Influence of uterine manipulator on oncological outcome in minimally invasive surgery of endometrial cancer: A systematic review and meta-analysis

Aim: The endoscopic approach for early-stage endometrial cancer (EC) treatment is considered gold standard. Some authors expressed their concern regarding uterine manipulator (UM) as a risk factor for tumor spillage and dissemination allowing peritoneal or lympho-vascular spaces invasion (LVSI). This meta-analysis aimed to evaluate the effect of UM on the presence of LVSI, recurrence rate and presence of atypical or malignant peritoneal cytology in patients with endometrial cancer. Methods: We searched electronic databases including PubMed, MEDLINE, Embase, Scopus, EBSCO, Google Scholar, and ClinicalTrials.gov. The pooled results were used to evaluate the association between the use of UM and oncological outcomes. This systematic review was reported according to PRISMA statement 2020. Statistical meta-analysis was performed using Review Manager software. Results: This systematic review included 18 studies (3 prospective studies, 13 retrospective studies, and 2 RCT). The pooled results showed no significant difference (RR: 0.86, 95% CI, 0.69 to 1.08) in the incidence of LVSI between manipulated hysterectomy and total abdominal hysterectomy (TAH) and between UM group and non-UM group in minimally invasive surgery (RR: 1.18, 95% CI, 0.76 to 1.85), no significant difference in the rate of recurrence (RR: 1.11, 95% CI, 0.71 to 1.74), in the incidence of positive peritoneal cytology between manipulated and non-manipulated hysterectomies in minimally invasive surgery (RR: 1.89, 95% CI, 0.74 to 4.83) and before and after the use of uterine manipulator (RR: 1.21, 95% CI, 0.68 to 2.16). We found a positive association between malignant cytology and hysterectomies in which a uterine manipulator had been used in a sub-group analysis where LH/LAVH were compared to TAH. (RR = 2.26, 95% CI, 1.08-4.71. P = 0.03). Conclusions: This meta-analysis supports that the use of uterine manipulator for minimally invasive treatment of endometrial cancer does not increase the rate of recurrence and LVSI. Therefore, the opportunity of any other studies on its use in endometrial cancer women should be questioned

Influence of uterine manipulator on oncological outcome in minimally invasive surgery of endometrial cancer: A systematic review and meta-analysis

Aim: The endoscopic approach for early-stage endometrial cancer (EC) treatment is considered gold standard. Some authors expressed their concern regarding uterine manipulator (UM) as a risk factor for tumor spillage and dissemination allowing peritoneal or lympho-vascular spaces invasion (LVSI). This meta-analysis aimed to evaluate the effect of UM on the presence of LVSI, recurrence rate and presence of atypical or malignant peritoneal cytology in patients with endometrial cancer. Methods: We searched electronic databases including PubMed, MEDLINE, Embase, Scopus, EBSCO, Google Scholar, and ClinicalTrials.gov. The pooled results were used to evaluate the association between the use of UM and oncological outcomes. This systematic review was reported according to PRISMA statement 2020. Statistical meta-analysis was performed using Review Manager software. Results: This systematic review included 18 studies (3 prospective studies, 13 retrospective studies, and 2 RCT). The pooled results showed no significant difference (RR: 0.86, 95% CI, 0.69 to 1.08) in the incidence of LVSI between manipulated hysterectomy and total abdominal hysterectomy (TAH) and between UM group and non-UM group in minimally invasive surgery (RR: 1.18, 95% CI, 0.76 to 1.85), no significant difference in the rate of recurrence (RR: 1.11, 95% CI, 0.71 to 1.74), in the incidence of positive peritoneal cytology between manipulated and non-manipulated hysterectomies in minimally invasive surgery (RR: 1.89, 95% CI, 0.74 to 4.83) and before and after the use of uterine manipulator (RR: 1.21, 95% CI, 0.68 to 2.16). We found a positive association between malignant cytology and hysterectomies in which a uterine manipulator had been used in a sub-group analysis where LH/LAVH were compared to TAH. (RR = 2.26, 95% CI, 1.08–4.71. P = 0.03). Conclusions: This meta-analysis supports that the use of uterine manipulator for minimally invasive treatment of endometrial cancer does not increase the rate of recurrence and LVSI. Therefore, the opportunity of any other studies on its use in endometrial cancer women should be questioned

