Value of total tumor load as a clinical and pathological factor in the prognosis of breast cancer patients receiving neoadjuvant treatment. Comparison of three populations with three different surgical approaches: NEOVATTL Pro 3 Study.

PURPOSE: This study aimed to compare the prognosis in terms of disease-free survival (DFS) in three populations of women with breast cancer (BC) treated with neoadjuvant systemic treatment (NAST) in which axillary lymph node dissection (ALND) was performed based on different total tumor load (TTL) thresholds in the sentinel nodes. METHODS: This was an observational, retrospective study carried out in three Spanish centers. Data from patients with infiltrating BC who underwent BC surgery after NAST and intraoperative sentinel lymph node biopsy (SLNB) performed by One Step Nucleic acid Amplification (OSNA) technique during 2017 and 2018 were analyzed. ALND was performed according to the protocol of each center, based on three different TTL cut-offs (TTL > 250, TTL > 5000, and TTL > 15,000 CK19-mRNA copies/µL for centers 1, 2, and 3, respectively). RESULTS: A total of 157 BC patients were included in the study. No significant differences in DFS were observed between centers (Hazard ratio [HR] center 2 vs 1: 0.77; p = 0.707; HR center 3 vs 1: 0.83; p = 0.799). Patients with ALND had a shorter DFS (HR 2.43; p = 0.136), albeit not statistically significant. Patients with a triple negative subtype had a worse prognosis than those with other molecular subtypes (HR 2.82; p = 0.056). CONCLUSION: No significant differences in DFS were observed between three centers with different surgical approaches to ALND based on different TTL cut-offs in patients with BC after NAST. These results suggest that restricting ALND to those patients with TTL ≥ 15,000 copies/µL is a reliable approximation, avoiding unnecessary morbidities caused by ALND.

A role for the transducer of the Hippo pathway, TAZ, in the development of aggressive types of endometrial cancer.

Although TAZ, the final effector of the Hippo pathway that modulates epithelial to mesenchymal transition and stemness, has been implicated in the development of different types of cancer, its role in endometrial cancer has not yet been studied. Thus, we evaluated the expression of TAZ in different types of endometrial cancer by immunohistochemistry. TAZ expression was detected in 76% of undifferentiated endometrial carcinomas, 54% of endometrial carcinosarcomas, 46% of endometrial serous carcinomas, 36% of grade 3 endometrioid carcinomas, and 18% of grade 1-2 endometrioid carcinomas, with statistically significant differences. We analyzed the WWTR1 gene that encodes TAZ by FISH and MassARRAY spectrometry, ruling out gene amplification and differential promoter methylation as the main mechanisms that modulate TAZ expression in endometrial tumors. However, we did detect a significant association between Scribble hypoexpression and delocalization with TAZ expression. Moreover, we demonstrated that TAZ promoted invasiveness, and it favored cell motility and tumor growth, in endometrial cancer cell lines. In addition, TAZ expression was associated with the transition from an epithelial to mesenchymal phenotype, both in vitro and in human tumors. Together, these data reveal a previously unknown role for TAZ and the Hippo pathway in the progression of aggressive subtypes of endometrial cancer.

ZEB1 overexpression associated with E-cadherin and microRNA-200 downregulation is characteristic of undifferentiated endometrial carcinoma.

Undifferentiated endometrial carcinomas are very aggressive high-grade endometrial carcinomas that are frequently under-recognized. This study aimed to analyze the molecular alterations underlying the development of these endometrial carcinomas, focusing on those related to dedifferentiation. We assessed a series of 120 tumors: 57 grade 1 and 2 endometrioid endometrial carcinomas, 15 grade 3 endometrioid endometrial carcinomas, 27 endometrial serous carcinomas, and 21 undifferentiated endometrial carcinomas. We found a high frequency of DNA mismatch repair deficiency (38%) and moderate rate of p53 overexpression (∼33%) in undifferentiated carcinomas. In contrast to the characteristic endometrioid phenotype, there was a dramatic downregulation of E-cadherin expression in the undifferentiated subtype. Quantitative methylation studies dismissed CDH1 promoter hypermethylation as the mechanism responsible for this change in gene expression, while immunohistochemistry revealed that the E-cadherin repressor ZEB1 was frequently overexpressed (62%) in undifferentiated endometrial carcinomas. This finding was accompanied by a sharp downregulation in the expression of the miR-200 family of microRNAs, well-known targets of ZEB1. Furthermore, there was enhanced expression of epithelial-to-mesenchymal transition markers in undifferentiated endometrial carcinomas, such as N-cadherin, cytoplasmic p120, and osteonectin. In addition, HMGA2, a regulator of epithelial-to-mesenchymal transition that is expressed in aggressive endometrial tumors, such as endometrial serous carcinomas and carcinosarcomas, was expressed in >20% of undifferentiated carcinomas. These results suggest that ZEB1 overexpression, associated with E-cadherin and miR-200s downregulation, and the expression of mesenchymal markers might enhance the metastatic potential of undifferentiated endometrial carcinomas, leading to a poor prognosis. In addition, our observations suggest that the immnohistochemical analysis of E-cadherin and ZEB1 can aid in the differential diagnosis of the more agressive undifferentiated endometrial carcinomas from grade 3 endometrioid carcinomas.

