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The aim of this study was to evaluate cytokine levels (IL-2, IL-8, TNF-α, IL-5, IL-6 and IL-10) in the peritoneal fluid in non-neoplastic tumours, benign ovarian neoplasms and malignant ovarian neoplasms. Peritoneal fluid or ascites was collected from 117 patients with neoplastic and non-neoplastic ovarian tumours. Cytokine levels were assessed by ELISA. The unpaired groups were compared by the Kruskal-Wallis test with Dunn's post-test. Higher IL-6 levels were found in malignant neoplasms when compared to non-neoplastic tumours (

The aim was to investigate the systemic levels of cytokines and the expression of the chemokine receptor CXCR2 in circulating neutrophils in patients with non-neoplastic ovarian lesions, benign neoplasia or malignant neoplasia.Controls and patients with ovarian tumours were pre-operatively compared for the production of cytokines (IL-2, IL-5, IL-6, IL-8, IL-10 and TNF-α) by ELISA, and for the expression of the chemokine receptor, CXCR2, in neutrophils, by flow cytometry. Randomly selected patients within the malignant group were re-evaluated for the inflammatory parameters at 30 days after surgery.The serum concentrations of IL-6, IL-8 and IL-10 were significantly higher in the benign and malignant neoplasia than in the control group, and their levels were significantly higher in ovarian cancer patients than in patients with non-neoplastic tumours or benign neoplasia. Treatment reduced IL-8 serum levels but did not affect CXCR2 expression in neutrophils. Cut-off values for IL-6, IL-8, and IL-10 comparing malignant vs. benign neoplasia were 11.3, 71.7, 14.8, and comparing malignant neoplasm vs. non-neoplastic lesions were 7.2, 43.5, 12.3, respectively.Serum IL-6, IL-8, and IL-10 levels, and expression of CXCR2 in circulating neutrophils seem promising for distinguishing ovarian cancer patients from patients with benign tumours.

Problem Studies have shown a relationship between endometriosis and ovarian cancer. Our aims were to evaluate and compare the dosages of cytokines IL-2, IL-5, IL-6, IL-8, IL-10, and TNF-α in serum, intracystic fluid, and peritoneal fluid of patients with ovarian endometrioma, malignant and benign ovarian neoplasms, and non-neoplastic ovarian tumors; to verify if there is a correlation between the values of these cytokines between ovarian endometrioma and ovarian malignancy; and to determine the best cut-off point for serum cytokines that can be used to differentiate patients with ovarian malignancy and endometrioma. Method of study The concentrations of cytokines were quantified by enzyme-linked immunosorbent assay (ELISA), analyzed by Kruskal-Wallis test with the Dunn post-test. Receiver operating feature (ROC) curve was used to obtain the area under the curve (AUC) and to determine the best cut-off values that could be used in the diagnosis of ovarian malignancy. Correlations of cytokine concentrations were performed by the Spearman test. Results IL-6, IL-8, and IL-10 concentrations were higher in patients with malignant neoplasia. When evaluating the area under the curve (AUC) of serum cytokine levels comparing patients with malignant neoplasia and endometriomas, there was statistical significance for IL-6, IL-8, and IL-10. Conclusion Our results showed utility in serum concentrations of IL-6, IL-10, and IL-8 as parameters that differentiate endometriomas from ovarian malignancies.

SUMMARY OBJECTIVE To relate disease-free survival and overall survival with type I and type II ovarian cancer and preoperative laboratory parameters biomarkers. METHODS A retrospective study was carried out based on the collection of data from medical records of patients with ovarian tumors. Kaplan-Mayer curves were drawn based on the statistical analysis of the data and were compared using the Log-rank test. RESULTS Disease-free survival in type I ovarian cancer was significantly higher than in type II (p=0.0013), as well as in those with normal levels of CA-125 (p=0.0243) and with a platelet-lymphocyte ratio (PLR) lower than 200 (p=0.0038). The overall survival of patients with type I ovarian cancer was significantly higher than in patients with type II, as well as in patients with normal CA-125 serum levels (p=0.0039) and those with a preoperative fasting glucose of less than 100 mg/dL. CONCLUSION CA-125 levels may predict greater overall and disease-free survival. PLR < 200 may suggest greater disease-free survival, whereas normal fasting glucose may suggest greater overall survival. RESUMO OBJETIVO Relacionar a sobrevida livre de doença e sobrevida global com câncer de ovário tipos I e II, assim como com parâmetros laboratoriais pré-operatórios biomarcadores. MÉTODOS Estudo retrospectivo realizado com base na coleta de dados de prontuários de pacientes com tumor ovariano. As curvas de Kaplan-Mayer foram realizadas em relação à análise estatística dos dados, sendo comparadas pelo teste de Log-rank. RESULTADOS A sobrevida livre de doença nas pacientes com câncer de ovário tipo I foi significativamente maior do que nas pacientes com câncer de ovário tipo II (p = 0,0013), bem como maior naquelas com níveis normais de CA-125 (p = 0,0243) e com relação plaquetas-linfócitos (RPL) inferior a 200 (p = 0,0038). A sobrevida global de pacientes com câncer de ovário tipo I foi significativamente maior do que em pacientes com tipo II, maior em pacientes com níveis séricos normais de CA-125 (p = 0,0039) e naquelas com glicemia de jejum pré-operatória menor que 100 mg / dL. CONCLUSÃO Os níveis de CA-125 podem predizer uma sobrevida global e livre de doença. A RPL < 200 pode sugerir uma maior sobrevida livre de doença, enquanto uma glicemia normal de jejum, uma maior sobrevida global.

The objectives of the study were to analyze the dosage of a cytokine panel (IL2, IL5, IL6, IL8, IL10, and TNF-α) in the peritoneal fluid and relate the dosage of these cytokines to prognostic para- meters and survival in ovarian cancer. Peritoneal fluid was collected intraopera- tively from 29 patients with primary malignant ovarian neoplasia. Cytokine panel dosing was performed with ELISA. Comparisons of cytokines with prognostic factors were performed using the Wilcoxon-Mann-Whitney test. ROC curves were used to determine the cutoff value of NLR, PLR, and IL6. Univariate and multivariate analysis of disease-free survival (DFS) or overall survival (OS) were performed (Kaplan-Meier and Cox regression). The differences were considered significant when the value of p.05. Higher levels of IL-6 were related to a neutrophil-lymphocyte ratio (NLR)3.18 (p = .04), a platelet-lymphocyte ratio (PLR)219.23 (p = .0051), CA-125 levels35 U/mL (p = .0019), stage IIIC (p = .0203), and DFS ≤ 24 months (p = .0267). For IL-8, higher levels were related to PLR219.23 (p = .0426), and CA-12535 U/mL (p = .0292). In the univariate analysis, IL-6 levels ≥87.23 in peritoneal fluid had a relationship with shorter DFS at significance threshold (p = .05), and with a shorter OS (p = .039). Multivariate survival analysis proved that IL-6 level in the peritoneal fluid was an independent predictor of OS. Therefore, IL-6 and IL-8 in peritoneal lavage were related to poor prognostic factors. These cytokines may represent new biomarkers for ovarian cancer therapies.