Late-onset intrauterine growth restriction and HHV-6 infection: A pilot study

Late-onset Intrauterine growth restriction (IUGR) refers to impaired growth and development of the fetus, characterized by placental morphological abnormalities that affect the fetus's supply of nutrients. Human leukocyte antigen-G (HLA-G) is physiologically expressed during pregnancy, but decreased in normal placenta during the last weeks of gestation possibly inducing childbirth. Several viruses involved in congenital infection, such as herpesviruses, exploit HLA-G expression as an immune-escape mechanism. To date, despite different congenital herpetic infections having been associated with late IUGR, no direct implication of Human herpesvirus 6 (HHV-6) infection has been reported. We evaluated HLA-G expression and HHV-6 infection in 11 placentas from late-onset IUGR newborns and 11 placentas from uncomplicated pregnancies by histopathological and immunohistochemistry analysis. We found higher levels of HLA-G expression and HHV-6 presence in IUGR placenta samples compared with control placenta samples. We report HHV-6 staining in IUGR placenta samples, characterized by high HLA-G expression. These preliminary data suggest a possible involvement of HHV-6 infection in HLA-G deregulation that might affect vessel remodeling and prevent the correct pregnancy outcome in the IUGR condition

Local mobility and personal communication services: market aspects and network solutions

p. 719-730Consiglio Nazionale delle Ricerche (CNR). Biblioteca Centrale / CNR - Consiglio Nazionale delle RichercheSIGLEITItal

Histone Deacetylase Inhibitors as a Therapeutic Strategy to Eliminate Neoplastic "Stromal" Cells from Giant Cell Tumors of Bone

Simple Summary Giant cell tumor of bone (GCTB) is an intermediate bone neoplasm which consists of several cell populations, including the neoplastic "stromal" cells. These cells harbor a mutation in one of the histone H3.3 genes (H3F3A), and are therefore considered as the driving component of GCTB. This mutation causes changes in the epigenetic landscape, leading to aberrant gene expression patterns that may drive tumor growth. Surgery is currently the only curative treatment option because contemporary systemic therapies cannot remove the neoplastic cells from GCTB lesions, leading to re-outgrowth of the tumor when the treatment is discontinued. Therefore, the aim of this study was to explore whether therapeutic targeting of the epigenome can eliminate the neoplastic cells from GCTB lesions. The findings from this study indicate that histone deacetylase (HDAC) inhibitors may represent such a treatment strategy, which could improve the quality of life of GCTB patients who currently require life-long treatment. The neoplastic "stromal" cells in giant cell tumor of bone (GCTB) harbor a mutation in the H3F3A gene, which causes alterations in the epigenome. Current systemic targeted therapies, such as denosumab, do not affect the neoplastic cells, resulting in relapse upon treatment discontinuation. Therefore, this study examined whether targeting the epigenome could eliminate the neoplastic cells from GCTB. We established four novel cell lines of neoplastic "stromal" cells that expressed the H3F3A p.G34W mutation. These cell lines were used to perform an epigenetics compound screen (n = 128), which identified histone deacetylase (HDAC) inhibitors as key epigenetic regulators in the neoplastic cells. Transcriptome analysis revealed that the neoplastic cells expressed all HDAC isoforms, except for HDAC4. Therefore, five HDAC inhibitors targeting different HDAC subtypes were selected for further studies. All GCTB cell lines were very sensitive to HDAC inhibition in both 2D and 3D in vitro models, and inductions in histone acetylation, as well as apoptosis, were observed. Thus, HDAC inhibition may represent a promising therapeutic strategy to eliminate the neoplastic cells from GCTB lesions, which remains the paramount objective for GCTB patients who require life-long treatment with denosumab.Cancer Signaling networks and Molecular Therapeutic