Low Prevalence of HER2-Positive Breast Carcinomas among Screening Detected Breast Cancers.

Conflicting results have been reported regarding the prevalence of screen-detected human epidermal growth factor receptor 2 (HER2)-positive breast carcinomas and non-screen detected HER2-positive breast carcinomas. To address this issue, we evaluated the prevalence of HER2-positive breast carcinomas in two independent regional screening programs in Spain. The clinicopathologic and immunohistochemical characteristics of 479 (306 and 173) screen-detected breast carcinomas and 819 (479 and 340) non-screen-detected breast carcinomas diagnosed in women between 50 and 69-year-olds were compared. The prevalence of HER2-positive breast carcinomas was 8.8% and 6.4% in the two series of screen-detected tumors, compared with 16.4% and 13% in non-screen-detected carcinomas. These differences were statistically significant. This lower prevalence of HER2-positive in-screen-detected breast carcinomas was observed in both hormone receptor positive (luminal HER2) and hormone-receptor-negative (HER2 enriched) tumors. In addition, a lower prevalence of triple-negative and a higher prevalence of luminal-A breast carcinomas was observed in screen-detected tumors. Moreover, a literature review pointed out important differences in subrogate molecular types in screen-detected breast carcinomas among reported series, mainly due to study design, technical issues and racial differences.

Proof of concept, design, and manufacture via 3-D printing of a mesh with bactericidal capacity: Behaviour in vitro and in vivo.

Currently, hernia treatment involves implantation of a mesh prosthesis, usually made of polypropylene, and the primary complication is infection of the device, which leads to an exponential increase in morbidity. Three-dimensional printing offers a method of dealing with complications of this magnitude. Therefore, in this study, the bactericidal properties and effectiveness of three-dimensional-printed meshes with polycaprolactone (PCL) and gentamicin were evaluated in vitro in Escherichia coli cultures, and their histological behaviour was examined in vivo. Different PCL meshes were implanted into four groups of rats, with 10 rats in each group: PCL meshes, PCL meshes with alginate and calcium chloride, PCL meshes with gentamicin, and PCL meshes with alginate and gentamicin. Thirty-six microporous meshes were manufactured, and their bactericidal properties were assessed. When the meshes did not include an antibiotic, an inhibition halo was not observed; when the gentamicin was free, an asymmetric inhibition area of 5.65 ± 0.46 cm2 was present; when the gentamicin was encapsulated, a rectangular area of 5.40 ± 0.38 cm2 was observed. In the rats, macroporous and microporous mesh implants produced mild inflammation and substantial fibrosis with collagen and neovascular foci. A significant difference was observed in fibroblastic activity between the PCL with alginate group and the PCL with alginate and gentamicin group microporous meshes (p = .013) and in collagen deposits between the macroporous and microporous meshes in the PCL mesh group (p = .033). The feasibility of manufacturing drug-doped printed PCL meshes containing alginate and gentamicin was verified, and the meshes exhibited bactericidal effects and good histopathological behaviour.

Enhanced chemopreventive activity of hydroxytyrosol on HL60 and HL60R cells by chemical conversion into thio derivatives.

Thio derivatives of hydroxytyrosol containing thiol, thioacetate and disulfide functionalities were synthesized from natural hydroxytyrosol (3,4-DHPEA) via 3,4-dihydroxyphenethyl halides. These compounds, containing the combination of catechol moiety and divalent sulfur functions, were tested for the pro-apoptotic and anti-proliferative activities on both parental HL60 and multi-drug resistant HL60R cells. It was found that all synthesized compounds were more effective than 3,4-DHPEA in inducing apoptosis on HL60R cells, and that the hydroxytyrosol disulfide was the most active pro-apoptotic and anti-proliferative compound on both HL60 and HL60R cells. Different from 3,4-DHPEA, all thio derivatives of hydroxytyrosol induced apoptosis by a mechanism not involving the release of H(2)O(2) in the culture medium. The data on HL60R cells suggest that these compounds could be able to reverse the resistance toward the most common drugs in cancer therapy.

Stereocontrolled synthesis of 2-substituted-1,3-azasilaheterocycles.

Chiral alpha-silylsulfinamides, prepared by the treatment of an alkyldiphenylsilane with lithium followed by its addition to a sulfinimine, can be applied to the synthesis of 1,3-azasilaheterocycles as derivatives of cyclic alkaloids. This synthetic route, which involves intramolecular substitution of an amino alcohol or cyclization of an amino acid promoted by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), represents a convenient means for accessing these silicon-containing heterocycles.