Careful breakthrough cancer pain treatment through rapid-onset transmucosal fentanyl improves the quality of life in cancer patients: results from the best multicenter study

Objectives: To explore the effect of breakthrough cancer pain (BTcP) treatment on quality of sleep and other aspects of the health-related quality of life (HRQoL) in patients with cancer pain. Methods: In an observational, multicenter, cohort study, cancer patients from palliative care units, oncology departments, and pain clinics and affected by BTcP were included. Enrolled patients were assessed at the four visits: T0 (baseline), T7, T14, and T28. Stable chronic background pain (numeric rating scale, NRS <= 4) during the whole study period was mandatory. BTcP was treated through transmucosal fentanyl. Three questionnaires were used to measure the HRQoL: EORTC QLQ-C15-PAL, Pittsburgh Sleep Quality Index (PSQI), and the Edmonton Symptom Assessment System (ESAS). RESULTS: In 154 patients, the HRQoL showed a significant improvement for all physical and emotional characteristics in the EORTC QLQ-C15-PAL, except for nausea and vomiting (linear p-value = 0.1) and dyspnea (Linear p-value = 0.05). The ESAS and PSQI questionnaires confirmed these positive results (p < 0.0001 and p = 0.002, respectively). Conclusions: This prospective investigation by an Italian expert group, has confirmed that careful management of BTcP induces a paramount improvement on the HRQoL. Because in cancer patients there is a high prevalence of BTcP and this severe acute pain has deleterious consequences, this information can have an important clinical significance

Study of the role of Ofd1 in limb and endochondral bone development

Oral-facial-digital type I (OFDI) syndrome is a X-linked male lethal developmental disorder and belongs to the heterogeneous group of developmental disorders known as Oral-facial-digital syndromes (OFDs). This syndrome is ascribed to ciliary dysfunction and is characterized by malformation of the face, oral cavity and digits. Conditional inactivation using different Cre lines allowed us to study the role of the Ofd1 transcript in limb and skeletal development at embryonic and post-natal stages. We generated three conditional mutants. The first mutants were generated by crossing the Ofd1fl line with the transgenic line (Msx2Cre) that express the Cre recombinase under the control of the Msx2 promoter in the AER and the ventral ectoderm starting from E9.5-10. Limbs of Ofd1fl|Msx2Cre mice, display no skeletal phenotype indicating that Ofd1 does not play a role in limb patterning and outgrowth, although we cannot exclude a role for Ofd1 at earlier stages or in the dorsal ectoderm. The second mutants were obtained by crossing Ofd1fl female mice with the Prx1Cre transgenic male mice that express the Cre recombinase in the limb bud mesenchyme from E9.5, when the expression of Prx1Cre is predominant in the forelimb mesenchyme. By E10.5 the expression is evident in both limbs. Ofd1fl|Prx1Cre mice display a more severe skeletal phenotype in the forelimbs than in the hindilmbs. Skeletal defects include polydactyly with unpatterned digits, partial fusion of carpal joint elements and shortened long bones. We demonstrated that polydactyly in Ofd1fl|Prx1Cre mice was associated with progressive loss of Shh signaling and an impaired processing of Gli3. Shortened long bones were due to defective Ihh signaling, decreased proliferation and to premature differentiation of hypertrophic chondrocytes. In addition Ofd1fl|Prx1Cre mice display defective formation of the bone collar. Immunofluorescence and ultrastructural studies allowed us to demonstrate that Ofd1 is necessary for correct ciliogenesis in the limb bud mesenchyme and chondrocytes of long bones. These results indicate that, contrary to what previously shown for the embryonic node, in the limb bud mesenchyme and in the chondrocytes, Ofd1 is necessary for normal ciliogenesis but not for cilia outgrowth. Overall, these results suggest that Ofd1 is required in the mesenchyme at early stages of limb morphogenesis for Shh signaling to determine anteroposterior patterning of the digits and at later stages for proper endochondral bone formation. Finally we generated a thirth mouse model with inactivation of Ofd1 in limb chondrocytes via Col2a-Cre-mediated recombination. Ofd1fl|Col2aCre display dwarfism by P30 days after birth that was accompanied by complete loss of growth plate and depletion of chondrocyte cilia. The results demonstrate a role for Ofd1 in the process of post-natal skeletal development