The aims of the study were to compare the levels of tumor necrosis factor alpha (TNF-α) and its soluble type I (sTNF-R1) and type II (sTNF-R2) receptors detected in intracystic liquid and serum from benign and malignant ovarian neoplasms and to relate them to prognostic factors in epithelial ovarian cancer. The patients were divided into benign ovarian neoplasms (n = 46) and malignant ovarian neoplasms (n = 17). The serum and intracystic samples were collected before and during surgery for ovarian cyst, respectively. The levels of TNF-α, sTNF-R1, and sTNF-R2 were measured using ELISA. Results were compared with the Mann-Whitney test. Concentration of sTNF-R2 in the intracystic samples collected from the malignant neoplasia was significantly higher than that of the benign neoplasias (p = 0.02). Higher intracystic levels of sTNF-R2 exhibited a significant association with tumor differentiation grades 2 and 3 (p = 0.0087). There was no statistical significance in relation to serum levels. Tumor microenvironment levels of sTNF-R2 may represent a factor of poor prognosis in epithelial ovarian cancer.

The development of new biomarkers for the diagnosis and prognosis of ovarian cancer may provide an opportunity for new therapies. In this study, we aimed to compare cytokines (interleukin [IL]-2, IL-5, IL-6, IL-8, IL-10 and tumour necrosis factor [TNF]-α) and nitric oxide (NO) metabolite levels in non-neoplastic tumours, benign primary ovarian tumours and malignant primary ovarian neoplasms. The secondary aim was to relate cytokine and intracystic NO metabolite levels to clinical, laboratory and pathologic characteristics for patients with primary ovarian malignancies. We evaluated 110 patients with adnexal masses. Cytokine concentrations were quantified by enzyme-linked immunosorbent assay and nitrate concentrations by enzymatic reduction of nitrite by nitrate reductase. Patients with malignant neoplasms had higher IL-6, IL-8 and NO levels compared to patients with benign neoplasms. Histologic grade 1 tumours were associated with elevated IL-2 levels, whereas anaemia was associated with elevated IL-6 levels. On average, those patients with elevated IL-8 levels also had a neutrophil/lymphocyte ratio (NLR) greater than 2.6 and less than 36 months of disease-free survival (DFS). Patients with normal CA 19-9 levels had elevated IL-10 levels. TNF-α was elevated in patients with two carcinogenesis and those with a platelet/lymphocyte ratio (PLR) less than 300. NO levels were higher in patients with an NLR less than 2.6 and CA 19-9 greater than 35 U/ml. Elevated intracystic cytokine levels, especially IL-6 and IL-8, are associated with worse prognosis in ovarian cancer.

The aim of the study was to correlate serum levels of IL-2, IL-5, IL-6, IL-8, IL-10, and TNF-α with clinical, laboratory, and pathological prognostic factors in patients with primary ovarian malignancy. Patients treated at the Pelvic Mass Ambulatory of the Discipline of Gynecology and Obstetrics/Oncology Research Institute (IPON) of the UFTM with confirmed diagnosis of malignant ovarian neoplasia (n = 26) were evaluated. Serum collection was performed preoperatively for the determination of tumor markers. The cytokines IL-2, IL-5, IL-6, IL-8, IL-10, and TNF-α were assayed by enzyme-linked immunosorbent assay (ELISA). The prognostic factors were compared using the Mann-Whitney test, with significance level lower than 0.05. When evaluating IL6, it was observed that higher serum levels were associated with overall survival less than 60 months (p = 0.0382). In the evaluation of IL8, higher serum levels were associated with neutrophil-to-lymphocyte ratio (NLR) ≥ 4 and platelet-to-lymphocyte ratio (PLR) ≥ 200 (p = 0.0198 and p = 0.0072, respectively), altered values of serum CA125 (p = 0.0457), and stage IIIC (p = 0.0486). Therefore, increased levels of IL-6 and IL-8 are associated with factors of worse prognosis in ovarian cancer. Additional studies with a larger sample of patients are needed to confirm the role of cytokines as prognostic factors, in the definition of treatment, and in the development of future target therapies.

Objective: To characterize the inflammatory profiles of patients with systemic lupus erythematosus receiving standard treatment compared to healthy controls. Patients and methods: Peripheral venous blood was collected from systemic lupus erythematosus patients (n = 14) and controls (n = 18) at enrollment. Blood samples were used for quantification, by flow cytometry, of CD11b (integrin) and Chemokine receptor CXCR2 expression surface antigen in neutrophils and lymphocytes, while cytokines were assayed in serum samples. Purified neutrophils were assayed by their ability to phagocytize human plasma-opsonized zymosan. Results: Patients had a median (interquartile range) disease activity index of 1.0 (0-2.0) characteristic of patients in remission. Interleukin-6 and interleukin-10 serum concentrations were significantly higher in the patient group compared to controls and the phagocytic index of circulating neutrophils was significantly reduced in patients compared to controls. The levels of interleukin-2, interleukin-5, interleukin-8 and tumor necrosis factor alpha did not significantly differ between patients and controls. Flow cytometric analysis revealed that the integrin expression levels were reduced in lymphocytes (but not in neutrophils) obtained from systemic lupus erythematosus patients, while surface expression of the chemokine receptor 2 was similar in both neutrophils and lymphocytes. Conclusion: Systemic lupus erythematosus patients receiving standard treatment presented with elevated systemic levels of interleukin-6 and interleukin-10, reduced neutrophil phagocytic capacity, and reduced lymphocyte expression of integrin even when symptoms were in remission. These alterations to innate immune components may put these individuals at a greater risk for acquiring infections. RESUMO Objetivo: Caracterizar os perfis inflamatórios de pacientes com lúpus eritematoso sistêmico (LES) que recebiam o tratamento padrão em comparação com controles saudáveis. Pacientes e métodos: Coletou-se o sangue venoso periférico de pacientes com LES (n = 14) e controles (n = 18) no momento da entrada no estudo. As amostras de sangue foram usadas para quantificação, por citometria de fluxo, da expressão dos antígenos de superfície CD11b (integrina) e CXCR2 em neutrófilos e linfócitos, enquanto as citocinas foram avaliadas em amostras de soro. Avaliou-se a capacidade dos neutrófilos purificados de fagocitar zimosan opsonizado com plasma humano. Resultados: Os pacientes apresentavam uma pontuação mediana (intervalo interquartil) no Sledai de 1 (0-2), característica de pacientes em remissão. As concentrações séricas de IL-6 e IL-10 foram significativamente maiores no grupo de pacientes em comparação com os controles; o índice de fagocitose de neutrófilos circulantes estava significativamente reduzido nos pacientes em comparação com os controles. Os níveis de IL-2, IL-5, IL-8 e TNF-α não diferiram significativamente entre pacientes e controles. A análise da citometria de fluxo revelou que os níveis de expressão de CD11b estavam reduzidos nos linfócitos (mas não nos neutrófilos) obtidos de pacientes com LES, enquanto a expressão do receptor de superfície CXCR2 foi semelhante em neutrófilos e linfócitos. Conclusão: Os pacientes com LES que recebiam tratamento padrão apresentaram níveis sistêmicos elevados de IL-6 e IL-10, redução na capacidade fagocítica dos neutrófilos e redução da expressão de CD11b em linfócitos, mesmo quando os sintomas estavam em remissão. Essas alterações nos componentes da imunidade inata podem colocar esses indivíduos em maior risco de adquirir infecções.

