BRAF Inhibitors in Non-Small Cell Lung Cancer.

RAF family proteins are serine-threonine kinases that play a central role in the MAPK pathway which is involved in embryogenesis, cell differentiation, cell proliferation and death. Deregulation of this pathway is found in up to 30% of all human cancers and BRAF mutations can be identified in 1.5-3.5% of NSCLC patients. Following the positive results obtained through the combination of BRAF and MEK inhibitors in BRAF-mutant melanoma, the same combination was prospectively assessed in BRAF-mutant NSCLC. In cohort B of the BRF113928 trial, 57 pretreated NSCLC patients were treated with dabrafenib plus trametinib: an ORR of 68.4%, a disease control rate of 80.7%, a median PFS of 10.2 months and a median OS of 18.2 months were observed. Similar results were reported in the first-line setting (cohort C), with an ORR of 63.9%, a DCR of 75% and a median PFS and OS of 10.2 and 17.3 months, respectively. The combination was well tolerated: the main adverse events were pyrexia (64%), nausea (56%), diarrhoea (56%), fatigue (36%), oedema (36%) and vomiting (33%). These positive results led to the approval of the combination of dabrafenib and trametinib for the treatment of BRAF V600E metastatic NSCLC patients regardless of previous therapy. Ongoing research should better define the role of new generation RAF inhibitors for patients with acquired resistance, the activity of chemo-immunotherapy or the combination of TKIs with chemotherapy or with immunotherapy in patients with BRAF-mutated cancers.

Could the perioperative use of opioids influence cancer outcomes after surgery? A scoping review protocol.

BACKGROUND: During and after general anaesthesia, opioids are commonly used for pain treatment. Since preclinical studies underlined the potential immunosuppressive activity of these drugs, it was postulated that their perioperative administration could influence cancer outcomes after surgery. Nevertheless, clinical data have been extrapolated mainly from retrospective analyses. Consequently, the precise link between perioperative opioid use and cancer recurrence/metastasis or cancer-related mortality/morbidity is still an unsolved issue. METHODS AND ANALYSIS: This scoping review is planned to follow the Joanna Briggs Institute recommendations. The authors will conduct a literature review through the PRISMA statement using PubMed and EMBASE databases; the Grey literature will be explored using Google Scholar and Conference Proceedings Citation Index (via Web of Science). The search strategy will be limited to articles published in the English language and to human studies. The database searches are planned from the inception to January 2022. Two reviewers will independently screen titles and abstracts, followed by a full-text screening of potentially relevant articles with standardised data extraction. Any disagreement for the inclusion between the two reviewers will be discussed with a third reviewer. ETHICS AND DISSEMINATION: The review aims to map the available literature, focusing on a possible association between perioperative opioid use and cancer outcomes in patients undergoing surgery. The proposed approach will be useful to identify and analyse the knowledge gap in the field and serve as a prerequisite for future research. SCOPING REVIEW REGISTRATION: Open Science Framework https://osf.io/vfhw6/ DOI 10.17605/OSF.IO/VFHW6.

Bibliometric Network Analysis on Rapid-Onset Opioids for Breakthrough Cancer Pain Treatment.

BACKGROUND AND OBJECTIVES: Proper breakthrough cancer pain (BTcP) management is of pivotal importance. Although rapid-acting, oral and nasal transmucosal, fentanyl formulations (rapid-onset opioids, ROOs) are licensed for BTcP treatment, not all guidelines recommend their use. Presumably, some research gaps need to be bridged to produce solid evidence. We present a bibliometric network analysis on ROOs for BTcP treatment. METHODS: Documents were retrieved from the Web of Science (WOS) online database. The string was "rapid onset opioids" or "transmucosal fentanyl" and "breakthrough cancer pain". Year of publication, journal metrics (impact factor and quartile), title, document type, topic, and clinical setting (in-patients, outpatients, and palliative care) were extracted. The software tool VOSviewer (version 1.6.17) was used to analyze the semantic network analyzes, bibliographic coupling, journals analysis, and research networks. RESULTS: 502 articles were found in WOS. A declining trend in published articles from 2014 to 2021 was observed. Approximately 50% of documents regard top quartile (Q1) journals. Most articles focused on ROOs efficacy, but abuse and misuse issues are poorly addressed. With respect to article type, we calculated 132 clinical investigations. The semantic network analysis found interconnections between the terms "breakthrough cancer pain," "opioids," and "cancers." The top co-cited article was published in 2000 and addressed pain assessment. The largest number of partnerships regarded the United States, Italy, and England. CONCLUSION: In this research area, most articles are published in top-ranked journals. Nevertheless, paramount topics should be better addressed, and the implementation of research networks is needed.

