Stromal IL2 is related to the neutrophil/lymphocyte ratio in epithelial ovarian cancer.

INTRODUCTION: There is a need for the development of new biomarkers for diagnosis and prognosis of ovarian cancer, which can ideally serve as targets for new therapeutic modalities and individualization of treatment. The objectives of this study were to determine the prognostic significance of the neutrophil/lymphocyte ratio in the peripheral blood of patients with ovarian cancer and tumor staging, and to associate this marker with the immune expression of a panel of cytokines. METHODS: The study included 24 patients with malignant ovarian neoplasia treated at the Pelvic Mass Outpatient Clinic of the Clinical Hospital of the Federal University of Triângulo Mineiro. The neutrophil/lymphocyte ratio was calculated as the absolute number of neutrophils divided by the absolute number of lymphocytes. Expression of the cytokines was evaluated by the immunohistochemistry method (IL2, IL5, IL6, IL8, IL10 and TNF-R1). Fisher's statistical test was used for the comparisons of immunohistochemical expression with the neutrophil/lymphocyte ratio, and the unpaired T-Test was used in the analysis of the association of this ratio with tumor staging. RESULTS: A neutrophil/lymphocyte ratio > 2.6 was significantly higher in the more advanced stages (II-IV) of malignant ovarian neoplasia (p = 0.0098). In addition, this ratio > 2.6 was associated with IL2 stromal immunostaining (1-3) (p = 0.0472). CONCLUSION: Stromal IL-2 is associated with higher a neutrophil/lymphocyte ratio, suggesting a worse prognosis in ovarian cancer and its role in tumor immunology; a neutrophil/lymphocyte ratio > 2.6 is associated with more advanced stages of malignant ovarian neoplasia.

Role of Intracystic Cytokines and Nitric Oxide in Ovarian Neoplasms.

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.

Parameters of blood count and tumor markers: a retrospective analysis and relation to prognostic factors in ovarian cancer.

PURPOSE OF INVESTIGATION: The aims of study were to evaluate potential prognostic laboratory factors in ovarian cancer (blood count parameters and tumor markers) and to relate these parameters with prognostic factors. MATERIALS AND METHODS: The authors evaluated patients that underwent surgical treatment and with confirmed histopathologic diagnosis of ovarian cancer. Age, FIGO stage, type of surgery, serum levels of tumor markers, parameters of blood count, disease-free and overall survival were recorded. Mann-Whitney test was performed. The significance level was less than 0.05. RESULTS: Higher levels of CA 125, CA 15.3, and platelets were found in the group with Stage hII/I, since hemoglobin levels were higher in stage I/II (p < 0.05). CEA levels were higher in the group of non-serous neoplasms (p < 0.05). Higher levels of CA125, CAIl5.3 and platelets were seen in the group histological grade 2/3 (p < 0.05). CONCLUSION: CA 125, CA 15.3, hemoglobin, and platelets can be related prognostic factors in ovarian cancer.

The immune response in malignant ovarian neoplasms.

The objective of this study was to review studies that have investigated the immune response in the presence of a malignant ovarian neoplasia. A review of the literature was performed to identify studies of malignant ovarian neoplasia, particularly studies that addressed the potential for cytokines, nitric oxide, and lymphocytes to mediate an immune response against ovarian cancer. Certain subsets of tumor-infiltrating leukocytes and/or tumor-associated leukocytes have been found to correlate with an improved disease prognosis, while other lymphocyte subsets (such as CD3+/CD4+/CD25+ T cells) have been associated with a poor prognosis. These data suggest that cytokines can have a protective role, or can promote an immune system defense against a cancer. In particular, certain cytokines (e.g., IL 8, IL 10) represent attractive candidates for the development of new diagnostic, prognostic, and therapeutic strategies for the treatment of ovarian cancer.

The importance of alpha/beta (alpha/13) interferon receptors and signaling pathways for the treatment of cervical intraepithelial neoplasias.

