Antibody-drug conjugates (ADC) against cancer stem-like cells (CSC) - Is there still room for optimism?

Cancer stem-like cells (CSC) represent a subpopulation of tumor cells with peculiar functionalities that distinguish them from the bulk of tumor cells, most notably their tumor-initiating potential and drug resistance. Given these properties, it appears logical that CSCs have become an important target for many pharma companies. Antibody-drug conjugates (ADC) have emerged over the last decade as one of the most promising new tools for the selective ablation of tumor cells. Three ADCs have already received regulatory approval and many others are in different phases of clinical development. Not surprisingly, also a considerable number of anti-CSC ADCs have been described in the literature and some of these have entered clinical development. Several of these ADCs, however, have yielded disappointing results in clinical studies. This is similar to the results obtained with other anti-CSC drug candidates, including native antibodies, that have been investigated in the clinic. In this article we review the anti-CSC ADCs that have been described in the literature and, in the following, we discuss reasons that may underlie the failures in clinical trials that have been observed. Possible reasons relate to the biology of CSCs themselves, including their heterogeneity, the lack of strictly CSC-specific markers, and the capacity to interconvert between CSCs and non-CSCs; second, inherent limitations of some classes of cytotoxins that have been used for the construction of ADCs; third, the inadequacy of animal models in predicting efficacy in humans. We conclude suggesting some possibilities to address these limitations

MicroRNA-551b expression profile in low and high-grade cervical intraepithelial neoplasia

OBJECTIVE: To evaluate the expression of microRNA (miR)-551b in patients with low and high grade cervical intraepithelial neoplasia (CIN) and to find an association with high-risk Human Papillomavirus (HR-HPV) infection-related prognostic biomarkers. PATIENTS AND METHODS: The expression level of miR-551b was determined in 50 paraffin-embedded cervical specimens (10 normal squamous epithelium, 18 condylomas, 8 CIN1, and 14 CIN2-3) using quantitative Real-time polymerase chain reaction (qRT-PCR). χ2-test compared miR-551b expression in different diagnosis groups. An Ordered Logistic Regression and a Probit correlation were made to correlate miR-551b expression levels with the cervical tissue histological findings. The immunohistochemical distribution of p16 and Ki-67 according to histopathological findings was also assessed. RESULTS: The distribution of the miR-551b expression profile was significantly lower in CIN1-3 samples compared to other histological diagnosis groups (condyloma and negative). The expression levels were inversely correlated to the cervical pathological grade, from negative to CIN2-3. A 1% increase in miR-551b expression level produced an increase of 19% to the probability of a minor histological grade diagnosis in a range from negative to CIN2-3 and an increase of 13% to the probability of a negative histological grade diagnosis. Among the cases with miR-551b expression < 0.02 (considered as cut-off value) a significant statistical correlation was found between p16 and Ki-67 expression and the diagnosis of CIN2-3. CONCLUSIONS: O ur d ata s howed a s ignificant inverse correlation between miR-551b expression and the histological grading of the lesions, suggesting a tumor suppressive function in the different stages of cervical dysplasia

Preterm birth after loop electrosurgical excision procedure (LEEP). how cone features and microbiota could influence the pregnancy outcome

OBJECTIVE: In the last years, the mean age of women who underwent cervical treatment for high-grade cervical intraepithelial neoplasia (CIN 2-3) is similar to the age of women having their first pregnancy. The aim of this study was to evaluate the risk of preterm birth in subsequent pregnancies after loop electrosurgical excision procedure (LEEP). PATIENTS AND METHODS: From January 2013 to January 2016 the study identified a total of 1435 women, nulliparous, who underwent LEEP for CIN 2-3, and who wished to have their first pregnancy. Before surgery, the lengths of the cervix were calculated by transvaginal sonography. After the treatment, the dimension of the removed tissue was evaluated. During the pregnancy, all women carried out periodic transvaginal sonography and vaginal-cervical swabs. RESULTS: The average age of patients was 31.96±5.24 years; the interval between the surgical procedure and pregnancy was 12.04±4.67 months; the gestational age at births was 37.53±2.91 weeks. The first vaginal and cervical swab performed during pregnancy was negative in 81.8% of patients. The most prevalent infections were related to C. Albicans, G. Vaginalis, and Group B Streptococcus (GBS). The rate of preterm delivery was significantly higher in women with a minor cervical length. CONCLUSIONS: The length and the volume of cervical tissue excised have been shown to be directly related to the risk for preterm birth. Furthermore, vaginal infections and their persistence during pregnancy in women with a history of LEEP may be associated with an increased risk for preterm birth, compared with women with no history of LEEP

Exposure to Endocrine Disruptors and Nuclear Receptors Gene Expression in Infertile and Fertile Men from Italian Areas with Different Environmental Features