An Overview on the Potential Roles of EGCG in the Treatment of COVID-19 Infection.

Coronavirus disease-19 (COVID-19) pandemic is currently ongoing worldwide and causes a lot of deaths in many countries. Although different vaccines for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection have been developed and are now available, there are no effective antiviral drugs to treat the disease, except for Remdesivir authorized by the US FDA to counteract the emergency. Thus, it can be useful to find alternative therapies based on the employment of natural compounds, with antiviral features, to circumvent SARS-CoV-2 infection. Pre-clinical studies highlighted the antiviral activities of epigallocatechin-3-gallate (EGCG), a catechin primarily found in green tea, against various viruses, including SARS-CoV-2. In this review, we summarize this experimental evidence and highlight the potential use of EGCG as an alternative therapeutic choice for the treatment of SARS-CoV-2 infection.

The psychological impact of COVID-19 pandemic on patients with neuroendocrine tumors: Between resilience and vulnerability.

The COVID-19 pandemic has added another layer of complexity to the fears of patients with neuroendocrine tumors (NETs). Little is known regarding the psychological impact of the COVID-19 outbreak on patients with gastroenteropancreatic or bronchopulmonary (BP) NETs. We longitudinally surveyed the mental symptoms and concerns of NET patients during the plateau phase of the first (W1) and second epidemic waves (W2) in Italy. Seven specific constructs (depression, anxiety, stress, health-related quality of life, NET-related quality of life, patient-physician relationship, psychological distress) were investigated using validated screening instruments, including DASS-21, EORTC QLQ-C30, EORTC QLQ GI.NET21, PDRQ9 and IES-R. We enrolled 197 patients (98 males) with a median age of 62 years. The majority of the patients had G1/G2 neoplasms. Some 38% of the patients were on active treatment. At W1, the prevalence of depression, anxiety and stress was 32%, 36% and 26% respectively. The frequency of depression and anxiety increased to 38% and 41% at W2, whereas no modifications were recorded in the frequency of stress. Poor educational status was associated with higher levels of anxiety at both W1 (odds ratio [OR] = 1.33 ± 0.22; p = .07) and W2 (OR = 1.45 ± 0.26; p = .03). Notably, post-traumatic stress symptoms were observed in the 58% of the patients, and both single marital status (OR = 0.16, 95% confidence interval [CI] = 0.06-0.48; p = .0009) and low levels of formal education (OR = 0.47, 95% CI = 0.23-0.99; p = .05) predicted their occurrence. No significant deteriorations of health-related quality of life domains were observed from W1 to W2. High patient care satisfaction was documented despite the changes in health systems resource allocation. NET patients have an increased risk of developing post-traumatic stress symptoms as result of the COVID-19 pandemic. Specific screening measures and psychological interventions should be implemented in NET clinics to prevent, recognize and treat mental distress in this vulnerable population.

Strategies to evaluate outcomes in long-COVID-19 and post-COVID survivors.

