First-in-Class Selenium-Containing Potent Serotonin Receptor 5-HT6 Agents with a Beneficial Neuroprotective Profile against Alzheimer's Disease.

Alzheimer's disease (AD) has a complex and not-fully-understood etiology. Recently, the serotonin receptor 5-HT6 emerged as a promising target for AD treatment; thus, here a new series of 5-HT6R ligands with a 1,3,5-triazine core and selenoether linkers was explored. Among them, the 2-naphthyl derivatives exhibited strong 5-HT6R affinity and selectivity over 5-HT1AR (13-15), 5-HT7R (14 and 15), and 5-HT2AR (13). Compound 15 displayed high selectivity for 5-HT6R over other central nervous system receptors and exhibited low risk of cardio-, hepato-, and nephrotoxicity and no mutagenicity, indicating its "drug-like" potential. Compound 15 also demonstrated neuroprotection against rotenone-induced neurotoxicity as well as antioxidant and glutathione peroxidase (GPx)-like activity and regulated antioxidant and pro-inflammatory genes and NRF2 nuclear translocation. In rats, 15 showed satisfying pharmacokinetics, penetrated the blood-brain barrier, reversed MK-801-induced memory impairment, and exhibited anxiolytic-like properties. 15's neuroprotective and procognitive-like effects, stronger than those of the approved drug donepezil, may pave the way for the use of selenotriazines to inhibit both causes and symptoms in AD therapy.

SYNCRIP Modulates the Epithelial-Mesenchymal Transition in Hepatocytes and HCC Cells.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) control gene expression by acting at multiple levels and are often deregulated in epithelial tumors; however, their roles in the fine regulation of cellular reprogramming, specifically in epithelial-mesenchymal transition (EMT), remain largely unknown. Here, we focused on the hnRNP-Q (also known as SYNCRIP), showing by molecular analysis that in hepatocytes it acts as a "mesenchymal" gene, being induced by TGFß and modulating the EMT. SYNCRIP silencing limits the induction of the mesenchymal program and maintains the epithelial phenotype. Notably, in HCC invasive cells, SYNCRIP knockdown induces a mesenchymal-epithelial transition (MET), negatively regulating their mesenchymal phenotype and significantly impairing their migratory capacity. In exploring possible molecular mechanisms underlying these observations, we identified a set of miRNAs (i.e., miR-181-a1-3p, miR-181-b1-3p, miR-122-5p, miR-200a-5p, and miR-let7g-5p), previously shown to exert pro- or anti-EMT activities, significantly impacted by SYNCRIP interference during EMT/MET dynamics and gathered insights, suggesting the possible involvement of this RNA binding protein in their transcriptional regulation.

A predictive score for optimal cytoreduction at interval debulking surgery in epithelial ovarian cancer: a two- centers experience.

BACKGROUND: Optimal cytoreduction (macroscopic Residual Tumor, RT = 0) is the best survival predictor factor in epithelial ovarian cancer (EOC). It doesn't exist a consolidated criteria to predict optimal surgical resection at interval debulking surgery (IDS). The aim of this study is to develop a predictive model of complete cytoreduction at IDS. METHODS: We, retrospectively, analyzed 93 out of 432 patients, with advanced EOC, underwent neoadjuvant chemotherapy (NACT) and IDS from January 2010 to December 2016 in two referral cancer centers. The correlation between clinical-pathological variables and residual disease at IDS has been investigated with univariate and multivariate analysis. A predictive score of cytoreduction (PSC) has been created by combining all significant variables. The performance of each single variable and PSC has been reported and the correlation of all significant variables with progression free survival (PFS) has been assessed. RESULTS: At IDS, 65 patients (69,8%) had complete cytoreduction with no residual disease (R = 0). Three criteria independently predicted R > 0: age ≥ 60 years (p = 0.014), CA-125 before NACT > 550 UI/dl (p = 0.044), and Peritoneal Cancer Index (PCI) > 16 (p < 0.001). A PSC ≥ 3 has been associated with a better accuracy (85,8%), limiting the number of incomplete surgeries to 16,5%. Moreover, a PCI > 16, a PSC ≥ 3 and the presence of R > 0 after IDS were all significantly associated with shorter PFS (p < 0.001, p < 0.001 and p = 0.004 respectively). CONCLUSIONS: Our PSC predicts, in a large number of patients, complete cytoreduction at IDS, limiting the rate of futile extensive surgeries in case of presence of residual tumor (R > 0). The PSC should be prospectively validated in a larger series of EOC patients undergoing NACT-IDS.