ResumoObjetivoCaracterizar os perfis inflamatórios de pacientes com lúpus eritematoso sistêmico (LES) que recebiam o tratamento padrão em comparação com controles saudáveis.Pacientes e métodosColetou‐se o sangue venoso periférico de pacientes com LES (n = 14) e controles (n = 18) no momento da entrada no estudo. As amostras de sangue foram usadas para quantificação, por citometria de fluxo, da expressão dos antígenos de superfície CD11b (integrina) e CXCR2 em neutrófilos e linfócitos, enquanto as citocinas foram avaliadas em amostras de soro. Avaliou‐se a capacidade dos neutrófilos purificados de fagocitar zimosan opsonizado com plasma humano.ResultadosOs pacientes apresentavam uma pontuação mediana (intervalo interquartil) no Sledai de 1 (0‐2), característica de pacientes em remissão. As concentrações séricas de IL‐6 e IL‐10 foram significativamente maiores no grupo de pacientes em comparação com os controles; o índice de fagocitose de neutrófilos circulantes estava significativamente reduzido nos pacientes em comparação com os controles. Os níveis de IL‐2, IL‐5, IL‐8 e TNF‐α não diferiram significativamente entre pacientes e controles. A análise da citometria de fluxo revelou que os níveis de expressão de CD11b estavam reduzidos nos linfócitos (mas não nos neutrófilos) obtidos de pacientes com LES, enquanto a expressão do receptor de superfície CXCR2 foi semelhante em neutrófilos e linfócitos.ConclusãoOs pacientes com LES que recebiam tratamento padrão apresentaram níveis sistêmicos elevados de IL‐6 e IL‐10, redução na capacidade fagocítica dos neutrófilos e redução da expressão de CD11b em linfócitos, mesmo quando os sintomas estavam em remissão. Essas alterações nos componentes da imunidade inata podem colocar esses indivíduos em maior risco de adquirir infecções.AbstractObjectiveTo characterize the inflammatory profiles of patients with systemic lupus erythematosus (SLE) receiving standard treatment compared to healthy controls.Patients and methodsPeripheral venous blood was collected from SLE patients (n = 14) and controls (n = 18) at enrollment. Blood samples were used for quantification, by flow cytometry, of CD11b (integrin) and CXCR2 expression surface antigen in neutrophils and lymphocytes, while cytokines were assayed in serum samples. Purified neutrophils were assayed by their ability to phagocytize human plasma‐opsonized zymosan.ResultsPatients had a median (interquartile range) SLEDAI score of 1.0 (0 ‐ 2.0) characteristic of patients in remission. IL‐6 and IL‐10 serum concentrations were significantly higher in the patient group compared to controls and the phagocytic index of circulating neutrophils was significantly reduced in patients compared to controls. The levels of IL‐2, IL‐5, IL‐8 and TNF‐ α did not significantly differ between patients and controls. Flow cytometric analysis revealed that the CD11b expression levels were reduced in lymphocytes (but not in neutrophils) obtained from SLE patients, while surface expression of the chemokine receptor CXCR2 was similar in both neutrophils and lymphocytes.ConclusionSLE patients receiving standard treatment presented with elevated systemic levels of IL‐6 and IL‐10, reduced neutrophil phagocytic capacity, and reduced lymphocyte expression of CD11b even when symptoms were in remission. These alterations to innate immune components may put these individuals at a greater risk for acquiring infections.

Oral squamous cell carcinoma (OSCC) is the most malignant lesion occurring in the head and neck. The Rho-kinases (ROCKs), effectors of Rho proteins, are involved in actin cytoskeletal organization, cell migration, and maintenance cortex. The HA-1077 inhibits the ROCKs. This study aimed to evaluate the effect of treatment with HA-1077 on cell motility in SCC-4 cells, a cell line originating from human OSCC. F-actin of SCC-4 cells treated or not with HA-1077 (1, 50 and 100 μmol/l), and also HA-1077 50 μmol/l and/or inhibitors Y-27632 30 μmol/l was stained with rhodamine-conjugated phalloidin and analyzed by confocal microscopy. Approximately 1×10 cells/well, control and treated with HA-1077 (25, 50, and 100 μmol/l) were added to the migration plate assay. In addition, 1×10 cells/well, control and treated with HA-1077 50 μmol/l, were tested by invasion assays (plate coated with Matrigel). The inhibition of ROCKs with HA-1077 and/or Y-27632 leads to morphological changes, affecting the organization of the actin. The inhibitory effect of HA-1077 (P0.0001) was dose dependent as the number of cells migrated at 100 μmol/l was statistically different: 25 μmol/l (P0.0001) and 50 μmol/l (P0.01). The number of cells treated with HA-1077 50 μmol/l decreased compared with control cells that invaded through Matrigel (P0.0001). This study shows an inhibitory effect of HA-1077 on cell migration and invasion, suggesting that the use of HA-1077 can be a potential therapy for OSCC.

Objectives: There are few studies in the literature correlating metabolic alterations with prognostic factors in breast cancer. The aims of this study were to evaluate serum levels of total cholesterol, HDL, LDL, triglycerides and fasting glucose, weight, body mass index and blood pressure, and relate them to prognostic factors (stage, lymph node involvement, histological grade, estrogen and progesterone receptors, ki-67 and Her2/neu) in patients with breast cancer. Methods: A retrospective study was conducted in Mastology Service of the Discipline of Gynecology and Obstetrics/Oncologycal Research Institute (IPON) of the Universidade Federal do Triângulo Mineiro (UFTM). We evaluated 100 patients with breast cancer treated at Mastology Clinic (surgical and/or clinical treatment). Serum levels of total cholesterol, HDL, LDL, triglycerides and fasting glucose, weight, body mass index, blood pressure, staging, lymph node involvement, histological grade and immunohistochemical panel (estrogen and progesterone receptors, ki-67 and HER-2/neu) were recorded. Data were expressed as the mean ± standard deviation, and the values were compared by using Student’s t-test. P-values less than 0.05 were considered statistically significant. Results: Histological grades 1 and 2 were significantly correlated with higher HDL serum levels (p=0.02). Higher levels of triglycerides were found more frequently in grade 3, and highest weight was related to Ki-67 positive, but only with a trend towards significance (p=0.07). Conclusion: HDL can be related to prognosis in breast cancer.

Objective: The objectives of the present study were to demonstrate the influence of neutrophils, platelets, and neutrophil–lymphocyte ratio (NLR) in the ovarian cancer prognosis and to compare these parameters with benign ovarian neoplasms. Materials and Methods: Records of patients underwent surgery for ovarian cysts were evaluated. There were 72 malignant neoplasms and 213 benign neoplasms. Age, parity, histologic type, tumor stage, type of surgery performed, chemotherapy, disease-free survival, serum levels of tumor markers, neutrophils, lymphocytes, platelets, and NRL were recorded. The Mann-Whitney, the Chi-square test and multiple linear regression were used. A P-value < 0.05 was established as the significance level. Results: Higher values of platelets, neutrophils, and NLR were found in malignant tumors (P = 0.0132, P = 0.0208, and P < 0.0001, respectively), while lymphocytes values were higher in benign group (P < 0.0001). Preoperative platelet count 300,000/mm3 was related to less aggressive histological types (P = 0.0148). NLR 24 months had most often neutropenia during chemotherapy (P = 0.0482). After multivariate analysis, platelets, NLR, and serum levels of CA15.3 were considered independent variables related to tumor staging (P = 0.028, P = 0.028, and P = 0.035, respectively). Conclusion: NLR and serum levels of platelets may represent potential prognostic factors in ovarian cancer, and they may also serve as therapeutic targets in the future treatment strategies.

Background/Aims: Growth differentiation factor 15 (GDF-15) is induced by pro-inflammatory cytokines. Higher levels of GDF-15 have been associated with malignancy. The aim of the study was to evaluate both tissue and serum levels of GDF-15 in ovarian neoplasms. Methods: A cohort study evaluated 31 patients with benign ovarian tumors and 34 patients with ovarian cancer were evaluated in 2 years. The inclusion criterion was histopathological diagnosis of ovarian epithelial neoplasia. Exclusion criteria were secondary malignant ovarian neoplasia and preoperative treatment. Serum and tissue levels of GDF-15 were assessed by enzyme-linked immunosorbent assay and immunohistochemistry, respectively. Chi-square test and unpaired t test were performed. Results: Serum levels were higher in the patients with malignant neoplasms than in the patients with benign tumors, yet the difference was not statistically significant. GDF-15 immunostaining was significantly more frequent in the stroma of the malignant tumors than in the stroma of the benign tumors (p = 0.0034). Conclusion: GDF-15 staining is elevated in the stroma of ovarian cancer, demonstrating that it may be a potential diagnostic and therapeutic target.

