow-up. Bone mineral density changes (DXA) above the least significant change (LSC) were considered significant, as recommended by International Society for Clinical Densitometry. Serum levels of bone markers were determined at baseline: N-terminal propeptide of type 1 collagen (P1NP) and C-terminal telopeptide of type 1 collagen (CTX) by electrochemiluminescence; osteoprotegerin (OPG) and receptor activator of nuclear factor kB ligand (RANKL) by ELISA. Results: 36.5% of patients presented bone loss and 17.5% bone gain at lumbar spine and/or femur. Patients were divided in three groups: bone mass loss (BL), no bone mass change (NC) and bone mass gain (BG). Patients with BL e NC took similar cumulative, mean and maximum GC doses during the study, but patients with BG took lower doses (BG vs. BL and BG vs. NC, p < 0.05). Baseline P1NP levels were different in the three groups (BL: 36.95 ± 23.37 vs. NC: 54.63 ± 30.82 vs. BG: 84.09 ± 43.85 ng/ml, p=0.001). Further multiple comparison analysis demonstrated significant differences in P1NP between BL vs. NC, p=0.031; BL vs. BG, p < 0.001 and NC vs. BG, p=0.039. No difference was observed concerning the levels of CTX, OPG/RANKL, risk factors for osteoporosis or disease related parameters. After multivariate analysis only lower P1NP levels remained as an independent risk factor for bone loss (p < 0.013). Conclusion: This study provides original evidence that lower levels of P1NP, the most specific bone formation marker, are predictive of bone loss in the next year in premenopausal SLE patients...

Predictable Marker for Regression of Barrett's Esophagus by Proton Pump Inhibitor Treatment in Korea

BACKGROUND/AIMS: There has been no report regarding the regression of Barrett's esophagus (BE) by continuous treatment of proton pump inhibitor (PPI). The aim of this study was to determine the regression rate of BE by PPI and predictable markers related to regression. METHODS: Thirty-five patients diagnosed as BE were consecutively enrolled and most of them took continuous PPI. The 25 patients underwent endoscopic surveillance and received biopsy. If the specialized intestinal metaplasia (SIM) was lost at any point of surveillance and did not recur, the case was regarded as the regression group. The proportion of SIM was graded and the mucin phenotype was decided using immunohistochemistry for MUC2, MUC5AC and MUC6. To assess the cell proliferation indexes and the degree of intestinal maturation, immunohistochemistry for Ki67 and CDX2 were performed. RESULTS: The regression of BE occurred in the 11 (44%) patients. The clinical and demographic factors showed no difference between the regression (n = 11) and persistence group (n = 14). The lower grade of SIM (P < 0.001) and gastric predominant mucin phenotype (P = 0.018) were more frequent, and the number of Ki67 positive cell per gland (P = 0.008) and the mean extent of CDX2 (P = 0.022) were lower in the regression group than in the persistence group. CONCLUSIONS: The regression of BE by PPI treatment was frequent in Korea. The immunohistochemical detection of mucin phenotype, grade of SIM, Ki67 and CDX2 expression in Barrett's mucosa could be useful as a predictable marker for regression of SIM in BE.

Risk stratification for indolent lymphomas / Estratificação de risco dos linfomas indolentes

Indolent B-cell lymphomas account for approximately 40 percent of all non-Hodgkin lymphomas (NHLs). Advances in technology have contributed to improvements in the diagnosis and classification of indolent non-Hodgkin lymphomas. Follicular Lymphomas are the most common although the frequency varies significantly throughout the world. The description of the Follicular Lymphoma International Prognostic Index (FLIPI) was an important step in identifying patient subgroups, but its use in the clinical practice has not been established yet. The use of a larger number of paraffin active monoclonal antibodies for immunohistochemistry, molecular cytogenetic studies including standard cytogenetics, multi-color fluorescence in-situ hybridization (FISH), polymerase chain reaction and locus-specific fluorescence insitu hybridization as well as developments in high-resolution techniquesincluding microarray gene expression profiling allow more accurate diagnosis andprecise definition of biomarkers of value in risk stratification. The identification ofdiseasespecific gene lists resulting from expression profiling provides a number ofpotential protein targets that can be validated using immunohistochemistry. Analysesof gene expression profiles or constitutive gene variations may also provide additional insight for prognostication in the near future. A comprehensive understanding of the biology of these distinct lymphoid tumors will allow us to identify novel diseaserelated genes and should facilitate the development of improved diagnosis, outcome prediction, and personalized approaches to treatment.

Os linfomas de células B indolentes representam aproximadamente 40 por cento do total de linfomas não Hodgkin (LNHs). O avanço das tecnologias novas tem contribuído para a melhora no diagnóstico e classificação dos LNH indolentes. O linfoma folicular é o mais comum e sua frequência varia significantemente pelo mundo. Adescrição do Índice Internacional de Prognóstico dos linfomas folicular (FLIPI) representa um passo importante na identificação de subgrupos de pacientes, mas seu uso na prática clínica ainda necessita ser estabelecido. O uso de um número maior de anticorpos monoclonais para imunoistoquímica, estudo citogenético incluindo citogenética convencional ou hibridização in-situ por fluorescência (FISH), bem como o desenvolvimento de técnicas de alta resolução incluindo a expressão por microarray possibilita maior acurácia no diagnóstico e definição precisa dos biomarcadores com valor na estratificação de risco. A identificação de genes específicos para os diversos tipos de linfomas permite o reconhecimento de potenciais proteínas alvo que podem ser validadas usando imunoistoquímica. Análises da expressão do perfil de genes ou variações genéticas constitutivas pode também prover conhecimentos adicionais para o prognóstico em um futuro próximo. Um entendimento da biologia desses distintos tumores linfoides permite-nos identificar novos grupos de genes relacionados à doença e deve facilitar o desenvolvimento diagnóstico, predizendo a evolução e permitindo tratamentos personalizados.