SARS-CoV-2 infection can impact the physical, cognitive, mental health of patients, especially in those recovered in intensive care units. Moreover, it was proved that the effects of the virus may persist for weeks or months. The term long-COVID or post-COVID syndrome is commonly used for indicating a variety of physical and psychological symptoms that continue after the resolution of the acute phase. This narrative review is aimed at providing an updated overview of the impact of physical, cognitive, and psychological health disorders in COVID-19 survivors, by summarizing the data already published in literature in the last year. Studies cited were found through PubMed searches. We also presented an overview of the post-COVID-19 health consequences on three important aspects: nutritional status, neurological disorders, and physical health. Moreover, to activate a correct health planning policy, a multidisciplinary approach for addressing the post- COVID-19 issue, has been proposed. Finally, the involvement of health professionals is necessary even after the pandemic, to reduce expected post-pandemic psychosocial responses and mental health disorders.

COVID-Pain: Acute and Late-Onset Painful Clinical Manifestations in COVID-19 - Molecular Mechanisms and Research Perspectives.

Although the respiratory manifestations of COVID-19 are predominant, signs and symptoms of an extra-pulmonary involvement are usually encompassed among the clinical picture of the disease. Several painful manifestations can occur during the acute phase but also as short- or long-term complications. Myalgia, joint pain, sore throat, abdominal pain, chest pain, and headache usually accompany respiratory symptoms, but they can also occur as isolated clinical findings or can be expressed regardless of the severity of COVID-19. On these premises, given the vast spectrum of clinical manifestations and the complexity of their pathogenesis, it would be more appropriate to refer to "COVID-pain", an umbrella term useful for encompassing all these clinical manifestations in a separate chapter of the disease. In this scenario, we addressed the topic from a molecular perspective, trying to provide explanations for the underlying pathophysiological processes. Consequently, this narrative review is aimed at dissecting the mechanisms of acute and chronic painful manifestations, summarizing fundamental concepts on the matter, controversies, current research gaps, and potential developments in this field.

Effects of the Hypnotic Alkylphenol Derivative Propofol on Breast Cancer Progression. A Focus on Preclinical and Clinical Studies.

Propofol is a hypnotic alkylphenol derivative with many biological activities. It is predominantly used in anesthesia and is the most used parenteral anesthetic agent in the United States. Accumulating preclinical studies have shown that this compound may inhibit cancer recurrence and metastasis. Nevertheless, other investigations provided evidence that this compound may promote breast cancer cell progression by modulating different molecular pathways. Clinical data on this topic are scarce and derive from retrospective analyses. For this reason, we reviewed and evaluated the available data to reveal insight into this controversial issue. More preclinical and clinical investigations are necessary to determine the potential role of propofol in the proliferation of breast cancer cells.

Multidimensional Statistical Technique for Interpreting the Spontaneous Breakthrough Cancer Pain Phenomenon. A Secondary Analysis from the IOPS-MS Study.

Breakthrough cancer pain (BTcP) is a temporary exacerbation of pain that "breaks through" a phase of adequate pain control by an opioid-based therapy. The non-predictable BTcP (NP-BTcP) is a subtype of BTcP that occurs in the absence of any specific activity. Since NP-BTcP has an important clinical impact, this analysis is aimed at characterizing the NP-BTcP phenomenon through a multidimensional statistical technique. This is a secondary analysis based on the Italian Oncologic Pain multiSetting-Multicentric Survey (IOPS-MS). A correlation analysis was performed to characterize the NP-BTcP profile about its intensity, number of episodes per day, and type. The multiple correspondence analysis (MCA) determined the identification of four groups (phenotypes). A univariate analysis was performed to assess differences between the four phenotypes and selected covariates. The four phenotypes represent the hierarchical classification according to the status of NP-BTcP: from the best (phenotype 1) to the worst (phenotype 4). The univariate analysis found a significant association between the onset time >10 min in the phenotype 1 (37.3%)' vs. the onset > 10 min in phenotype 4 (25.8%) (p < 0.001). Phenotype 1 was characterized by the gastrointestinal type of cancer (26.4%) with respect to phenotype 4, where the most frequent cancer affected the lung (28.8%) (p < 0.001). Phenotype 4 was mainly managed with rapid-onset opioids, while in phenotype 1, many patients were treated with oral, subcutaneous, or intravenous morphine (56.4% and 44.4%, respectively; p = 0.008). The ability to characterize NP-BTcP can offer enormous benefits for the management of this serious aspect of cancer pain. Although requiring validation, this strategy can provide many indications for identifying the diagnostic and therapeutic gaps in NP-BTcP management.

