Molecular and pathophysiological relationship between obesity and chronic inflammation in the manifestation of metabolic dysfunctions and their inflammation­mediating treatment options (Review).

Obesity reaches up to epidemic proportions globally and increases the risk for a wide spectrum of co­morbidities, including type­2 diabetes mellitus (T2DM), hypertension, dyslipidemia, cardiovascular diseases, non­alcoholic fatty liver disease, kidney diseases, respiratory disorders, sleep apnea, musculoskeletal disorders and osteoarthritis, subfertility, psychosocial problems and certain types of cancers. The underlying inflammatory mechanisms interconnecting obesity with metabolic dysfunction are not completely understood. Increased adiposity promotes pro­inflammatory polarization of macrophages toward the M1 phenotype, in adipose tissue (AT), with subsequent increased production of pro­inflammatory cytokines and adipokines, inducing therefore an overall, systemic, low­grade inflammation, which contributes to metabolic syndrome (MetS), insulin resistance (IR) and T2DM. Targeting inflammatory mediators could be alternative therapies to treat obesity, but their safety and efficacy remains to be studied further and confirmed in future clinical trials. The present review highlights the molecular and pathophysiological mechanisms by which the chronic low­grade inflammation in AT and the production of reactive oxygen species lead to MetS, IR and T2DM. In addition, focus is given on the role of anti­inflammatory agents, in the resolution of chronic inflammation, through the blockade of chemotactic factors, such as monocytes chemotractant protein­1, and/or the blockade of pro­inflammatory mediators, such as IL­1ß, TNF­α, visfatin, and plasminogen activator inhibitor­1, and/or the increased synthesis of adipokines, such as adiponectin and apelin, in obesity­associated metabolic dysfunction.

Primary vulvar leiomyosarcoma localized in the Bartholin's gland area: A case report and review.

Vulvar sarcomas located in the Bartholin's gland area are extremely uncommon mesenchymal vulvar tumors. These neoplasms can be mistaken as Bartholin' gland benign lesions such as cysts or abscesses, leading to a delay in the diagnosis of underlying malignancy. Currently, only a few cases of these aggressive cancers have been reported in the literature. A 42-year-old female patient without any previous complaint presented to Obstetrics and Gynecology Department of 'G. Chaztikosta' General Hospital due to a vulvar lump in the area of the left Bartholin's gland with a 6-month history of progressive swelling. Pelvic examination showed a solid mass of 6.5-cm in maximum diameter, localized in the left Bartholin's gland. The patient underwent wide local excision and histopathological examination of hematoxylin and eosin-stained sections indicated intersecting fascicles of spindle cells, with moderate to severe atypia. The number of mitoses was up to 8 per 10 high power fields. The neoplasm to its greatest extent was circumscribed and in places had an invasive growth pattern. Tumoral necrosis was not seen. Involved Bartholin' gland by the tumor was identified. The tumor extended focally to the surgical margin. The neoplastic cells showed positive staining for smooth muscle actin, desmin, HHF35, caldesmon, vimentin and estrogen and progesterone receptors. Immunohistochemistry was negative for S100, myoglobulin, keratin 116, CD117, CD34 and CD31. The patient denied further surgery or/and local radiotherapy, although the mass was >5-cm and a focally infiltrative surgical margin was found. During the close follow-up, no local recurrences or metastases were observed 53 months after surgery. In conclusion, wide local tumor excision with free surgical margins is a good option of surgery for vulvar leiomyosarcomas. In recurrences, a new extensive surgical resection of the lesion and radiotherapy are suggested. Ipsilateral lympadenectomy is indicated when there is a pathologic lymph node. Chemotherapy is provided in cases of distal metastases.

Immunohistochemical expression of insulin-like growth factor-1Ec in primary endometrial carcinoma: Association with PTEN, p53 and survivin expression.

Chronic hyperinsulinemia due to insulin resistance and elevated levels of insulin-like growth factor (IGF)-1 and IGF-2 are suggestive of a significantly higher risk of endometrial carcinoma. There is a wealth of evidence showing differential expression of IGF-1 isoforms in various types of cancer. In the present study, 99 archived endometrial carcinoma tissue sections were retrospectively assessed by immunohistochemistry for IGF-1Ec isoform expression. Expression of IGF-1Ec was also assessed in nine cases of non-neoplastic endometrial tissue adjacent to the tumor, in 30 cases with normal endometrium and in 30 cases with endometrial hyperplasia. Furthermore, the association between IGF-1Ec and the concurrent expression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), p53 or survivin was assessed, as well as their combined expression in association with clinicopathological variables. In endometrial carcinoma, IGF-1Ec expression was high in non-endometrioid carcinoma (serous papillary or clear cell carcinoma) compared with that in endometrioid adenocarcinoma. IGF-1Ec expression was also high in the presence of tumoral necrosis. Furthermore, there was a significant correlation between the histological differentiation and the sum of staining intensity and the number of IGF-1Ec immunopositive cells in endometrial carcinoma. There was a moderate negative correlation between co-expression of IGF-1Ec and PTEN, for both the number of immunopositive cells (P=0.006, ρ=-0.343) and the sum of staining (scores and intensity; P=0.006, ρ=-0.343). Furthermore, there was a positive correlation between the sum of staining (scores and intensity) and co-expression of IGF-1Ec and survivin (P=0.043, ρ=0.225). However, there was no association between concomitant expression of IGF-1Ec and p53. These results emphasized the importance of IGF-1Ec expression during development of non-estrogen dependent endometrial adenocarcinoma. IGF-1Ec and PTEN may function opposingly during endometrial carcinogenesis. By contrast, IGF-1Ec and survivin may share common molecular pathways and may promote, in parallel, tumoral development.