Risk Assessment and Pharmacogenetics in Molecular and Genomic Epidemiology / 예방의학회지

In this article, we reviewed the literature on risk assessment (RA) models with and without molecular genomic markers and the current utility of the markers in the pharmacogenetic field. Epidemiological risk assessment is applied using statistical models and equations established from current scientific knowledge of risk and disease. Several papers have reported that traditional RA tools have significant limitations in decision-making in management strategies for individuals as predictions of diseases and disease progression are inaccurate. Recently, the model added information on the genetic susceptibility factors that are expected to be most responsible for differences in individual risk. On the continuum of health care, from diagnosis to treatment, pharmacogenetics has been developed based on the accumulated knowledge of human genomic variation involving drug distribution and metabolism and the target of action, which has the potential to facilitate personalized medicine that can avoid therapeutic failure and serious side effects. There are many challenges for the applicability of genomic information in a clinical setting. Current uses of genetic markers for managing drug therapy and issues in the development of a valid biomarker in pharmacogenetics are discussed.

Availability of Multimarker IndexTM in Prediction of Ischemic Stroke Severity

PURPOSE: The Multimarker IndexTM (MMX) is derived from 4 biochemical markers (S100 beta, MMP-9, D-dimer, BNP) and is known to be useful in the early detection of stroke. Assessment of severity in the early stages of stroke is as important as early detection of stroke itself, so that early intensive management can be applied. We evaluated wheather MMX is correlated with stroke severity as measured by NIHSS. METHODS: MRI-confirmed stroke patients were prospectively enrolled for analysis of MMX from their serum, and initial NIHSS was recorded. Patients were divided into three convenient groups according to the time from symptom onset. In each group, correlation of MMX and NIHSS was studied. RESULTS: Fifty-one patients were enrolled, and MMX was found to be positively correlated with NIHSS (p<0.01). In subgroup analysis, group A (presented to ED within 6 hours of symptom onset), and group B (presented to ED from 6-12 hours after symptom onset) showed the same positive correlation between MMX and NIHSS (p=0.017, p<0.001), but in group C (presented to ED after more than 12 hours after symptom onset), there was no correlation (p=0.840). CONCLUSION: MMX positively correlated with stroke severity measured by NIHSS for patients presenting to ED within 12 hours of symptom onset.

Availability of Bedside N-terminal Pro-Brain Natriuretic Peptide Measurement as Prognostic Marker About Development of Major Adverse Cardiovascular Events in Patients of Acute Coronary Syndromes

PURPOSE: Natriuretic peptide levels are known to be associated with cardiac output and ventricular function. Recently it has been suggested that N-terminal pro-brain natriuretic peptide (NT-pro-BNP) is available as a prognostic marker for acute coronary syndrome patients. We compared NTpro- BNP levels between patients with and without major adverse cardiovascular events (MACEs) who visited the emergency room due to acute coronary syndrome. METHODS: We designed a case-only study with study subjects recruited retrospectively by medical chart review. Patients who visited the emergency room from 1 May 2006 to 31 February 2007 and were diagnosed with acute coronary syndrome were enrolled. Subjects who did not receive bedside measurement of NT-proBNP levels were excluded. To analyze by subtype of acute coronary syndrome, we classified study subjects into the following group: ST elevation myocardial infarction, non-ST elevation myocardial infarction, or unstable angina. RESULTS: The level of NT-proBNP was 2,592+/-917 pg/ml in MACEs patients, and 1,289+/-1,261 pg/ml in patients without MACEs, a statistically significant difference (p<0.0001). The MACEs patients showed higher level of NT-proBNP than patients without MACEs in the ST elevation myocardial infarction group (p=0.439), the non-ST elevation myocardial infarction group (p=0.004), and the unstable angina group (p=0.009). CONCLUSION: Initial bedside NT-pro-BNP levels are higher in MACEs patients. Although the study size was small and the result should be carefully interpreted, it supports the hypothesis that NT-pro-BNP can as a marker to evaluate MACEs in acute coronary syndrome.

Expression of CD44s, v3 and v6 in Squamous Cell Carcinoma of the Head and Neck / 대한이비인후과학회지

BACKGROUND AND OBJECTIVES: CD44 is a transmembrane glycoprotein that mediates cell adhesion through binding to extracelluar matrix molecules such as hyaluronan. Multiple isoforms of CD44 are generated by alternative splicing of 10 separate exons (v1-v10). Some of them have been noted as markers for tumor metastasis and prognosis in several studies. We investigated whether CD44s, v3 and v6 may be a useful markers in the head and neck squamous cell carcinoma. MATERIALS AND METHOD: Paraffin embedded tissue sections, which was diagnosed as squamous cell carcinoma of the head and neck from 41 patients were stained immunohistochemically with monoclonal Ab of CD44s, v3 and v6. The results were compared with the primary tumor status, lymph node metastasis, histopathologic differentiation and survival. RESULTS: Various levels of immunoreactivities of the CD44s, CD44v3 and CD44v6 were detected dominantly in cancer cell membrane. The positive rate of CD44s, CD44v3 and CD44v6 were 59%, 66%, 71%, respectively. The decreased expression of CD44s and CD44v6 was significantly correlated to lymph node metastasis but was not affected by T-stage, histopathologic differentiation and survival. CD44v3 had no correlation with the T-stage, N-stage, pathologic differentiation nor survival. CONCLUSION: The expression of CD44s and CD44v6 in the head and neck squamous cell carcinoma may be a biologic marker for lymph node metastasis.