The Role of Anti-Nerve Growth Factor Monoclonal Antibodies in the Control of Chronic Cancer and Non-Cancer Pain.

Nerve growth factor (NGF) belongs to the neurotrophin family and plays a fundamental role in the endurance of sensory and sympathetic neurons during embryogenesis. NGF, by interacting with tropomyosin receptor kinase A receptor (TrkA), modulates the pain pathway through the enhancement of the neurotrophic and nociceptor functions. Moreover, it has been demonstrated that NGF is upregulated in patients with chronic pain syndromes, which are difficult to treat. Thus, new non-pharmacological approaches, based on the use of different species-specific monoclonal antibodies (mAbs) targeting the NGF pathway, have been tested for the treatment of chronic pain in preclinical and clinical studies. With regard to preclinical investigations, anti-NGF mAbs have been used for the management of osteoarthritis (OA) and chronic low back pain animal models, with encouraging results. Moreover, anti-NGF mAb therapy is effective in animal models of neuropathic cancer pain. As regards patients with OA, although phase II and phase III clinical trials with tanezumab led to pain reduction, the safety was not observed in all these patients. Here, we review the preclinical and clinical studies on anti-NGF mAb therapy in chronic syndromes, dissect the role of NGF in pain transduction, and highlight the use of anti-NGF mAbs in humans.

Advantages and issues of concern regarding approaches to peripheral nerve block for total hip arthroplasty.

In older patients with comorbidities, hip fractures are both an important and debilitating condition. Since multimodal and multidisciplinary perioperative strategies can hasten functional recovery after surgery improving clinical outcomes, the choice of the most effective and safest pathway represents a great challenge. A key point of concern is the anesthetic approach and above all the choice of the locoregional anesthesia combined with general or neuraxial anesthesia.

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.

Naloxone Counteracts the Promoting Tumor Growth Effects Induced by Morphine in an Animal Model of Triple-negative Breast Cancer.

BACKGROUND/AIM: Our group has previously demonstrated, in in vitro and in vivo studies on triple-negative breast cancer, that morphine promoted breast cancer progression whereas naloxone was able to reduce it. In this subsequent investigation, we aimed to assess the combinatorial effects of these two drugs in an animal model of triple negative breast cancer. MATERIALS AND METHODS: In order to evaluate the in vivo effects of the combination of morphine and naloxone in human breast cancer, a mouse model of human triple-negative breast cancer was generated by injecting the MDA-MB-231 cells subcutaneously in nude mice. Naloxone and morphine were daily intraperitoneally co-injected in mice for 4 weeks at two different doses. Micro-vessel formation was detected by fluorescein isothiocyanate-dextran (100 µl) injected into the lateral tail vein of mice and confirmed by immunohistochemistry for PECAM-1 on mice tumor sections. RESULTS: In vivo experiments showed that naloxone was able to counteract the promoting effects of morphine on tumor growth. No impairment of micro-vessel formation in tumors of mice treated with the two drugs was observed. CONCLUSION: Herein, we demonstrated that naloxone was able to counteract the promoting effects of morphine on tumor growth without impairing micro-vessel formation.

Multimodal approaches and tailored therapies for pain management: the trolley analgesic model.