Primary tumor location predicts the site of local relapse after nipple-areola complex (NAC) sparing mastectomy.

PURPOSE: To assess the oncological safety of nipple-areola complex (NAC) sparing mastectomy in breast cancer patients. METHODS: From 2010 to 2015, 518 breast cancer patients were submitted to NAC sparing mastectomy. Breast MRI and intraoperative assessment of the subareolar (SD) and proximal (ND) nipple ducts were performed to predict NAC involvement. Significant associations between pre- and postoperative variables with SD/ND involvement and with the risk of local recurrence were retrospectively investigated. RESULTS: SD/ND were involved in 26.1% of the cases. Final pathology of SD/ND was predicted by tumor-NAC distance at MRI and intraoperative pathology with 75 and 93% accuracy, respectively. NAC involvement was more frequent in case of positive ND than positive SD (68.3 vs. 38.3%; p = 0.003). Fourteen (2.7%) local relapses developed over a mean follow-up of 33 months. Ki-67 ≥25% (p = 0.002) and high tumor grade (p = 0.027) correlated with local recurrence. Most relapses developed in the subcutaneous tissue of the quadrant where the primary tumor was located (12/14; 85.7%). No local relapses occurred in patients who received post-mastectomy radiotherapy as compared to patients who did not, although they had a higher rate of positive surgical margins (40.5 vs. 16.2%; p = 0.000). CONCLUSIONS: NAC involvement can be predicted by MRI and intraoperative pathology of ND/SD. Local recurrences after NAC sparing mastectomy almost invariably develop in the same quadrant where the primary tumor was located and in highly proliferative tumors.

MRI and intraoperative pathology to predict nipple-areola complex (NAC) involvement in patients undergoing NAC-sparing mastectomy.

BACKGROUND: Nipple-areola sparing mastectomy (NSM) with immediate implant reconstruction is an option for patients with non-locally advanced breast cancer. The prediction of occult tumour involvement of the nipple-areola complex (NAC) may help select candidates to NSM. PATIENTS AND METHODS: We prospectively recorded clinical and pathological data, magnetic resonance imaging (MRI) results and intraoperative pathological assessments of the subareolar (SD) and proximal nipple ducts (ND) of 112 consecutive breast cancer patients scheduled for NSM. All parameters were correlated with final pathological NAC assessment by univariate and multivariate analysis. RESULTS: Thirty-one patients (27.7%) had tumour involvement of the NAC. At univariate analysis, age (p=0.001), post-menopausal status (0.003), tumour central location (p=0.03), tumour-NAC distance measured by MRI (p=0.000) and intraoperative pathologic assessment (SD+ND) (p=0.000) were significantly correlated with NAC involvement. At multivariate analysis, only MRI tumour-NAC distance (p=0.008) and menopausal status (p=0.039) among all preoperative variables retained statistical significance. The sensitivity and specificity of MRI tumour-NAC distance were 32.2% and 88.6% and those of intraoperative pathologic assessment were 46.7% and 100%, respectively. Sensitivity, specificity and accuracy of the double assessment (MRI plus intraoperative pathology) were 50.0%, 96.2% and 84.1%, respectively. CONCLUSION: Intraoperative pathologic assessment and tumour-NAC distance measured by MRI are the most important predictors of occult NAC involvement in breast cancer patients. A negative pathological assessment and a tumour-NAC distance ⩾ 5 mm allow optimal discrimination between NAC positive and NAC negative cases and may serve as a guide for the optimal planning of oncological and reconstructive surgery.

Omission of axillary dissection after a positive sentinel node dissection may influence adjuvant chemotherapy indications in operable breast cancer patients.