INTRODUCTION: Immunotherapies have been effective in treating various forms of cancer, including cervical intraepithelial neoplasias (CINs) predominantly caused by human papilloma virus (HPV). DEVELOPMENT: To establish persistent infections in stratified epithelia, HPV induces proliferative lesions. Viral gene products are able to change gene expression and cellular proteins. Interferons (IFNs) are inducible glycoproteins that have immunomodulatory, antiviral, antiproliferative, and antiangiogenic effects. In particular, interferon-alpha (IFN-alpha) has been shown to inhibit the development and progression of cervical cancer. In this review, actions of interferons alpha/beta (alpha/beta), including their receptors and signaling pathways, are described, as well as their clinical importance in the immune response against cervical lesions. CONCLUSION: The interaction of IFN-alpha/beta with its receptor results in a series of phosphorylation events. These mechanisms can be ineffective in IFN response, then it can also compromise the therapeutic effects of immunotherapy.

GTPases Rho distribution in intraepithelial and invasive neoplasias of the uterine cervix.

PURPOSE OF INVESTIGATION: To evaluate the distribution of GTPases RhoA, RhoB, and Cdc42 in cervical intraepithelial neoplasias (CIN) and invasive neoplasias of the uterine cervix. MATERIALS AND METHODS: samples of neoplastic lesions of the uterine cervix of 44 patients were classified in: CIN I (n = 10), CIN II (n = 10), CIN III (n = 09), and invasive carcinoma (n = 15). Antibodies anti-RhoA, anti-RhoB, and anti-Cdc42 were used and staining was classified as: negative, mild, moderate, and intense positive. RESULTS: When compared with dysplastic cells, superficial cells showed: higher expression of RhoB in CIN I (p = 0.0018), and lower expression of Cdc42 in CIN I (p = 0.0225). The authors observed higher expression of RhoA (p = 0.0002) and RhoB (p = 0.0046) in CIN dysplastic cells when compared with invasive carcinoma cells. CONCLUSIONS: GTPases Rho may be involved with the regulation of biological processes, important to the progression of cervical neoplasias. Probably, RhoA is important for maintenance of cell differentiation and RhoB protects cells from malignant cervical neoplasia.

An evaluation of immune system cell infiltrate in the cervical stroma of patients with grade III cervical intraepithelial neoplasia after treatment with intralesional alpha-2B interferon.

The aim of this study was to characterize infiltrating immune cells in cervical stroma biopsy samples from patients diagnosed with cervical intraepithelial neoplasias (CINs) who were treated with IFN-alpha 2b. The authors studied 13 volunteers who were diagnosed with Cervical intraepithelial neoplasia CIN II or III and who received intra-lesional treatment with IFN-alpha 2b. They collected pre- and post-treatment biopsies from each patient. They also examined the slides under a common optical microscope with a X400 lens for biopsy sample sections that were labeled with immunohistochemistry for T lymphocyte, B lymphocyte, natural killer cell, macrophage, iNOS, and perforin markers. The presence of immune response cells in the lesion was observed after treatment with intralesional IFN-alpha 2b in patients with CIN II/III changes, a reduction in CD4+ and CD8+ T lymphocyte infiltration in the women who responded well to treatment. However, there was a significant increase in these markers in samples from women who did not respond to treatment. Nonetheless, immunotherapy with IFN-alpha 2b administered intralesionally in patients with CIN II/III yields favorable results in patients who do not smoke.

Frequency of endometriosis and adenomyosis in patients with leiomyomas, gynecologic premalignant, and malignant neoplasias.

OBJECTIVE: This study investigated the association between gynecological neoplasms, endometriosis, and adenomyosis in women who underwent surgical treatment for gynecological cancer and uterine leiomyoma during reproductive years or after menopause. MATERIALS AND METHODS: Information was collected from patient records from the Hospital's database from 1985 to 2007. The study included 502 women, of which 375 were premenopausal and 132 were postmenopausal. RESULTS: A significant association was observed between the occurrence of adenomyosis in cancer in women with four or more pregnancies, and in women aged over 40 years (p < 0.0001). The frequency of adenomyosis was significantly higher than the frequency of endometriosis for cancer in two sites (p = 0.0419) or for leiomyomas (p < 0.0001). CONCLUSION: Therefore adenomyosis is more frequently found than endometriosis in women with leiomyomas or cancer in two sites in premenopausal women, and clinicians need to be aware of patients with adenomyosis and the risk of cancer.

Loss of heterozygosity in the fragile histidine triad (FHIT) locus and expression analysis of FHIT protein in patients with breast disorders.