Chronic pain is described as a manifestation of real or potential tissue damage. It is identified as a perception influenced by the complex interactions of biological, psychological, and social factors. Different types of pain and their comorbidities dramatically affect patients' quality of life and their families. Due to diverse etiology and pathogenesis, pain management represents a controversial issue in clinical practice. In 1986, the WHO developed a three-step ladder model based on the use of analgesics for pain management according to pain intensity in a linear up or down movement. Despite its huge value for pain relief, this model has some limitations, and some controversies in the pharmacotherapy of pain management have arisen so far. To bypass these difficulties, the concept of WHO analgesic ladder has been contested and changed into a four bidirectional step model which postulates the use of the invasive procedures (neuromodulatory and neurosurgical procedures). Moreover, with the introduction of the neuromatrix theory for dealing the acute and the chronic pain, the WHO model was newly reinterpreted and changed into a platform analgesic model that includes multimodal pharmacological and alternative treatments applicable to all pain conditions, although excludes the precision therapies. Here, we summarize and revise these concepts in order to propose a new model termed "trolley analgesic model" that will allow adopting tailored therapies with dynamic multimodal approaches for pain management according to 1) the pain intensity, 2) the physiopathology of pain, 3) the complexity of symptoms, 4) the presence of comorbidity, and 5) the physiopathological factors and the social context.

The effects of naloxone on human breast cancer progression: in vitro and in vivo studies on MDA.MB231 cells.

BACKGROUND: Naloxone is viewed as a specific competitive opioid antagonist acting at the level of opioid receptors (µ, δ, and κ) with blended agonist-adversary or agonist action. The role of naloxone in tumor cell growth has been poorly studied in human cancer cell lines. MATERIALS AND METHODS: In the present study, we report findings from in vitro and in vivo experiments performed to evaluate the effects of naloxone on human breast cancer cell growth and progression. In vitro assays were conducted on estrogen receptor-negative human breast carcinoma cells, MDA.MB231, treated with naloxone at different concentrations (10-100 µM). In vivo experiments were performed on a mouse model of human triple-negative breast cancer generated by using MDA.MB231 injected subcutaneously in mice. Naloxone was daily intraperitoneally injected in mice at 0.357 mg/kg for 2 weeks and at 0.714 mg/kg for the next 2 weeks. Microvessels formation was detected by fluorescein isothiocyanate-dextran (100 µL) injected into the tail vein of mice and confirmed by immunohistochemistry with CD31 on mice tumor sections. RESULTS: In vitro tests showed that the cell proliferation of MDA.MB231 was inhibited by naloxone in a dose-dependent manner, whereas the cell death was increased. In vivo studies demonstrated that tumors of mice treated with naloxone were significantly smaller than those observed in the control groups, as long as naloxone was administered. Finally, naloxone was not able to impair the microvessel formation in tumors of treated mice. CONCLUSION: Our data showed, for the first time, that naloxone reduced breast cancer progression without affecting angiogenesis.

Anesthetic dreaming, anesthesia awareness and patient satisfaction after deep sedation with propofol target controlled infusion: A prospective cohort study of patients undergoing day case breast surgery.

BACKGROUND: Anesthetic dreaming and anesthesia awareness are well distinct phenomena. Although the incidence of intraoperative awareness is more common among patients who reported a dream after surgery, the exact correlation between the two phenomena remains an unsolved rebus. The main purpose of this study was to investigate anesthetic dreaming, anesthesia awareness and psychological consequences eventually occurred under deep sedation. Intraoperative dreaming experiences were correlated with dream features in natural sleep. METHODS: Fifty-one patients, undergoing surgical excision of fibroadenomas under a Bispectral index-guided deep sedation anesthesia with propofol target controlled infusion, were enrolled into this prospective study. Psychological assessment was performed through the State Trait Anxiety Inventory. A questionnaire was adopted to register dreaming and anesthesia awareness. Data were collected after emergence (t0), 24 hours (t1), 1 month (t2), 6 months (t3). RESULTS: Six patients (12%) reported anesthetic dreaming at t0 confirming the response at each subsequent evaluation. One patient (2%) confirmed dreaming during anesthesia in all, but denied it at t0. There was a high correlation between the intraoperative dream contents and the features of dreams in natural sleep. No cases of anesthesia awareness were detected. A similar level of satisfaction was observed in dreaming and no-dreaming patients. CONCLUSIONS: Anesthetic dreaming does not seem to influence satisfaction of patients undergoing deep sedation with propofol target controlled infusion. A psychological assessment would seem to improve the evaluation of possible psychological consequences in dreamer patient.