BACKGROUND: This study was designed to evaluate how the omission of axillary dissection would have altered the indication for adjuvant chemotherapy (ACT) in patients with early breast cancer submitted to conservative surgery with one or two positive sentinel lymph nodes (SLNs). METHODS: We identified 321 women in our institutional database who fulfilled the characteristics. All underwent completion axillary lymph node dissection (AD). Each case was blindly reviewed by our breast team in two rounds, and the total number of positive lymph nodes was disclosed only in the second. At each round, the panel chose between: (1) recommend, (2) discuss, (3) do not recommend ACT. Changes between round 1 and 2 were studied by the marginal homogeneity test. Exploratory logistic regression analyses were performed to study predictors of non-SLN involvement and of changes in the indication for ACT. RESULTS: AD revealed non-SLNs metastases in 96 patients (30 %). Fifty-two patients (16 %) had their initial indication changed at round 2 (p < 0.001). Most of the changes were toward ACT (83 %), and all except two occurred in patients with immunohistochemically defined luminal A and luminal B/HER2-negative tumors. In these two subgroups, a Ki67 above the median value (21 %) was the only independent predictor of no change in the indication to ACT at round 2. CONCLUSIONS: Omission of AD in patients with one or two positive SLNs may change the indication to ACT in a significant proportion of patients with hormone receptor-positive/HER2-negative tumors. All implications should be taken into account before abandoning AD, including a possible biologically tailored surgical approach.

Nipple-areola complex sparing mastectomy with periareolar pexy for breast cancer patients with moderately ptotic breasts.

BACKGROUND: Nipple-areola complex sparing mastectomy (NSM) with immediate implant reconstruction has been recently introduced for breast cancer patients who are not candidates for breast preserving surgery. As the cosmetic results in moderately ptotic breasts may not be optimal, a modified NSM with a periareolar pexy (PP-NSM) was introduced at our Institution. Patients selection criteria and complication rates of PP-NSM were prospectively recorded and compared with those of the classical NSM. RESULTS: Over a period of 11 months, 22 PP-NSMs and 35 NSMs were performed. The mean jugular-nipple distance was significantly longer in the PP-NSM as compared with the NSM (22.6 vs. 19.6 cm; p=0.000), whereas the mean inframammary fold-areola distance was superimposable (5.4 cm). The periareolar mastopexy led to a mean cranial transposition of the nipple-areola complex (NAC) of 2.2 cm (range 1.5-4 cm). Mean breast weight was significantly higher in the PP-NSM as compared with the NSM cohort (336 vs. 236 g; p=0.003). The only case of total NAC necrosis occurred in the PP-NSM group. Partial NAC necrosis was slightly more frequent in the PP-NSM than in the NSM group (13.6% vs. 2.9%%; p=n.s.), possibly due to the higher percentage of smokers (41.0% vs. 14.0%; p=0.05). Early cosmetic results were good to excellent from the surgeon's and the patient's point of view in over 80% of the cases. CONCLUSIONS: PP-NSM allows good cosmetic results and low complication rates in patients with moderately ptotic breasts requiring a mastectomy. In particular, PP-NSM seems to be a good option for women at high risk for developing breast cancer and for selected patients affected by non-locally advanced breast cancer.

Perioperative outcomes of laparoendoscopic single-site surgery (LESS) versus conventional laparoscopy for adnexal disease: a case--control study.

OBJECTIVE: This study aimed to evaluate the potential advantages of laparoendoscopic single-site surgery (LESS) approach with respect to conventional laparoscopy. METHODS: Thirty LESS patients were matched 2:1 with a previous cohort of 58 patients undergoing conventional laparoscopy for the same type of surgery (controls). RESULTS: Median operative time (38.5 vs 54 minutes; P = .09) and estimated blood loss (20 vs 30 mL; P = .008) were more favorable in patients undergoing LESS treatment compared with those undergoing conventional laparoscopy. Rupture of the cyst was observed in 11 out of 30 cases (36.6%) and 26 of 58 controls (44.8%; P = .46). Median length of stay was 1 day in the cases and 2 in the controls (P = .03). CONCLUSIONS: Decreases in operative time, estimated blood loss, or length of stay should not be considered a benefit attributable to LESS; rather it seems there are no differences between these 2 surgical approaches after an adequate selection of patients.

Laparoendoscopic single-site surgery for the treatment of benign adnexal diseases: a pilot study.