Histone Deacetylase Inhibitors as a Therapeutic Strategy to Eliminate Neoplastic "Stromal" Cells from Giant Cell Tumors of Bone

Simple Summary Giant cell tumor of bone (GCTB) is an intermediate bone neoplasm which consists of several cell populations, including the neoplastic "stromal" cells. These cells harbor a mutation in one of the histone H3.3 genes (H3F3A), and are therefore considered as the driving component of GCTB. This mutation causes changes in the epigenetic landscape, leading to aberrant gene expression patterns that may drive tumor growth. Surgery is currently the only curative treatment option because contemporary systemic therapies cannot remove the neoplastic cells from GCTB lesions, leading to re-outgrowth of the tumor when the treatment is discontinued. Therefore, the aim of this study was to explore whether therapeutic targeting of the epigenome can eliminate the neoplastic cells from GCTB lesions. The findings from this study indicate that histone deacetylase (HDAC) inhibitors may represent such a treatment strategy, which could improve the quality of life of GCTB patients who currently require life-long treatment. The neoplastic "stromal" cells in giant cell tumor of bone (GCTB) harbor a mutation in the H3F3A gene, which causes alterations in the epigenome. Current systemic targeted therapies, such as denosumab, do not affect the neoplastic cells, resulting in relapse upon treatment discontinuation. Therefore, this study examined whether targeting the epigenome could eliminate the neoplastic cells from GCTB. We established four novel cell lines of neoplastic "stromal" cells that expressed the H3F3A p.G34W mutation. These cell lines were used to perform an epigenetics compound screen (n = 128), which identified histone deacetylase (HDAC) inhibitors as key epigenetic regulators in the neoplastic cells. Transcriptome analysis revealed that the neoplastic cells expressed all HDAC isoforms, except for HDAC4. Therefore, five HDAC inhibitors targeting different HDAC subtypes were selected for further studies. All GCTB cell lines were very sensitive to HDAC inhibition in both 2D and 3D in vitro models, and inductions in histone acetylation, as well as apoptosis, were observed. Thus, HDAC inhibition may represent a promising therapeutic strategy to eliminate the neoplastic cells from GCTB lesions, which remains the paramount objective for GCTB patients who require life-long treatment with denosumab

Liver transcriptomics highlights interleukin-32 as novel NAFLD-related cytokine and candidate biomarker

Objective: Efforts to manage non-alcoholic fatty liver disease (NAFLD) are limited by the incomplete understanding of the pathogenic mechanisms and the absence of accurate non-invasive biomarkers. The aim of this study was to identify novel NAFLD therapeutic targets andbiomarkers by conducting liver transcriptomic analysis in patients stratified by the presence of the PNPLA3 I148M genetic risk variant. Design: We sequenced the hepatic transcriptome of 125 obese individuals. 'Severe NAFLD' was defined as the presence of steatohepatitis, NAFLD activity score 654 or fibrosis stage 652. The circulating levels of the most upregulated transcript, interleukin-32 (IL32), were measured by ELISA. Results: Carriage of the PNPLA3 I148M variant correlated with the two major components of hepatic transcriptome variability and broadly influenced gene expression. In patients with severe NAFLD, there was an upregulation of inflammatory and lipid metabolism pathways. IL32 was the most robustly upregulated gene in the severe NAFLD group (adjusted p=1 710-6), and its expression correlated with steatosis severity, both in I148M variant carriers and non-carriers. In 77 severely obese, and in a replication cohort of 160 individuals evaluated at the hepatology service, circulating IL32 levels were associated with both NAFLD and severe NAFLD independently of aminotransferases (p<0.01 for both). A linear combination of IL32-ALT-AST showed a better performance than ALT-AST alone in NAFLD diagnosis (area under the curve=0.92 vs 0.81, p=5 710-5). Conclusion: Hepatic IL32 is overexpressed in NAFLD, correlates with hepatic fat and liver damage, and is detectable in the circulation, where it is independently associated with the presence and severity of NAFLD