Aim To verify if patients with cervical neoplasia produce mediators that reduce leukocyte function. Methods Control neutrophils incubated with normal serum or serum from pre-invasive or invasive neoplasia patients were assayed for chemotaxis. Mediators were assayed in serum and in leukocyte supernatants. Experiments were also performed in random patients after surgery. Results Neutrophils incubated with patient sera, but not normal sera, failed to migrate towards the chemoattractants. In invasive neoplasia compared to controls, IL-6 and IL-8, and IL-10 and TNF-α were elevated in serum and in neutrophil supernatants, respectively. Nitrite levels were elevated in mononuclear cell supernatants from patients than controls. After surgery, serum cytokine levels were reduced, mainly in pre-invasive patients. Neutrophils treated with serum from pre-invasive patients undergone surgery had restored migration. Conclusion Patients with cervical neoplasia produce mediators, predominantly induced by tumor cells, able to impair the inflammatory response at very early stages of disease.

The aim of this paper was to evaluate the parameters of blood count and tumor markers in borderline ovarian tumors. We evaluated 21 patients who had confirmed histopathologic diagnosis of borderline ovarian tumor. We recorded age, parity, tumor type, stage of cancer, serum levels of tumor markers (CA-125, CA-15.3, CA-19.9, CEA, AFP), and the parameters of blood count, fasting glucose, disease-free survival and overall. The patients were divided into two groups, stage IA (n=13) and stage IB-IIIC (n=8). The unpaired t-test and Fisher's exact test were used, with P values of less than 0.05 being considered to indicate statistical significance. Levels of red blood cells, hematocrit, and hemoglobin were significantly higher in stage IA when compared with stage IB-IIIC (P<0.05). The levels of tumor marker CEA had a tendency to be higher in the group stage IB-IIIC (0.08). Abnormal levels of CEA and CA-19.9 were found more frequently in stages IB-IIIC. Therefore, parameters of blood count, CEA, and CA-19.9 should be targeted for further research in identifying prognostic factors in borderline tumors.

The aim was to evaluate the impact of anthracycline-based chemotherapy on neutrophil count and infections in breast cancer women. The medical records of patients were retrospectively and prospectively reviewed (8-year period). Patients were grouped according to anthracyclines at different doses: (1) Scheme 1 (n = 56, 224 courses): 50-60 mg/m(2); and (2) Scheme 2 (n = 25, 100 courses): 65-75 mg/m(2), associated to cyclophosphamide and 5-fluorouracil, at 21-day intervals between courses. Neutrophil count was performed on diagnosis and 48-72 h before each chemotherapy course. Patients were followed up for neutrophil count and infection episodes for three consecutive courses. Multivariate analysis was used to determine independent factors for infection. After the first course, neutrophil count was reduced than baseline (P < 0.001) and maintained during the subsequent courses, without differences between courses or groups. There were 49 infection episodes (63.2% urinary, 18.4% neutropenic fever and 18.4% diverses), mainly between course 1-2 (39%) and course 3-4 (38%) of chemotherapy. Patients evaluated as presenting or not with infection episodes did not differ in neutrophil count. The number of chemotherapy courses (P < 0.05), but not age, neutrophil count or chemotherapy regimen, was associated with infection. We concluded that progressive chemotherapy, but not neutrophil count, was an independent factor for infection.

Leukocyte migration is a key event in the inflammatory response to tumors. The tumor releases specific chemokines that control migration of leukocytes and functions of these cells after their arrival at the tumor site. In addition to these local changes in the tumor microenvironment, the host response to malignant solid tumors also gives rise to systemic effects, the most frequent of which are leukocytosis, neutrophilia and lymphopenia. These hematological findings are significantly correlated with advanced tumor stage and, therefore, poor disease prognosis. The ratio of neutrophil and lymphocyte counts has been suggested as a simple parameter of systemic inflammation in cancer patients. An elevated neutrophil to lymphocyte ratio has been shown to be an independent prognostic factor for cancers at various different sites, suggesting that this parameter is a clinically accessible and useful biomarker for patient survival. The effect of tumor development on circulating leukocyte number has not been clarified. One proposed mechanism is that tumor cells produce soluble factors such as granulocyte colony stimulating factor, which mobilize precursor cells in the bone marrow, or other mediators that alter cell differentiation. Leukocyte counts may be readily obtained at the time of diagnosis, and these data could be useful as stratification factors in clinical trials and in identifying patients with poor prognosis, leading to better treatment strategies.

Aims and background Our aim was to evaluate the effect of treatment on the in vitro migration of circulating mononuclear cells in cervical cancer patients at different stages. Methods We prospectively investigated 24 patients with cervical neoplasia, without prior treatment, submitted to surgery or chemotherapy as therapeutic conduct. Controls were healthy volunteer women (n = 23). Mononuclear cells were isolated from peripheral venous blood before and after treatment, and their migration capacity was evaluated in a microchemotaxis chamber assay towards the chemotactic stimuli fMLP, MCP-1 and RANTES, compared to basal migration. Serum levels of nitric oxide metabolites were assayed by the Griess reaction. Results Increased mononuclear cell migration in response to the chemotactic stimuli, compared to basal migration, was observed in controls and patients, without differences between them. After treatment (n = 14), mononuclear cell migration in response to MCP-1 and RANTES was increased compared to pre-treatment. Serum levels of nitric oxide metabolites were more elevated in patients (n = 19) than in controls (n = 17), but decreased after treatment (n = 15). Conclusions The results suggest that the production of soluble circulating factors by tumor cells could interfere with the functional activity of blood mononuclear cells.

To determine parameters associated with the evolution of sepsis, a five-year retrospective study was conducted in a university hospital. One hundred and four consecutive sepsis patients were evaluated, of whom 55.8% were men. The mortality was 68.3% and was associated with older age (p

Tumor sections from nonneoplastic (n=15), benign (n=28), and malignant ovarian tumors (n=20) were obtained from 63 women. Immunohistochemistry of the tumor sections demonstrated that inducible nitric oxide synthase (iNOS) expression was increased in ovarian cancer samples compared to nonneoplastic or benign tumor samples. Using the Griess method, nitric oxide (NO) metabolite levels were also found to be elevated in malignant tumor samples compared to benign tumor samples (P<.05). For stage I ovarian cancer, intracystic NO levels>80 μMwere more frequent than NO levels<80 μM, and iNOS expression in well-differentiated carcinomas was greater than in moderately/poorly differentiated carcinomas (P<.05). These data suggest an important role for NO in ovarian carcinogenesis.

The reduction of circulating neutrophil migration to infection sites is associated with a poor outcome of severe sepsis. α-1-Acid glycoprotein (AGP) was isolated from the sera of severely septic patients by HPLC and acrylamide gel electrophoresis and identified by mass spectrometry. Both the isolated protein and commercial AGP inhibited carrageenin-induced neutrophil migration into the rat peritoneal cavity when administered i.v. at a dose of 4.0 μg per rat (95 pmol per rat). Analysis by intravital microscopy demonstrated that both proteins inhibited the rolling and adhesion of leukocytes in the mesenteric microcirculation. The inhibitory activity was blocked by 50 mg/kg aminoguanidine, s.c., and was not demonstrable in inducible nitric oxide synthase (iNOS) knockout mice. Incubation of AGP with neutrophils from healthy subjects induced the production of NO and inhibited the neutrophil chemotaxis by an iNOS/NO/cyclic guanosine 3,5-monophosphate-dependent pathway. In addition, AGP induced thel-selectin shedding by neutrophils. The administration of AGP to rats with mild cecal ligation puncture sepsis inhibited neutrophil migration and reduced 7-day survival from ≈80% to 20%. These data demonstrate that AGP, an acute-phase protein, inhibits neutrophil migration by an NO-dependent process and suggest that AGP also participates in human sepsis.