PURPOSE OF INVESTIGATION: The fragile histidine triad (FHIT) gene is a tumor suppressor frequently inactivated in various types of tumors. The authors evaluated the occurrence of loss of heterozygosity (LOH) in the FHIT locus and FHIT protein changes in breast tissue. MATERIALS AND METHODS: Blood and breast tissue samples were obtained from 35 women with mammary disorders. The occurrence of LOH in FHIT locus was assayed by polymerase chain reaction (PCR), and the results obtained from blood and breast tissues from each patient were compared. FHIT protein expression was evaluated by immunohistochemistry. RESULTS: LOH in the FHIT gene occurred in 48.6% (17/35) of patients with mammary disorder. Among patients with malignant breast disorders, 59.1% (13/22) presented LOH in the FHIT gene in comparison with patients with benign breast lumps, in which the LOH was observed in 30.8% (4/13) of women, suggesting that changes in this gene occur prior to the process of mammary carcinogenesis. The changes in the locus of the FHIT gene occur with greater frequency in the coded region of the gene, principally near exons 5 and 8, where the FRA3B site and the histidine triad respectively are found. Changes in FHIT did not modify protein expression. The association between menopause and LOH in the FHIT gene was evident. CONCLUSIONS: LOH in the FHIT gene may be related to menopause in women with breast disorders.

IL-17 and IL-22 serum cytokine levels in patients with squamous intraepithelial lesion and invasive cervical carcinoma.

PURPOSE: Several works correlate the synthesis of IL-17 and IL-22 with tumoral progression. However, there are no studies of these cytokines on cervical cancer. The authors studied the concentration of IL-17 and IL-22 on serum obtained from patients with different grades of squamous intraepithelial lesions (SILs) and invasive cervical carcinoma. MATERIALS AND METHODS: Eighty-one women were enrolled in this study, including 23 in the healthy control (with no history of infection or lesions), 11 with low-grade squamous intraepithelial lesion (LSIL), 36 with high-grade squamous intraepithelial lesion (HSIL), and 11 who were diagnosed anatomo-pathologically with invasive carcinoma. Levels of the IL-17 and IL-22 cytokines were measured in the serum obtained from these patients using the enzyme-linked immunoabsorbent assay (ELISA) method. RESULTS: IL-17 and IL-22 displayed a similar pattern of results, with an increase in the serum level of LSIL patients, when compared with serum from HSIL patients (respectively, mean- pg/ml: 22.50 vs 12.20, and 168.2 vs 61.48, p < 0.05). CONCLUSION: Concentrations of IL-17 and IL-22 in the peripheral blood of patients with LSIL were increased compared to HSIL patients.

Frequency of recurrence after surgical treatment of cervical intraepithelial neoplasia grade 1-3.

PURPOSE OF INVESTIGATION: The objective was to demonstrate the frequency of invasive cervical cancer or recurrent CIN in patients treated by a previous diagnosis of CIN 1-3. METHODS: We analyzed 1,397 records colpocytologic and medical records. Recurrence of CIN or invasive neoplasia of the cervix after treatment of CIN was assessed. The chi-square test was used for statistical analysis (significance level set at less than 0.05). RESULTS: We obtained 696 CIN 1, 244 CIN 2, 451 CIN 3, and six squamous carcinoma. Regarding patients who relapsed, there were 6/690 (0.9%) patients had an initial diagnosis of CIN 1, 8/236 (3.4%) CIN 2 and 21/430 (4.9%) CIN 3 (p < 0.0001). Comparing the frequency of relapse among each group, we found: CIN 1 vs CIN 2: p = 0.0073; CIN 1 vs CIN 3: p < 0.0001; CIN 2 vs CIN 3: p = 0.38. CONCLUSION: Although the number of relapses when comparing CIN 2 and CIN 3 were not significant, the data suggest that CIN 2 has lower recurrence rates, so these patients require more conservative treatment if a desire of future pregnancy is expressed.

Immune response and immunotherapy in intraepithelial and invasive lesions of the uterine cervix.

Infection with the human papillomavirus virus (HPV) induces innate and acquired immune responses in the cervical stroma, which are a delicate, balanced and generally unpredictable immunological defense. Because of the immunological breaks that the HPV virus causes, eradication of infected cells does not occur, potentially leading to development of intraepithelial and invasive lesions. Advances in our understanding of the immune system and in the definition of antigens in tumor cells has led to many new treatment strategies. As a result, immunotherapy has the potential to be the most specific treatment for tumors, and one that requires elaboration. Recently, immunotherapy with interferon and dendritc cells has been used on intrapepithelial and invasive cervical lesions with promising results.

