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 Potential Roles of Epigallocatechin-3-Gallate in the Treatment of Ovarian Cancer: Current State of Knowledge

Ovarian cancer represents the principal leading cause of women dying in the world. The first standard of care involved surgical resection followed by chemotherapy with taxane and platinum, mainly connected with cytotoxic chemotherapies causing diverse severe side effects. Unfortunately, recurrence represents a significant problem, and finally, patients develop resistance to cytotoxic chemotherapy. Other alternative treatments had been developed so far to reduce side effects; however, the outcomes are yet not empowering. Current shreds of evidence showed that epigallocatechin-3-gallate (EGCG) possesses an anticancer effect on ovarian carcinoma, mainly through the inhibition of different genetic signaling pathways which are closely linked with tumorigenesis. This review recapitulates these findings and highlights the roles of EGCG for the chemoprevention and treatment of ovarian cancer

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

Delayed Emergence from Anesthesia: What We Know and How We Act

The emergence from anesthesia is the stage of general anesthesia featuring the patient's progression from the unconsciousness status to wakefulness and restoration of consciousness. This complex process has precise neurobiology which differs from that of induction. Despite the medications commonly used in anesthesia allow recovery in a few minutes, a delay in waking up from anesthesia, called delayed emergence, may occur. This phenomenon is associated with delays in the operating room, and an overall increase in costs. Together with the emergence delirium, the phenomenon represents a manifestation of inadequate emergence. Nevertheless, in delayed emergence, the transition from unconsciousness to complete wakefulness usually occurs along a normal trajectory, although slowed down. On the other hand, this awakening trajectory could proceed abnormally, possibly culminating in the manifestation of emergence delirium. Clinically, delayed emergence often represents a challenge for clinicians who must make an accurate diagnosis of the underlying cause to quickly establish appropriate therapy. This paper aimed at presenting an update on the phenomenon, analyzing its causes. Diagnostic and therapeutic strategies are addressed. Finally, therapeutic perspectives on the "active awakening" are reported

Awareness during emergence from anesthesia: Features and future research directions

The anesthesia awareness with recall (AAWR) phenomenon represents a complication of general anesthesia consisting of memorization of intraoperative events reported by the patient immediately after the end of surgery or at a variable distance from it. Approximately 20% of AAWR cases occur during emergence from anesthesia. Clinically, these unexpected experiences are often associated with distress especially due to a sense of paralysis. Indeed, although AAWR at the emergence has multiple causes, in the majority of cases the complication develops when the anesthesia plan is too early lightened at the end of anesthesia and there is a lack of use, or misuse, of neuromuscular monitoring with improper management of the neuromuscular block. Because the distress caused by the sense of paralysis represents an important predictor for the development of severe psychological complications, the knowledge of the phenomenon, and the possible strategies for its prophylaxis are aspects of considerable importance. Nevertheless, a limited percentage of episodes of AAWR cannot be prevented. This paradox holds also during the emergence phase of anesthesia which represents a very complex neurophysiological process with many aspects yet to be clarified

Towards a better understanding of anesthesia emergence mechanisms: Research and clinical implications

: Emergence from anesthesia (AE) is the ending stage of anesthesia featuring the transition from unconsciousness to complete wakefulness and recovery of consciousness (RoC). A wide range of undesirable complications, including coughing, respiratory/cardiovascular events, and mental status changes such as emergence delirium, and delayed RoC, may occur during this critical phase. In general anesthesia processes, induction and AE represent a neurobiological example of "hysteresis". Indeed, AE mechanisms should not be simply considered as reverse events of those occurring in the induction phase. Anesthesia-induced loss of consciousness (LoC) and AE until RoC are quite distinct phenomena with, in part, a distinct neurobiology. Althoughanaesthetics produce LoC mostly by affecting cortical connectivity, arousal processes at the end of anesthesia are triggered by structures deep in the brain, rather than being induced within the neocortex. This work aimed to provide an overview on AE processes research, in terms of mechanisms, and EEG findings. Because most of the research in this field concerns preclinical investigations, translational suggestions and research perspectives are proposed. However, little is known about the relationship between AE neurobiology, and potential complications occurring during the emergence, and after the RoC. Thus, another scope of this review is to underline why a better understanding of AE mechanisms could have significant clinical implications, such as improving the patients' quality of recovery, and avoiding early and late postoperative complications

Phytocannabinoids in Triple Negative Breast Cancer Treatment: Current Knowledge and Future Insights

Triple negative breast cancer (TNBC) represents an aggressive subtype of breast cancer, which is deficient in estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Thus, TNBC cells are unable to respond to the conventional hormonal therapies, making chemotherapy the only therapeutic choice. Patients with TNBC develop metastasis and recurrence over time and have reduced survival compared to patients with other subtypes of breast cancer. Therefore, there is a need for innovative therapies. Data emerged from pre-clinical studies, highlighted various antitumor activities of plant-derived Cannabis sativa and synthetic cannabinoids (CBs), including delta-9-tetrahydrocannabinol (THC) and non-psychoactive cannabidiol (CBD). On the contrary, some studies indicated that CBs might also promote tumor progression. At present, clinical studies on the effects of CBs from Cannabis sativa in cancer patients are few. In the present study, we reviewed known and possible interactions between cannabinoids and TNBC therapies

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