The role of general anesthetics and the mechanisms of hippocampal and extra-hippocampal dysfunctions in the genesis of postoperative cognitive dysfunction

Postoperative cognitive dysfunction (POCD) is a multifactorial process with a huge number of predisposing, causal, and precipitating factors. In this scenario, the neuroinflammation and the microglial activation play a pivotal role by triggering and amplifying a complex cascade involving the immuno-hormonal activation, the micro circle alterations, the hippocampal oxidative stress activation and, finally, an increased blood-brain barrier's permeability. While the role of anesthetics in the POCD's genesis in humans is debated, a huge number of preclinical studies have been conducted on the topic and many mechanisms have been proposed to explain the potential neurodegenerative effects of general anesthetics. Probably, the problem concerns on what we are searching for and how we are searching and, surprisingly, preclinical studies showed that anesthetics may also manifest neuroprotective properties. The aim of this paper is to offer an overview on the potential impact of general anesthetics on POCD. Mechanisms of hippocampal and extra-hippocampal dysfunction due to neuroinflammation are discussed, whereas further research perspectives are also given

The Role of Morphine in Animal Models of Human Cancer: Does Morphine Promote or Inhibit the Tumor Growth?

Morphine, a highly potent analgesic agent, is widely used to relieve pain and suffering of patients with cancer. Additionally, it has been reported that morphine is important in the regulation of cancerous tissue. Morphine relieves pain by acting directly on the central nervous system, although its activities on peripheral tissues are responsible for many adverse side effects. For these reasons, it is very important also to understand the role of morphine in cancer treatment. The published literature reporting the effect of morphine on tumor growth presents some discrepancies, with reports suggesting that morphine may either promote or inhibit the tumor growth. It has been also demonstrated that morphine modulates angiogenesis which is important for primary tumour growth, invasiveness, and the development of metastasis. This review will focus on the latest findings on the role of morphine in the regulation of cancer cell growth and angiogenesis

The efficacy of Epigallocatechin-3-gallate (green tea) in the treatment of Alzheimer’s disease: an overview of pre-clinical studies and translational perspectives in clinical practice

Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder and the most common form of dementia characterized by cognitive and memory impairment. One of the mechanism involved in the pathogenesis of AD, is the oxidative stress being involved in AD‘s development and progression. In addition, several studies proved that chronic viral infections, mainly induced by Human herpesvirus 1 (HHV-1), Cytomegalovirus (CMV), Human herpesvirus 2 (HHV-2), and Hepatitis C virus (HCV) could be responsible for AD’s neuropathology. Despite the large amount of data regarding the pathogenesis of Alzheimer’s disease (AD), a very limited number of therapeutic drugs and/or pharmacological approaches, have been developed so far. It is important to underline that, in recent years, natural compounds, due their antioxidants and anti-inflammatory properties have been largely studied and identified as promising agents for the prevention and treatment of neurodegenerative diseases, including AD. The ester of epigallocatechin and gallic acid, (−)-Epigallocatechin-3-Gallate (EGCG), is the main and most significantly bioactive polyphenol found in solid green tea extract. Several studies showed that this compound has important anti-inflammatory and antiatherogenic properties as well as protective effects against neuronal damage and brain edema. To date, many studies regarding the potential effects of EGCG in AD’s treatment have been reported in literature. The purpose of this review is to summarize the in vitro and in vivo pre-clinical studies on the use of EGCG in the prevention and the treatment of AD as well as to offer new insights for translational perspectives into clinical practice

Curcumin Inhibits Tumor Growth and Angiogenesis in an Orthotopic Mouse Model of Human Pancreatic Cancer

Pancreatic cancer is a malignant neoplasm originating from transformed cells arising in tissues forming the pancreas. The best chemotherapeutic agent used to treat pancreatic cancer is the gemcitabine. However, gemcitabine treatment is associated with many side effects. Thus novel strategies involving less toxic agents for treatment of pancreatic cancer are necessary. Curcumin is one such agent that inhibits the proliferation and angiogenesis of a wide variety of tumor cells, through the modulation of many cell signalling pathways. In this study, we investigated whether curcumin plays antitumor effects in MIA PaCa-2 cells. In vitro studies showed that curcumin inhibits the proliferation and enhances apoptosis of MIA PaCa-2 cells. To test whether the antitumor activity of curcumin is also observed in vivo, we generated an orthotopic mouse model of pancreatic cancer by injection of MIA PaCa-2 cells in nude mice. We placed mice on diet containing curcumin at 0.6% for 6 weeks. In these treated mice tumors were smaller with respect to controls and showed a downregulation of the transcription nuclear factor NF-κB and NF-κB-regulated gene products. Overall, our data indicate that curcumin has a great potential in treatment of human pancreatic cancer through the modulation of NF-κB pathway