Depression is a mood disorder that is more prevalent in women and has been closely associated with chronic stress. Many models of depression have been suggested that consider different forms of stress. In fact, stress is present in the life of every human being, but only a few develop depression. Accordingly, it seems wrong to consider all stressed animals to be depressed, emphasizing the importance of predisposition for this mood disorder. Based on this finding, we evaluated a predisposition to depressive behavior of female rats on the forced swim test (FST), and the more immobile the animal was during the FST, the more predisposed to depression it was considered to be. Then, animals were subjected to the stress of social isolation for 21 days and were re-evaluated by the FST. The Predisposed/Isolated rats presented higher immobility times. Once all the rats had prior experience in the FST, we calculated an Index of Increase by Isolation, confirming the previous results. Based on this result, we considered the Predisposed/Isolated group as presenting depressive behavior ('Depressed') and the Nonpredisposed/Nonisolated group as the control group ('Nondepressed'). The animals were distributed into 4 new groups: Nondepressed/Vehicle, Nondepressed/Amitriptyline, Depressed/Vehicle, Depressed/Amitriptyline. After 21 days of treatment, only the Depressed/Vehicle group differed from the other 3 groups, demonstrating the efficacy of amitriptyline in treating the depressive behavior of the Depressed animals, validating the model. This study shows that conducting an FST prior to any manipulation can predict predisposition to depressive behavior in female rats and that the social isolation of predisposed animals for 21 days is effective in inducing depressive behavior. This behavior can be considered real depressive behavior because it takes into account predisposition, chronic mild stress, and the prevalent gender.

Sepsis and septic shock continue to be a major cause of morbidity and mortality in critically ill patients. During the onset of sepsis, a massive inflammatory reaction is mediated via cell-derived cytokines and chemokines that target end-organ receptors in response to injury or infection. Polymorphonuclear leucocytes are critical effector cells during the inflammatory process and their migration to the infectious focus is extremely important for the local control of bacterial growth and consequently for the prevention of bacterial dissemination. In addition to the inflammatory process, sepsis and septic shock cause a profound loss in the peripheral vasomotor tone resulting in a huge decrease in the peripheral resistance, a central event in the derangement of hemodynamic and perfusional parameters. Nitric oxide (NO) is a simple molecule produced by numerous cell types that has been implicated in a wide range of physiological and pathological processes, exerting both detrimental and beneficial effects. It is an important modulator of neutrophil adherence and activation, of cardiovascular homeostasis and end organ perfusion. The induction of the inducible isoform of NO synthase leads to an increased NO production which is involved both in the impairment of neutrophil migration and in the cardiovascular disfunction present in sepsis and septic shock. Thus, a better knowledge of the role of NO in the inflammatory, cardiovascular and immune aspects of sepsis may provide us with more efficient therapeutic alternatives to treat sepsis and septic shock.

To investigate the in vitro chemotactic function of neutrophils obtained from patients with sepsis.Prospective study in which purified neutrophils obtained from septic patients and nonseptic control volunteers were assayed for chemotactic function induced by N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) and leukotriene B4. The sera nitrate concentrations also were quantified.University hospital.Twenty patients with sepsis caused by different infectious foci.Routine blood tests, blood or other site cultures, blood collection for neutrophil purification sera collection for nitrate assay.Neutrophils from septic patients exhibited significantly less chemotactic activity than neutrophils obtained from healthy volunteers, in response to FMLP (93.4 +/- 6.6 vs. 51 +/- 8.3 migrated neutrophils) and leukotriene B4 (90.2 +/- 10 vs. 42.4 +/- 11.6 migrated neutrophils) stimuli, in a microchemotaxis chamber assay. The impaired chemotaxis occurred mainly in neutrophils from nonsurvivor patients. The extent of neutrophil chemotaxis inhibition (survivor/nonsurvivor) was 33.43%/61.67% and 43.4%/86.98%, in response to FMLP and leukotriene B4, respectively. Increased serum nitrate (micromoles of NO2 + NO3) concentrations were detected in septic patients, compared with controls, but no differences were found between survivor (91.84 +/- 14.12) and nonsurvivor (102.6 +/- 17.36) groups.Septic patients present suppressed neutrophil chemotactic responses to FMLP and leukotriene B4 stimuli compared with healthy controls. This is accompanied by increased serum concentrations of nitrate. The impairment of neutrophil chemotaxis was observed mainly in the cells obtained from nonsurvivor patients and may thus be an additional factor contributing to disease outcome.

To investigate the role of NO in the inhibition of neutrophil migration by circulating endotoxin, mice were pretreated with NO synthase inhibitors or with a free radical scavenger (D-penicillamine), before intravenous LPS injection. LPS dose-dependently inhibited the thioglycollate-induced neutrophil migration into the peritoneal cavities. Aminoguanidine, a selective inducible NO synthase inhibitor, abolished the inhibition of neutrophil migration and the increase in serum nitrate levels induced by a nonlethal dose of LPS. During lethal endotoxemia aminoguanidine partially abolished the neutrophil migration inhibition. Additionally, D-penicillamine prevented the inhibition of neutrophil migration caused by LPS. However, Nitro-L-Arginine, a selective constitutive NO synthase inhibitor, did not prevent neutrophil migration inhibition. Aminoguanidine treatment did not affect the systemic increased levels of TNF-alpha, IL-1beta, and IL-10, suggesting that NO is the final mediator involved in the inhibition of neutrophil migration. Our results suggest that NO released by the inducible NO synthase mediates the inhibition of neutrophil migration mediated by circulating LPS.

1 The i.v. administration of tumor necrosis factor-α (TNF-α), interleukin-8 (IL-8) and the recently described macrophage-derived neutrophil chemotactic factor (MNCF) inhibits the recruitment of neutrophils to the inflammatory site. 2 Pretreatment of mice with the NO synthase antagonist, NG-monomethyl-l-arginine (l-NMMA, 15–60 mg kg−1), but not the inactive enantiomer d-NMMA (30 mg kg−1), prevented in a dose-dependent manner the TNF-α, IL-8 and MNCF-mediated inhibition of neutrophil migration into thioglycollate-challenged peritoneal cavities. 3 Treatment of the neutrophils with TNFα (10−7m), IL-8 (10−7m) or MNCF blocked their migration towards FMLP in the chemotaxis assay. The pretreatment of the neutrophils with l-NMMA (50–200 μm) prevented in a dose-dependent manner the inhibition of FMLP-induced chemotaxis by IL-8, but did not alter the inhibition caused by TNF-α or MNCF. Different concentrations of the NO donors, S-nitroso-N-acetylpenicillamine (SNAP) or 3-morpholino-sydnonimine (SIN-1), did not alter this chemotaxis. 4 Preincubating the neutrophils with l-NMMA (200 μm) significantly increased the TNF-α (10−7m) and MNCF-mediated neutrophil adhesion to unstimulated endothelial cells, but had no effect on IL-8 (10−7m)-mediated adhesion. 5 Although NO donors did not directly affect the mechanisms of neutrophil motility, NO is involved in the in vitro inhibitory action of IL-8 on chemotaxis. The TNF-α and MNCF-mediated inhibition of neutrophil migration seems to be indirect, by affecting the mechanisms of adhesion. It was concluded that TNF-α-, IL-8- and MNCF-mediated inhibition of neutrophil migration is associated with the stimulation of NO production. British Journal of Pharmacology (1998) 124, 1369–1374; doi:10.1038/sj.bjp.0701965