Internal levels of selected endocrine disruptors (EDs) (i.e., perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), di-2-ethylhexyl-phthalate (DEHP), mono-(2-ethylhexyl)-phthalate (MEHP), and bisphenol A (BPA)) were analyzed in blood/serum of infertile and fertile men from metropolitan, urban and rural Italian areas. PFOS and PFOA levels were also evaluated in seminal plasma. In peripheral blood mononuclear cells (PBMCs) of same subjects, gene expression levels of a panel of nuclear receptors (NRs), namely estrogen receptor α (ERα) estrogen receptor β (ERβ), androgen receptor (AR), aryl hydrocarbon receptor (AhR), peroxisome proliferator-activated receptor γ (PPARγ) and pregnane X receptor (PXR) were also assessed. Infertile men from the metropolitan area had significantly higher levels of BPA and gene expression of all NRs, except PPARγ, compared to subjects from other areas. Subjects from urban areas had significantly higher levels of MEHP, whereas subjects from rural area had higher levels of PFOA in both blood and seminal plasma. Interestingly, ERα, ERβ, AR, PXR and AhR expression is directly correlated with BPA and inversely correlated with PFOA serum levels. Our study indicates the relevance of the living environment when investigating the exposure to specific EDs. Moreover, the NRs panel in PBMCs demonstrated to be a potential biomarker of effect to assess the EDs impact on reproductive health

Maximizing rehabilitation outcomes in geriatric hip fracture patients: the impact of surgical variables

Background and aim: Hip fracture is a major traumatic event with high mortality and disability rate. Its management in the acute setting and in the rehabilitation process is highly debated. This study evaluates the possible determinants of hip fracture rehabilitation outcome, among which surgical intervention type, weight-bearing status and hospitalization length Methods: The data of 738 hip fracture patients, who completed rehabilitation process in our centre, were collected and patients' functional abilities at the time of admission and discharge were analysed. Results: It has been observed that functional recovery depends on several factors: the type of surgery, the post-operative course and related complications, the hospitalisation time, the surgeon's techniques and expertise and the Orthopaedics centre where the operation is performed. Conclusions: In conclusion, data integration in perspective of an individualised rehabilitation program appears crucial for the functional recovery of the hip fracture patient

Usefulness of a simple sleep-deprived EEG protocol for epilepsy diagnosis in de novo subjects.

OBJECTIVE: In case series concerning the role of EEG after sleep deprivation (SD-EEG) in epilepsy, patients' features and protocols vary dramatically from one report to another. In this study, we assessed the usefulness of a simple SD-EEG method in well characterized patients. METHODS: Among the 963 adult subjects submitted to SD-EEG at our Center, in the period 2003-2010, we retrospectively selected for analysis only those: (1) evaluated for suspected epileptic seizures; (2) with a normal/non-specific baseline EEG; (3) still drug-free at the time of SD-EEG; (4) with an MRI analysis; (5) with at least 1year follow-up. SD-EEG consisted in SD from 2:00 AM and laboratory EEG from 8:00 AM to 10:30 AM. We analyzed epileptic interictal abnormalities (IIAs) and their correlations with patients' features. RESULTS: Epilepsy was confirmed in 131 patients. SD-EEG showed IIAs in 41.2% of all patients with epilepsy, and a 91.1% specificity for epilepsy diagnosis; IIAs types observed during SD-EEG are different in generalized versus focal epilepsies; for focal epilepsies, the IIAs yield in SD-EEG is higher than in second routine EEG. CONCLUSIONS: This simple SD-EEG protocol is very useful in de novo patients with suspected seizures. SIGNIFICANCE: This study sheds new light on the role of SD-EEG in specific epilepsy populations

Two Case Reports of Biliary Tract Injuries during Laparoscopic Cholecystectomy

Background and Study Aims. Biliary tract injuries (BTI) represent the most serious and potentially life-threatening complication of cholecystectomy occurring also during laparoscopic approaches. Patients and Methods. We describe and discuss two different cases of BTI occurring during laparoscopic cholecystectomy (LC). Results. Two patients developed BTI during LC and one evidenced the complication during the LC itself and was treated during the same LC in real time. The other patient evidenced BTI only after the primary intervention and was successfully reoperated in laparotomy after 10 days from the LC. Conclusions. The factors that predispose to the occurrence of BTI during cholecystectomy and the cautions to be used to prevent BTI are discussed

Ultrasound and cone beam CT fusion for liver ablation : technical note

Purpose: To assess the feasibility of fusion imaging between intraprocedural ultrasound (US) and contrast-enhanced cone-beam CT (CBCT) for small (&lt; 2 cm) hepatocellular carcinoma (HCC). Materials and methods: Six patients (five males, one female, age range 58\u201380, mean 69 years), with small (mean diameter 16.8 mm) HCC poorly visible at US underwent percutaneous microwave ablation under US/CBCT fusion guidance. During general anesthesia with apnea control, a contrast- enhanced CBCT was acquired with an active tracker. Subsequently, real time US images were fused with CBCT images, and treatment performed under fusion imaging guidance. Feasibility of fusion imaging and percutaneous ablation were assessed, correct targeting (distance from center of tumor and center of ablation area &lt;5 mm) and one-month primary technical efficacy were evaluated. Major and minor complications as well as overall procedural time were recorded. Results: US/CBCT fusion was feasible in all cases, allowing for completion of the treatment as previously planned (technical success 100%). Correct targeting was achieved in 4/6 cases (66%), while in two cases, center of tumor and center of ablated area were respectively 7 and 8 mm distant. At 1 month CT scan, all tumors were completely ablated (primary technical efficacy 100%). No major or minor complications occurred. Mean overall procedure time was 127 min. Conclusions: US/CBCT fusion is a feasible technique for liver ablation, and might represent a useful tool to increase the correct targeting of poorly US-visible HCC nodules in the angio suite