The underestimated role of psychological and rehabilitation approaches for management of cancer pain. A brief commentary.

Individually tailored pharmacological regimen is the standard approach for treating patients affected by cancer pain, allowing the control of symptoms in approximately 90% of cases. If this strategy is ineffective it is possible to use more complex invasive, or minimally invasive, techniques. Nevertheless, both patients and health care professionals often underestimate the impact of cancer pain on psychological distress, and do not consider the potential benefits of psychological treatments to help manage cancer pain. These non-pharmacological strategies should be part of the multidisciplinary pain therapy, supporting and strengthening drug therapy. The purpose of this brief commentary is to discuss the role of psychological and rehabilitation approaches for improving the quality of life and the psychosocial outcomes in patients with cancer pain.

A 7-Year Retrospective Multisource Analysis on the Incidence of Anesthesia Awareness With Recall in Cancer Patients: A Chance of Collaboration Between Anesthesiologists and Psycho-Oncologists for Awareness Detection.

Although randomized controlled studies reported an incidence of anesthesia awareness with recall ∼1 to 2 per 1000 (0.1-0.2%), recent data from the NAP5 study showed an incidence of only 1:19,600. Although in a prospective study many tools for anesthesia awareness detection can be used, a retrospective analysis requires a careful collection of information.The aim of the study was to evaluate the incidence of anesthesia awareness with recall in a cohort of cancer patients through a multisource retrospective analysis, and the clinical description, including the psychological outcome, of the cases detected. We also tested whether our retrospective analysis would be improved by a routinely psycho-oncological assessment. As secondary endpoints we evaluated the use of depth of anesthesia monitoring over a large cohort of patients, and the correlation between the brain monitoring and the incidence of awareness.We have carried out a 7-year retrospective analysis in a large cohort of cancer patients on the incidence of awareness with recall during general anesthesia. Of 35,595 patients assessed for eligibility, 21,099 were studied. We analyzed all data from the operative rooms' database, the anesthesia records, and from the database of the surgical divisions. In addition we examined reports from psychologists and spontaneous reports to the quality team of the hospital.Two certain cases of awareness were detected, with an incidence of 1:10,550 (0.0095%). They occurred during elective surgery, in female patients without other risk factors. One case came from the report of a psychologist. In both episodes, brain monitoring was not applied and no long-term psychological sequelae were reported.Despite the limitations, our investigation suggests that the incidence of anesthesia awareness is very low, also in a specific cohort of patients, such as the cancer patients, and even when the depth of anesthesia monitoring is rarely used. The limitations caused by both the retrospective analysis and the absence of specific tools for direct awareness detection, such as structured interviews, can be filled with an effective postoperative psychological assessment which is often of routine in a cancer center. This observation could suggest the usefulness of inserting specific questions within the psychological tools commonly used by psycho-oncologists.

Efficacy and gastrointestinal tolerability of oral oxycodone/naloxone combination for chronic pain in outpatients with cancer: an observational study.

Combination opioid agonist/antagonist therapy has been shown to preserve bowel function in patients with chronic cancer pain. This retrospective study evaluated the efficacy and tolerability of prolonged-released fixed-dose oxycodone-naloxone (PR OXN) in consecutive outpatients with chronic cancer pain. Of 206 patients prescribed PR OXN (mean age 61.3 ± 12.9 years; 52.9% female), 31.5% were opioid naïve. PR OXN was associated with a significant decrease in pain score measured on a visual analogue scale over 28 days (P < .0001), without adverse effects on bowel function, nor change in laxative use. PR OXN efficacy and tolerability were similar in opioid-naïve and -experienced patients, and among age-stratified subgroups. No severe side effects occurred. In a real-life outpatient setting, PR OXN provided analgesia without bowel dysfunction in patients with chronic cancer pain.