Coffee intake decreases risk of postmenopausal breast cancer: A dose-response meta-analysis on prospective cohort studies

Abstract: Aim: A dose-response meta-analysis was conducted in order to summarize the evidence from prospective cohort studies regarding the association between coffee intake and breast cancer risk. Methods: A systematic search was performed in electronic databases up to March 2017 to identify relevant studies; risk estimates were retrieved from the studies and linear and non-linear dose-response analysis modelled by restricted cubic splines was conducted. A stratified and subgroup analysis by menopausal and estrogen/progesterone receptor (ER/PR) status, smoking status and body mass index (BMI) were performed in order to detect potential confounders. Results: A total of 21 prospective studies were selected either for dose-response, the highest versus lowest category of consumption or subgroup analysis. The dose-response analysis of 13 prospective studies showed no significant association between coffee consumption and breast cancer risk in the non-linear model. However, an inverse relationship has been found when the analysis was restricted to post-menopausal women. Consumption of four cups of coffee per day was associated with a 10% reduction in postmenopausal cancer risk (relative risk, RR 0.90; 95% confidence interval, CI 0.82 to 0.99). Subgroup analyses showed consistent results for all potential confounding factors examined. Conclusions: Findings from this meta-analysis may support the hypothesis that coffee consumption is associated with decreased risk of postmenopausal breast cancer

Radio-frequency ablation-based studies on VX2rabbit models for HCC treatment

Hepatocellular carcinoma (HCC) is the fifth most frequent cancer worldwide with high morbidity, mortality and increasing incidence. It is of note that the main curative therapies for HCC are hepatic resection and transplantation although the majority of patients at the time of presentation are not eligible for resection or orthotopic liver transplantation (OLT) due to the underlying cirrhosis. Currently, a variety of loco-regional therapies, including radiofrequency ablation (RFA), percutaneous ethanol injection (PEI), microwave coagulation therapy (MCT), transarterial chemoembolization (TACE) and others, have been developed as alternative treatment options for HCC. Among these techniques, RFA is currently the most widely used treatment, due to its several advantages, such as safety and efficacy. To date, the effectiveness of RFA for HCC is reduced by the presence of residual tumor as a consequence of insufficient treatment. In order to ameliorate the effects of RFA on HCC, several in vivo studies, have been performed on its application as single or in combination treatment with drugs or others loco-regional therapies, by using rabbit VX2 liver model. This represents an ideal model of liver cancers and is widely used for imaging and other experimental studies due to the rapid growth of these tumors and their similarity to human hepatocellular carcinoma. In order to elucidate the therapeutic potential of RFA with adjuvant treatments for HCC, we reviewed the latest findings on the RFA-based studies in rabbit VX2 hepatocarcinoma models

Dissecting the Role of Curcumin in Tumour Growth and Angiogenesis in Mouse Model of Human Breast Cancer

Breast cancer is considered the most common cancer for women worldwide and it is now the second leading cause of cancer-related deaths among females in the world. Since breast cancer is highly resistant to chemotherapy, alternative anticancer strategies have been developed. In particular, many studies have demonstrated that curcumin, a derivative of turmeric, can be used as natural agent in treatment of some types of cancer by playing antiproliferative and antioxidant effects. In our study, we assessed the antitumor activities of curcumin in ER-negative human breast cancer cell line resistant to chemotherapy, MDA.MB231 by in vitro and in vivo experiments. In vitro data allowed us to demonstrate that curcumin played a role in regulation of proliferation and apoptosis in MDA.MB231 cells. In vivo, by generation of mouse model of breast cancer, we showed that treatment of curcumin inhibited tumor growth and angiogenesis. Specifically, we showed that curcumin is able to deregulate the expression of cyclin D1, PECAM-1, and p65, which are regulated by NF-κB. Our data demonstrated that curcumin could be used as an adjuvant agent to chemotherapy in treatment of triple negative breast cancer