Immunotherapy with dendritic cells for gynecological neoplasias: a new therapeutic approach?

The immune system consists of a complex collection of mediators and cells that act in a coordinated way to eliminate neoplastic cells. One of immunotherapy's promises is the development of cellular vaccines, or more specifically, vaccines with dendritic cells. However, we still have a lot left to study and learn, since we already know that patients with tumors of the same histological grade can have completely different behaviors when given the same immunological stimulus. We believe that antitumor immunotherapy will lead to a personalized vaccine, since the scheme of treatment, the stimuli and the dosages need to be tailored to each patient.

Myofibroblastic inflammatory breast tumor and fibrosarcoma: a case report.

Myofibroblastic inflammatory tumors can occur in any human tissue. They are benign lesions and more common in young patients. We describe the case of a 41-year-old patient with a nodule measuring 2.5 x 1.5 cm in the superior lateral quadrant of the left breast. The pathological examination showed proliferation of the spindle cells in dense fascicles interspersed by colagen among frequent plasmocytes, lymphocytes and eosinophils, associated with scarce typical mitosis. In the same site ten years before the patient had undergone a nodulectomy and the diagnosis was a benign filloid tumor. The patient returned with a nodule in the surgical scar at follow-up and the incisional biopsy showed a malignant filloid tumor with a sarcomatous component. A mastectomy was performed.

Immunological evaluation of vaginal secretion in patients with high-grade cervical intraepithelial neoplasia treated with intralesional interferon alpha-2b.

INTRODUCTION: Conservative treatment with intralesional interferon (IFN) is a therapeutic option for cervical intraepithelial neoplasia (CIN) patients of childbearing age. MATERIALS AND METHODS: The study group was made up of patients diagnosed with a high-grade lesion and treated with intralesional human recombinant IFNalpha-2b. Vaginal secretion was collected during IFNalpha-2b treatment for analysis of cytokines and viral load. RESULTS: The initial histology diagnostic was 62.5% (n = 5) with CIN 2 and 37.5% (n = 3) with CIN 3. In terms of clinical evaluation and anatomopathology, 6.5% (n = 5) had a good clinical response, while 37.5% (n = 3) had therapeutic failure. All the patients with therapeutic failure were smokers. Interleukin 6 and tumor necrosis factor-alpha concentrations were raised at the sixth application for the patient group who failed to respond to therapy compared to the responsive group (p = 0.0357). Patients with a good response exhibited a reduction in human papillomavirus viral load (p = 0.03). CONCLUSIONS: Patients that had a good response had lower concentrations of inflammatory cytokines than did non-responders.

Expression of cytokines in cervical stroma in patients with high-grade cervical intraepithelial neoplasia after treatment with intralesional interferon alpha-2b.

Conservative treatment with interferons (IFNs) has the advantage of preserving reproductive capacity in patients with grade 2 or 3 cervical intraepithelial neoplasia (CIN). The objective of this work was to study patients with high-grade CIN treated with intralesional IFN alpha-2b and to analyze the expression of Th1, Th2 and Th3 cytokines in cervical stroma. We observed that patients with a satisfactory response (60%) to treatment with IFN alpha-2b expressed more Th1 (IFN-gamma TNF-alpha, IL-2) cytokines, with a significant reduction in the viral load of high-risk human papillomavirus (p = 0.0313). All patients with therapeutic failure were smokers and had higher expression of cytokines Th2 (IL-4) or Th3 (TGF-beta2 and TGF-beta3).

The clinical use of type 1 interferon in gynecology.

Interferons were initially described in terms of their role in blocking viral replication. They are important cytokines that act on various aspects of cell physiology. Importantly, they can affect cell proliferation or induce the differentiation of neoplastic cells. The exact way in which the interferon complex (IFN) acts on tumours is still unknown, although their use in clinical practice has been widely recommended, especially with tumours that are resistant to conventional treatments, or in situations where surgical removal might lead to a loss of organ function. IFN can be employed as a treatment for various chronic diseases, including tumours. Indeed interferon cytokines are the therapy of choice in certain situations. However, one of the difficulties yet to be overcome is the need for frequent administrations of the drug. We believe that the development of new formulations is needed to match the demand for its use in oncology treatment.