To investigate the mechanisms affecting neutrophil migration capacity in breast cancer patients before and after chemotherapy. Peripheral venous blood was collected at the time of diagnosis and immediately prior to the 4th cycle of an anthracycline-based chemotherapy regimen for patients diagnosed with different stages of breast cancer (n = 30), for experimental assays. Blood samples were also collected from a healthy control group (n = 17). IL-8 serum concentrations were higher in the patient group than in the control group (p = 0.02), and chemotherapy did not further affect this increase. Levels of TNF-α, IL-6, and IL-10 did not differ between controls and patients, or in relation to chemotherapy. Serum levels of nitric oxide (NO) metabolites were elevated following chemotherapy compared to levels detected prior to treatment (p = 0.01). When the supernatants of lipopolysaccharide-stimulated mononuclear cells and neutrophils obtained from the patients were assayed for levels of nitrite, these levels were significantly higher and unchanged, respectively, compared with controls. Expression levels of the chemokine receptors, CXCR1 and CXCR2, were significantly reduced in patients compared to controls, and chemotherapy did not further affect these differences. Furthermore, filamentous actin content for IL-8-activated neutrophils was reduced with chemotherapy (median 8.85; range 3.38–13.43) compared to the content detected prior to treatment (median 9.23; range 2.86–22.16) (p = 0.001). Elevated systemic levels of IL-8 and NO, desensitization to CXCR activation, and reduction in actin polymerization may affect neutrophil motility in patients before and after chemotherapy.

In a previous study, we demonstrated the presence of a neutrophil recruitment inhibitory factor (NRIF) in the supernatants of LPS-stimulated macrophages. Recently, the purification of a 54 kDa protein, identified as the macrophage-derived neutrophil chemotactic factor (MNCF) was reported. Since NRIF and MNCF are obtained under the same conditions, and, since the intravenous administration of TNF-α and IL-8 inhibits neutrophil migration, we have investigated whether MNCF could be responsible for this inhibitory activity. After affinity chromatography of the macrophage supernatants on a D-galactose column, the inhibitory activity was recovered in both the unbound (D-gal−) and bound (D-gal+) fractions, with MNCF being found in the D-gal+fraction. Further gel filtration of the latter on Superdex 75 yielded a single peak containing both activities. In a cytotoxicity assay, most of the TNF found in the crude supernatants was recovered in the D-gal−fraction. Furthermore, the incubation of the D-gal−fraction with anti-TNF-α plus anti-IL-8 antisera partially prevents its inhibitory effect on neutrophil migration, but had no effect on the D-gal+activity. Overall, these results suggest that the D-gal−inhibitory effect is partially mediated by TNF-α and IL-8, and that MNCF accounts for the inhibition of neutrophil migrationin vivoby the D-gal+fraction.

The aim of the study was to evaluate blood leukocyte counts in patients with uterine cervical neoplasia.Patients treated at a university hospital were reviewed retrospectively. Disease progression was monitored, beginning in 1990 to 2002, for at least 5 years. Blood count parameters included absolute leukocyte, neutrophil and lymphocyte counts, leukocytosis (white blood cells10³/μL), neutrophilia (neutrophils ≥ 70% of leukocytes), lymphopenia (lymphocytes ≤ 15% of leukocytes), and the neutrophil-lymphocyte ratio (NLR), categorized as less than 5 or 5 or greater.A total of 315 patients were enrolled: 182 (57.8%) with preinvasive neoplasia (cervical intraepithelial neoplasia [CIN] group), 95 (30.1%) with stages I to II (early group), and 38 patients (12.1%) with stages III to IV neoplasia (advanced group). Neutrophil and lymphocyte counts were elevated and reduced, respectively, at advanced stages compared with the CIN group (P0.05). Leukocytosis, neutrophilia, lymphopenia, and an NLR of 5 or greater were more frequent at advanced stages compared with the CIN and early-stage groups (P0.05). Moreover, neutrophilia was also significantly more frequent at early stage compared with the CIN group. The advanced group with neutrophilia had increased frequency of recidivism and metastasis than patients in the CIN group with neutrophilia (P0.05).Patients with advanced cervical cancer had significantly higher frequency of leukocyte alterations, although they may occur apart from the preinvasive stages. Overall, neutrophilia was the best indicator of cancer invasiveness.

PURPOSE: To investigate the effects of different conditions used during cardiopulmonary bypass (CPB) surgery on accompanying production of cytokine and nitric oxide (NO). METHODS: Patients undergoing CPB for the first time were prospectively enrolled and divided into two groups according to CPB parameters performed: i) normothermia (36.5-37°C) with blood cardioplegia (NB group, n=10) and ii) hypothermia (29-31°C) with crystalloid cardioplegia (HC group, n=10). Plasma samples obtained following intubation (baseline), during (5 and 30 min) and after (4 and 24 h) CPB were assayed for cytokines (ELISA) and NO metabolites (Griess reaction). RESULTS: Peak concentrations of interleukin (IL)-6 and IL-8 were reached at 4 h post CPB in both groups, but in the HC group those levels increased earlier and persisted for longer (24 h) compared to baseline (P < 0.05). IL-10 levels also increased at 4 h compared to baseline, but only significantly so in the HC group. NO metabolites were reduced in HC group at all time points compared to baseline (P < 0.05), while no significant differences were detected in the NB group. CONCLUSION: The association between increased systemic levels of cytokines and reduced NO production in the HC group suggests that different myocardial protection and/or perfusion temperature used during CPB may contribute to the extent of inflammatory response. OBJETIVO: Investigar a hipótese de que diferentes procedimentos durante o bypass cardiopulmonary (BCP) causa diferentes níveis de citocinas (IL) e óxido nítrico (NO). MÉTODOS: Pacientes submetidas a BCP foram prospectivamente estudadas de acordo com bypass realizado sobre normotermia (36.5-37°C) com cardioplegia sanguínea (NB group, n=10) or hipotermia (29-31°C) com cardioplegia cristalóide (HC group, n=10). Amostras de Plasma foram obtidas após a intubação (linha de base), durante (5, 30 min) e após (4, 24 h) o BCP. Os ensaios foram realizados através de ELISA (IL) e metabólitos do NO (reação de Griess). RESULTADOS: Os picos de concentrações de IL-6 and IL-8 estavam aumentados em 4 h pós BCP em ambos os grupos, mas no grupo HC estes níveis aumentaram precocemente e persistiram aumentadas por 24 h, comparado a linha de base (P

Neutrophil migration is a key event in the inflammatory response of any origin, and neutrophils may present antitumor activity. We investigated the number and function of circulating neutrophils obtained from patients with cervical neoplasia at different stages. Patients with preinvasive (cervical intraepithelial neoplasia, CIN3,n= 6) or microinvasive ([MICRO] stage IA1,n= 4) neoplasia were evaluated together as CIN/MICRO group (n= 10), while patients at stages II–IV were evaluated as invasive group (INV,n= 12). Healthy women served as controls (n= 15). For patients, analysis of leukogram on diagnosis showed a significant elevated neutrophil count in INV group compared with that in CIN/MICRO group. A neutrophil/lymphocyte ratio ≥5 was observed in 67% patients from INV group compared with only 10% from CIN/MICRO group. Neutrophil migration, assayed in a microchemotaxis chamber in response to the chemoattractants (10−7M)N-formyl-L-methionyl-l-leucyl-l-phenylalanine, leukotriene B4, or interleukin-8, was reduced in INV group than in controls or CIN/MICRO group. Surgical treatment in randomly selected patients from CIN/MICRO group (four CIN, one MICRO) increased neutrophil migration to all chemoattractants compared with time on diagnosis. The serum levels of nitric oxide (NO) metabolites, assayed by the Griess reaction, were higher in patients (n= 19) than in controls (n= 15), without differences related to tumor stage, but were reduced in patients after surgery compared with pretreatment (n= 10). Taken together, the results suggest that neutrophils play a role in the host response in cervical cancer. Soluble circulating mediators released by tumor cells, such as NO, could interfere early in the capacity of neutrophils to migrate, thus impairing host immune response.