BACKGROUND: This study aimed to validate the feasibility, efficacy, and safeness of laparoscopic treatment for benign adnexal diseases through a single transumbilical access in a prospective series of patients. METHODS: A prospective clinical trial including 30 women was conducted in our teaching and research division. Patients underwent different laparoscopic procedures by the laparoendoscopic single-site (LESS) approach using a multiport trocar, conventional laparoscopic instrumentation, and standardized surgical technique, with evaluation of the multiaccess conversion rate. RESULTS: The patients underwent different laparoscopic procedures (10 bilateral adnexectomies; 22 cystectomies, and 3 chromosalpingographies) by the LESS approach using a multiport trocar and conventional laparoscopic instrumentation with standardization of this innovative minimally invasive technique. The laparoscopic procedures were completed through a single access in 28 cases (93.4%). In two cases, at the end of the intervention, hemostasis required one additional sovra-pubic access. No major intra- or postoperative complications were observed. The mean hospital stay was 1.3 days. CONCLUSIONS: The results of this study suggest the feasibility of the LESS approach in gynecologic surgery with a low conversion rate for multi-access laparoscopy, a rapid learning curve, limited complications, and good results in terms of cosmesis and postoperative pain. More clinical data are needed to confirm these advantages over standard laparoscopic technique.

Laparoendoscopic single-site surgery for fertility-sparing staging of border line ovarian tumors: initial experience.

OBJECTIVE: To report feasibility of laparoscopic fertility-sparing staging of border line ovarian tumors (BOTs) by using a laparoendoscopic single-site trocar through a unique transumbilical access. STUDY DESIGN: This study was conducted in our University Hospital. Four young patients, intended to be submitted to benign adnexal cysts enucleation by an innovative laparoendoscopic single-site approach using a multiport trocar inserted through a unique transumbilical access and straight laparoscopic devices, were found to be affected by border line ovarian tumor at intraoperative frozen analysis. Consequently patients were conservatively staged carrying out all the requested procedures in respect of oncologic guidelines and their child bearing desire, using same single-port access approach. Main outcome measures were conversion rate to multiaccess standard laparoscopic technique or to laparotomic approach and evaluation of intraoperative and postoperative-related complications. RESULTS: All the laparoscopic staging procedures were feasible through a single transumbilical access: no conversion to multiaccess standard laparoscopic technique nor laparotomy and no intraoperative or postoperative complications were observed. Mean operative time was 79 minutes. All patients were discharged home on day 1 with complete satisfaction toward cosmetic outcome. Final pathologic analysis confirmed stage FIGO 1A for all cases. The patients are free from recurrence at 10 months follow-up. CONCLUSIONS: Laparoendoscopic single-site staging of border line ovarian tumors with preservation of fertility is feasible and effective with standard laparoscopic instruments. More clinical data are needed to confirm these advantages compared with standard multiaccess laparoscopic technique.

Laparoendoscopic single-site surgery for the treatment of benign adnexal disease: a prospective trial.

Background. To validate feasibility, efficacy, and safeness of laparoscopic treatment of benign adnexal diseases through a single transumbilical access (LESS) in a prospective series of patients. Methods. A prospective clinical trial including 30 women has been conducted at the Division of Gynecology of Catholic University of Sacred Hearth of Rome. Patients underwent different laparoscopic procedures by LESS utilizing a multiport trocar and conventional straight laparoscopic instrumentation. Intra and perioperative outcome has been reported. Results. Ten mono/bilateral adnexectomies and 20 cystectomies have been performed by LESS approach. Laparoscopic procedures were completed through a single access in 28 cases (93.4%). No major intra- or postoperative complications were observed. Mean hospital stay was 1.3 days. Conclusions. LESS approach is feasible to treat benign adnexal disease with a very low conversion rate and no early or late complications. More clinical data are needed to confirm these advantages compared to standard laparoscopic technique.

Laparoendoscopic single-site surgery (LESS) for ovarian cyst enucleation: report of first 3 cases.