Expression of anti-apoptotic protein survivin in human endometrial carcinoma: Clinical and pathological associations as a separate factor and in combination with concomitant PTEN and p53 expression.

Endometrial carcinoma is one of the most common types of gynecological cancer. A total of 99 cases of primary endometrial carcinoma were investigated for survivin expression by immunohistochemistry. Furthermore, the association between concomitant survivin, PTEN and p53 expression, and clinicopathological parameters was examined. Immunopositivity for survivin was identified in 88% of cases. Concomitant survivin, PTEN and p53 expression (staining scores and intensity) was observed in 60% of endometrial adenocarcinomas. A significant association was identified between the sum of staining intensity and scores of survivin immunopositive cells, and patient age (P=0.028), histological grade (P<0.001), clinical stage (P=0.018) and fallopian tube and/or ovarian invasion (P=0.039). A negative tendency for correlation was observed between surivin and PTEN immunostaining scores (P=0.062; ρ=-0.238). Specimens with high scores of survivin expression tended to show decreased scores of PTEN immunostaining, and vice versa. However, in circumstances with an increased co-expression of survivin and PTEN, a statistically significant association with histological types was observed (P=0.020). A statistically significant positive correlation was identified between survivin and p53 sum co-expression (P=0.008; ρ=0.300). Furthermore, a significant association was identified between survivin and p53 concomitant sum expression and age of patients (P=0.001), histological type (P=0.020), clinical stage (P=0.037), histological differentiation (P=0.001) and presence of fallopian tube and/or ovarian invasion (P=0.026). The present findings suggested that survivin may be an indicator of unfavorable outcome in older patients with endometrial carcinoma, in specific circumstances that are dependent on different concomitant genetic alterations and different combinations of molecular signaling pathways. Increased expression levels of survivin and PTEN may serve a role in the development of more aggressive endometrial carcinoma during their interaction. In addition, protein expression levels of survivin and p53 are positively correlated and may share a common molecular pathway to promote endometrial carcinogenesis. These findings provided evidence that survivin and p53 combined may be useful markers for the prediction of tumor behavior and prognosis.

Expression of p53 and PTEN in human primary endometrial carcinomas: Clinicopathological and immunohistochemical analysis and study of their concomitant expression.

Endometrial carcinoma is a common malignancy of the female genital tract. Alterations in the expression levels of various oncogenes and tumor suppressor genes serve important roles in the carcinogenesis and biological behavior of endometrial carcinoma. The aim of the present study was to evaluate the combination and individual expression of p53 and phosphatase and tensin homolog (PTEN) protein in human endometrial carcinoma. In addition, the correlation of these proteins with clinicopathological parameters was also assessed. Retrospective immunohistochemical analysis of the expression of p53 and PTEN tumor suppressor proteins was conducted in 99 women with endometrial carcinoma. The overall rate of p53 and PTEN positivity was 89 and 77%, respectively, according to the sum of stain intensity and scores of immunopositive cells. The sum of p53 positivity correlated strongly with PTEN expression (ρ=0.256; P=0.044). The concomitant sum of p53 and PTEN expression was identified in 45% of patients with endometrial adenocarcinoma. Notably, the sum of the immunohistochemical expression of p53 was significantly correlated with patient age (P=0.037), histologic type (P=0.008), histologic grade (P=0.002) and fallopian and/or ovarian invasion (P=0.014). Furthermore, PTEN expression was associated with myometrial invasion (ρ=-0.377; P=0.002) and clinical stage (P=0.019). In addition, concomitant p53 and PTEN expression was correlated with patient age (P=0.008) and histologic differentiation (P=0.028). The findings indicated a correlation between the expression of p53 and PTEN in endometrial adenocarcinoma, which suggested an intrinsic association between expression levels of these tumor suppressor genes. The study also suggested that concomitant p53 and PTEN expression contributed in characterizing the tumor behavior of endometrial carcinoma. Taken together, the present study suggested the combined expression of p53 and PTEN in the development of high-grade endometrial carcinoma in older patients. In addition, the findings indicated activation of different molecular pathways in the tumor progression between low-grade and high-grade endometrial carcinomas.