The deregulation of inflammatory response during sepsis seems to reflect the overproduction of mediators, which suppress leukocyte functions. We investigated the intracellular mechanisms underlying the inability of neutrophils from severe septic patients to migrate toward chemoattractants. Patients with sepsis (52) and 15 volunteers were prospectively enrolled. Patients presented increased circulating levels of tumor necrosis factor-α, interferon-γ, interleukin (IL)–8, and IL-10. Patients showed reduced neutrophil chemotaxis to formyl-methionyl-leucyl-phenylalanine (FMLP), leukotriene B4 (LTB4) or IL-8. No difference in the transcription or expression of the IL-8 receptor, CXCR1, was detected in neutrophils from controls and patients. However, septic neutrophils failed to increase tyrosine phosphorylation and actin polymerization in response to IL-8 or LTB4. In contrast, septic neutrophils, similar to controls, showed phagocytic activity that induced actin polymerization and augmented phosphotyrosine content. Treatment of control neutrophils with cytokines and lipopolysaccharide (LPS) to mimic endogenous septic environment inhibited actin polymerization and tyrosine phosphorylation in response to IL-8 or LTB4. High expression of G protein–coupled receptor kinase 2 (GRK2) and GRK5 was detected in septic neutrophils and control cells treated with cytokines plus LPS. Data suggest that endogenous mediators produced during sepsis might continually activate circulating neutrophils, leading to GRK activation, which may induce neutrophil desensitization to chemoattractants.

Sepsis and septic shock continue to be a major cause of morbidity and mortality in critically ill patients. During the onset of sepsis, several inflammatory mediators, including cytokines, chemokines and nitric oxide are released systemically and mediate most of the pathophysiological events present in sepsis and septic shock, such as cardiovascular dysfunction and target-organ lesions. Polymorphonuclear leukocytes are critical effector cells during the inflammatory process and their migration to the infection focus is extremely important for the local control of bacterial growth and consequently for the prevention of bacterial dissemination. In experimental models and in human sepsis a profound failure of neutrophil migration to the infection focus is observed. It seems that the failure of neutrophil migration is dependent on toll-like receptor 4 (TLR4) and mediated by cytokines and chemokines, which induce the production of nitric oxide that inhibits neutrophil adhesion to venular endothelium and also the neutrophil chemotactic ability.

Sepsis is a systemic inflammatory response commonly caused by bacterial infection. We demonstrated that the outcome of sepsis induced by cecal ligation and puncture (CLP) correlates with the severity of the neutrophil migration failure towards infectious focus. Failure appears to be due to a decrease in the rolling and adhesion of neutrophil to endothelium cells. It seems that neutrophil migration impairment is mediated by the circulating inflammatory cytokines, such as TNF-alpha and IL-8, which induce the nitric oxide (NO) production systemically. It is supported by the fact that intravenous administration of these cytokines reduces the neutrophil migration induced by different inflammatory stimuli, and in severe sepsis the circulating concentrations of the cytokines and chemokines are significantly increased. Moreover, the neutrophil migration failure and the reduction in the rolling/adhesion were not observed in iNOS-/- mice and, aminoguanidine prevented this event. We also demonstrated that the failure of neutrophil migration is a Toll-4 receptor (TLR4) dependent mechanism, since it was not observed in TLR4 deficient mice. Furthermore, it was also observed that circulating neutrophils obtained from septic patients present failure of neutrophil chemotaxis toward fMLP, IL-8, and LTB4 and an increased in sera concentrations of NO3 and cytokines. In conclusion, we demonstrated that, in sepsis, failure of neutrophil migration is critical for the outcome and that NO is involved in the process.

Neutrophil migration is a key host event against infection. Chemotherapy may alter neutrophil function and favor increased risk of infection. Herein, we investigated the effect of chemotherapy on the migration capacity of circulating neutrophils obtained from breast cancer patients and mechanisms involved in this event. Breast cancer women (n=23) at disease stage I-III and healthy control women (n=25) were prospectively enrolled. No differences in the in vitro migratory responses towards the chemotactic stimuli N-formyl- L-methionyl- L-leucyl- L-phenylalanine (fMLP), leukotriene B(4) (LTB(4)) and interleukin (IL)-8 were observed in purified neutrophils from controls and patients, in a microchemotaxis chamber assay. However, the migration capacity evaluated upon chemotherapy (5-fluoruracil, adriamycin and cyclophosphamide, 21-day intervals between cycles, total leukocyte count >/=2,000/mm(3)), on the day immediately before the beginning of the sixth cycle, showed that patient neutrophils (n=14) failed to migrate in response to fMLP compared to response observed upon diagnosis. Considering patients (n=8) with documented bacterial infection between cycles, the number of migrated neutrophils (mean+/-SD) compared to response at diagnosis was markedly reduced upon chemotherapy to either fMLP (30.1+/-8.26 vs. 2.81+/-1.28) or LTB(4) (15.72+/-4.8 vs. 2.8+/-1.64) stimuli respectively. Treatment of control neutrophils with sera of chemotherapy-treated patients with infective episodes, to test for the presence of circulating immunosuppressive factors, significantly reduced the migratory capacity of healthy neutrophils to fMLP, LTB(4) and IL-8, in a dose-dependent way. But no significant differences were found in the serum levels of nitric oxide (NO) metabolites, tumor necrosis factor (TNF)-alpha, IL-6, IL-8 and IL-10 collected at the same time as the collection of blood for neutrophil migration experiments. In conclusion, breast cancer patients showed suppressed neutrophil migratory response upon chemotherapy, accompanied by bacterial infection episodes. Circulating factors are involved, at least partially, in the inhibitory mechanism on neutrophil migration.

Aims and Background Cells and soluble mediators obtained from tumor effusions are useful in evaluating the tumor microenvironment. Our aim was to examine cytologically and to quantify the leukocyte infiltrate, nitric oxide, cytokines and tumor markers in the intracystic fluid from patients with a cystic adnexal mass, for a possible differentiation between benign and malignant findings. Methods and Study Design Sixty-six women who had their cystic fluids collected were prospectively divided into benign tumor (22, 33.3%), malignant tumor (10, 15.2%) or other gynecological alterations (34, 51.5%). Cytology, total and differential leukocyte counts were determined by light microscopy. Tumor markers, cytokines and nitric oxide were assayed in the supernatants using the Immutile system, ELISA and Griess reaction, respectively. Results The sensitivity and specificity of the cytological analysis was 66.7% and 97.7%, respectively. The levels of CA 19.9, CA 15.3, α-fetoprotein, carcinoembryonic antigen, progesterone and β-HCG were significantly higher in the benign and/or malignant group than in the other gynecological alterations. Also, the local concentrations of CA 15.3 and β-HCG were significantly higher in malignant than in benign tumors. In malignant tumors, increased leukocyte counts and higher concentrations of IL-6, IL-10 and nitric oxide were detected than in benign tumors or other gynecological alterations. Conclusions In malignant tumors, the microenvironment could be differentiated from benign tumors or other gynecological alterations by cystic fluid analysis.