OBJECTIVE: To report the feasibility of ovarian cyst enucleation by using a laparoendoscopic single-site trocar through a transumbilical access. DESIGN: Case reports. SETTING: Teaching and research hospital. PATIENT(S): Three patients affected by large ovarian cysts. INTERVENTION(S): Enucleation of three large ovarian cysts by using a laparoendoscopic single-site approach with a new multiport trocar and standard laparoscopic instruments. MAIN OUTCOME MEASURE(S): Conversion to a multiaccess standard laparoscopic technique. RESULT(S): No conversion to multiaccess standard laparoscopic technique and no intraoperative or postoperative complications were observed. Mean operative time was 79.6 minutes. All patients were discharged home on day 1. CONCLUSION(S): Laparoendoscopic single-site enucleation of large ovarian cysts with ovary sparing is feasible with standard laparoscopic instruments, safe and effective, with good results in terms of cosmesis and postoperative pain. More clinical data are needed to confirm these advantages compared with standard laparoscopic technique.

Attitudes of Italian gynaecologists towards prophylactic oophorectomy at hysterectomy for non-malignant conditions.

OBJECTIVE: To compare the attitudes of Italian oncologic gynaecologists towards prophylactic oophorectomy at hysterectomy for a non-neoplastic reason. STUDY DESIGN: A four-item two-part questionnaire was submitted to 170 gynaecologists attending a national conference on gynaecologic oncology. RESULTS: About 92% of gynaecologists reported they would perform prophylactic oophorectomy in women over 50 years, but only 14% said they would in patients aged 45-50; a family history of cancer emerged as a major decision-making criterion for performing oophorectomy in the younger set of patients. CONCLUSION: Our brief survey confirms the wide variability in attitudes among gynaecologists towards performing prophylactic oophorectomy at hysterectomy for a non-neoplastic pathology in women aged 40-50.

Pretreatment serum hemoglobin level as a predictive factor of response to neoadjuvant chemotherapy in patients with locally advanced squamous cervical carcinoma: a preliminary report.

OBJECTIVE: The aim of this study was to evaluate the predictive value of pretreatment serum hemoglobin level (Hb) together with a series of clinical and pathological variables available before neoadjuvant chemotherapy in locally advanced squamous cervical cancer. METHODS: The influence on response to neoadjuvant chemotherapy of a series of pretreatment clinico-pathological features: hemoglobin level at diagnosis, age, parity, menopausal status, body mass index, clinical stage, tumor diameter, and nuclear grading were analyzed on 73 patients with locally advanced cervical cancer treated with platinum-based neoadjuvant chemotherapy followed by radical surgery. The relationships between pretreatment variables and response to chemotherapy were assessed in univariate and multivariate settings. A univariate and multivariate logistic regression model was adapted to predict an "optimal" response (pathological complete response or more than 50% reduction in tumoral diameter) or "sub-optimal" response (<50% reduction in tumoral diameter). RESULTS: Seventy-three patients-clinical stage: Ib2: 29 (39.7%) IIa: 22 (30.1%) IIb: 22 (30.1%)-received 3 cycles of platinum-based neoadjuvant chemotherapy followed by type III radical hysterectomy. A complete response to neoadjuvant chemotherapy was significantly associated with higher level of pretreatment hemoglobin (mean 14.0 mg/dl) compared to patients with > or =50% response (12.7 mg/dl) or <50% (11.9 mg/dl) (P = 0.002). At multivariate analysis, Hb level was found to be the most powerful and significantly related factor to response to neoadjuvant chemotherapy. A hemoglobin threshold of 12 mg/dl was able to distinguish between patients-with > or =12 mg/dl-at higher probability to respond to neoadjuvant chemotherapy from the ones at lower probability (hemoglobin level under 12 mg/dl). Patients with a complete response to chemotherapy had a 100% survival compared to 93.1% and 53.8% for patients with responses > or =50% and <50% respectively (P = 0.0001). Patients with a pretreatment hemoglobin level of > or =12 mg/dl showed a survival of 87% compared to 63% for patients with a lower hemoglobin level (P = 0.008). CONCLUSIONS: Pretreatment Hb level showed a prognostic and independent predictive value for response to neoadjuvant chemotherapy in locally advanced cervical cancer. In our preliminary report, performed on a limited sample, a threshold of 12 mg/dl seems to be helpful to distinguish between "optimal" and "non-optimal" response.