AIMS: This brief review focuses on the current understanding of the complex relationship of tumor-associated mononuclear cells (TAMs) with neoplastic cells, summarizing their immunological efficiency, cytokine profile and production of nitric oxide (NO) in the tumor microenvironment, with current insights on how this might affect tumor growth. DATA SOURCE: Data was obtained through Medline from articles indexed during the last 10 years. The main key words used in the research were: cancer, ovarian cancer, cytokine, nitric oxide (NO), mononuclear cell, lymphocyte, macrophage. SELECTION OF STUDIES AND DATA COLLECTION: 30 studies were reviewed, which contained data regarding the production of cytokines and NO by TAMs or malignant cells, and tried to establish a correlation between these mediators and tumor growth, especially in ovarian carcinoma. DATA SUMMARY: TAMs consist mainly of macrophages and T lymphocytes which present lower proliferative indices and cytotoxicity compared to autologous blood monocytes, although they are able to release various cytokines. The profile of cytokine expression could help to explain both the immunological impairment observed in patients with advanced carcinoma diseases and the potential of TAMs to exert antitumor activity, which makes these cells an attractive target for therapeutic intervention. NO is also produced in the tumor microenvironment. Several reports in animals suggest a tumoricidal role for NO, but in human tumors its role has not been well-established and may change during tumor progression. OBJETIVOS: Analisar a complexa relação entre as células mononucleares associadas ao tumor (TAMs) e as células neoplásicas, sendo resumidos sua competência imunológica, perfil da produção de citocinas e de óxido nítrico (NO) no microambiente tumoral, com aspectos atuais de como a produção desses mediadores poderia afetar o crescimento tumoral. ORIGEM DOS DADOS: Os dados foram obtidos de artigos indexados através da rede Medline durante os últimos 10 anos. As palavras-chave utilizadas na pesquisa foram basicamente: câncer, carcinoma ovariano, citocina, óxido nítrico, células mononucleares, linfócito, macrófago. SELEÇÃO DOS ESTUDOS E COLETA DOS DADOS: Foram revistos 30 trabalhos contendo dados relacionados à produção de citocinas e NO por TAMs e/ou células neoplásicas e que tentaram estabelecer uma correlação entre a produção desses mediadores e o crescimento tumoral, particularmente no carcinoma ovariano. RESUMO DOS DADOS: As TAMs consistem principalmente de macrófagos e linfócitos T que apresentam baixo índice proliferativo e baixa citotoxicidade comparada aos monócitos autólogos do sangue, embora sejam capazes de liberar várias citocinas. O perfil da expressão de citocinas poderia ajudar a explicar tanto a deficiência imunológica observada em pacientes com carcinoma em fase avançada como também o potencial das TAMs em exercer atividade antitumoral, o que torna essas células um alvo para intervenção terapêutica. Além das citocinas, o NO também é produzido no microambiente tumoral. Várias observações em animais sugerem um papel tumoricida para o NO, mas em tumores humanos seu papel não foi estabelecido podendo ser alterado durante a progressão do tumor.

A 25-year-old white woman with a vaginal invasive epidermal carcinoma was treated with interferon-α 2b (3,000,000 U intralesional, every two days for a total of 18 applications). Follow-up with Papanicolaou and colposcopy showed complete regression of the vaginal lesion. After three years the patient got pregnant. The prenatal course was uneventful and a vaginal delivery was performed. She is currently in follow-up without any signs of recurrence.

Background There is a direct correlation between glycemic load and the risk of developing many malignant neoplasms. Aims The aim of this study was to determine the plasma glucose levels in women with cervical cancer. Methods The study included 177 women with anatomopathologically diagnosed uterine cervical cancer (stages 0–IV) treated between 1980 and 2008 at the Gynecology and Obstetrics outpatient service of the UFTM, Brazil. The plasma glucose levels of all patients were assayed at the time of diagnosis and correlated with tumor staging. Results We statistically compared the plasma glucose levels of group 1 (cervical intraepithelial neoplasia 2–3), group 2 (stage I–II), group 3 (stage III–IV), and group 4 (control group: leiomyomas). Patient groups with poor prognosis (groups 2 and 3) showed significantly higher plasma glucose levels ( P < 0.05) than those with less aggressive lesions (group 1). Plasma glucose levels were significantly higher in groups 2 and 3 than in group 4 ( P < 0.05). The comparison of number of patients with plasma glucose level >90 mg/dl showed CIN versus I/II: P = 0.0753; OR = 2.018; (95% CI: 0.9236 to 4.410) and CIN versus III/IV: P = 0.0975; OR = 2.400; (95% CI: 0.8335 to 6.911). Conclusion We observed an association between high plasma glucose levels and cervical cancer cases with poor prognoses. Plasma glucose tests should be routinely used as additional prognostic parameters in patients with cervical neoplasias.

1. A neutrophil recruitment inhibitory factor (NRIF) recovered from the crude supernatant of lipopolysaccharide (LPS)-stimulated macrophages inhibited neutrophil migration following both intratracheal and intravenous administration of LPS, but did not alter the pattern of leukopenia/leucocytosis induced by intravenous LPS. 2. The correlation between airway infiltration by inflammatory cells and hyperreactivity in lungs from actively sensitized and challenged guinea-pigs was investigated by use of NRIF. 3. Increased eosinophil counts were found in the bronchoalveolar lavage fluid from guinea-pigs sensitized with 10 micrograms ovalbumin and challenged at day 14 by the intranasal administration of the antigen. The increase was evident 5 h after challenge and persisted at 24 h. Neutrophil numbers were also increased at this time. Pretreatment with NRIF suppressed the leucocyte increase in the bronchoalveolar lavage fluid. 4. Bronchoconstriction and histamine release induced by 3 ng PAF injected into the isolated lungs were increased in challenged guinea-pigs as compared to sensitized but unchallenged controls. Pretreatment of the animals with NRIF did not interfere with this response, but significantly reduced the bronchoconstriction induced by ovalbumin injection. 5. Even though the increased number of inflammatory cells in bronchoalveolar lavage and airway hyperresponsiveness were concomitant, NRIF inhibited cellular infiltration but failed to alter airway hyperreactivity to PAF, demonstrating that these events may occur independently. Conversely, the inhibition of antigen-induced bronchoconstriction by NRIF suggests that this response is dependent upon the emigration of granulocytes.

Inhibitory effect upon neutrophil migration to the inflammatory focus was previously detected in the cell-free incubation fluid of lipopolysaccharide (LPS)-stimulated macrophage monolayers. In the present study we showed that the neutrophil recruitment inhibitory activity from this supernatant was mainly detected in a fraction (P2) obtained by gel filtration chromatography on Sephacryl S-300. P2 fraction was able to inhibit ‘in vivo’ neutrophil emigration induced by different inflammatory stimuli, but it did not affect ‘in vitro’ neutrophil chemotaxis induced by FMLP. When injected intravenously, P2 inhibited oedema induced by carrageenin or immunological stimulus but not the oedema induced by dextran, thus affecting cell-dependent inflammatory responses. It was observed that P2 also induced neutrophil migration when injected locally in peritoneal cavities. This activity was significantly reduced by pretreatment of the animals with dexamethasone. Cytokines, such as IL-8 and TNF-α that are known to exhibit inhibitory effect upon neutrophil migration, were not detected in P2 fraction by highly sensitive assays. Overall the results suggest the existence of a novel cytokine exhibiting ‘in vivo’ neutrophil inhibitory activity, referred as NRIF.