Changes in Cancer Patients' and Caregivers' Disease Perceptions While Receiving Early Palliative Care: A Qualitative and Quantitative Analysis.

BACKGROUND: Little is known about the underlying mechanisms through which early palliative care (EPC) improves multiple outcomes in patients with cancer and their caregivers. The aim of this study was to qualitatively and quantitatively analyze patients' and caregivers' thoughts and emotional and cognitive perceptions about the disease prior to and during the EPC intervention, and in the end of life, following the exposure to EPC. MATERIALS AND METHODS: Seventy-seven patients with advanced cancer and 48 caregivers from two cancer centers participated in semistructured interviews. Their reports were qualitatively and quantitatively analyzed by the means of the grounded theory and a text-analysis program. RESULTS: Participants reported their past as overwhelmed by unmanaged symptoms, with detrimental physical and psychosocial consequences. The EPC intervention allowed a prompt resolution of symptoms and of their consequences and empowerment, an appreciation of its multidimensional approach, its focus on the person and its environment, and the need for EPC for oncologic populations. Patients reported that conversations with the EPC team increased their acceptance of end of life and their expectation of a painless future. Quantitative analysis revealed higher use of Negative Affects (p < .001) and Biological Processes words (p < .001) when discussing the past; Agency words when discussing the present (p < .001); Positive Affects (p < .001), Optimism (p = .002), and Insight Thinking words (p < .001) when discussing the present and the future; and Anxiety (p = .002) and Sadness words (p = .003) when discussing the future. CONCLUSION: Overall, participants perceived EPC to be beneficial. Our findings suggest that emotional and cognitive processes centered on communication underlie the benefits experienced by participants on EPC. IMPLICATIONS FOR PRACTICE: By qualitative and quantitative analyses of the emotional and cognitive perceptions of cancer patients and their caregivers about their experiences before and during EPC interventions, this study may help physicians/nurses to focus on the disease perception by patients/caregivers and the benefits of EPC, as a standard practice. The analysis of words used by patients/caregivers provides a proxy for their psychological condition and support in tailoring an EPC intervention, based on individual needs. This study highlights that the relationship of the triad EPC team/patients/caregivers may rise as a therapeutic tool, allowing increasing awareness and progressive acceptance of the idea of death.

Docetaxel and prednisone with or without enzalutamide as first-line treatment in patients with metastatic castration-resistant prostate cancer: CHEIRON, a randomised phase II trial.

BACKGROUND: Pre-clinical data suggest that docetaxel and enzalutamide interfere with androgen receptor translocation and signalling. The aim of this study is to assess the efficacy of their concurrent administration in the first-line treatment for metastatic castration-resistant prostate cancer (mCRPC). METHODS: In this open-label, randomised, phase II trial, previously untreated mCRPC patients were randomised 1:1 to receive eight 21-d courses of docetaxel 75 mg/m2, oral prednisone 5 mg twice daily and oral enzalutamide 160 mg/d (arm DE), or the same treatment without enzalutamide (arm D). The primary end-point was the percentage of patients without investigator-assessed disease progression 6 months after the first docetaxel administration. RESULTS: The 246 eligible patients were randomly assigned to receive docetaxel, prednisone and enzalutamide (n = 120) or docetaxel and prednisone (n = 126). The 6-month progression rate was 12.5% (95% confidence interval [CI] 8.1-20.6) in arm DE and 27.8% (95% CI 22.8-39.4) in arm D (chi-squared test 10.01; P = 0.002). The most frequent grade III-IV adverse events were fatigue (12.5% in arm DE versus 5.6% in arm D), febrile neutropenia (9.3% versus 4.0%) and neutropenia (7.6% versus 5.6%). CONCLUSIONS: The combination of enzalutamide and docetaxel appears to be more clinically beneficial than docetaxel alone in previously untreated mCRPC patients, although serious adverse events were more frequent. Our findings suggest that first-line treatment with this combination could lead to an additional clinical benefit when prompt and prolonged disease control is simultaneously required. Clearly, these results should be considered cautiously because of the study's phase II design and the absence of an overall survival benefit. TRIAL REGISTRATION NUMBERS: EudraCT 2014-000175-43 - NCT02453009.

Different semantic and affective meaning of the words associated to physical and social pain in cancer patients on early palliative/supportive care and in healthy, pain-free individuals.

Early palliative/supportive care (ePSC) is a medical intervention focused on patient's needs, that integrates standard oncological treatment, shortly after a diagnosis of advanced/metastatic cancer. ePSC improves the appropriate management of cancer pain. Understanding the semantic and emotional impact of the words used by patients to describe their pain may further improve its assessment in the ePSC setting. Psycholinguistics assumes that the semantic and affective properties of words affect the ease by which they are processed and comprehended. Therefore, in this cross-sectional survey study we collected normative data about the semantic and affective properties of words associated to physical and social pain, in order to investigate how patients with cancer pain on ePSC process them compared to healthy, pain-free individuals. One hundred ninety patients and 124 matched controls rated the Familiarity, Valence, Arousal, Pain-relatedness, Intensity, and Unpleasantness of 94 words expressing physical and social pain. Descriptive and inferential statistics were performed on ratings in order to unveil patients' semantic and affective representation of pain and compare it with those from controls. Possible effects of variables associated to the illness experience were also tested. Both groups perceived the words conveying social pain as more negative and pain-related than those expressing physical pain, confirming previous evidence of social pain described as worse than physical pain. Patients rated pain words as less negative, less pain-related, and conveying a lower intense and unpleasant pain than controls, suggesting either an adaptation to the pain experience or the role played by ePSC in improving patients' ability to cope with it. This exploratory study suggests that a chronic pain experience as the one experienced by cancer patients on ePSC affects the semantic and affective representation of pain words.

Early versus delayed palliative/supportive care in advanced cancer: an observational study.

OBJECTIVE: The positive impact of early palliative care interventions in advanced cancer patients has so far been largely evaluated in randomised controlled trials. This study aimed at providing information on the value of early palliative/supportive care, integrated with standard oncologic care, in a real-life setting. METHODS: This was a retrospective observational study of 292 advanced cancer patients consecutively admitted at Carpi Hospital in Modena, Italy, between 2014 and 2017. For the purpose of this analysis, patients were classified into two groups (early and delayed palliative/supportive care patients), and analysed for different clinical indicators. Early and delayed palliative/supportive care were classified according to the time elapsed from advanced cancer diagnosis until palliative/supportive care start. RESULTS: A total of 200 patients (68%), with at least three visits, were included in the analyses. The frequency of chemotherapy use in the last 60 days of life was 3.4% and 24.6% in the early and delayed groups, respectively (adjusted OR=0.1; 95% CI 0.0 to 0.4; p=0.002). The estimated survival probability at 1 year was 74.5% (95% CI 65.0% to 85.4%) and 45.5% (95% CI 37.6% to 55.0%), in the early and delayed groups, respectively. Performance status, pain and all the Edmonton Symptom Assessment Scale items, assessed at baseline and at 1 to 12 weeks after the intervention, showed significant improvement over time. However, no between-group differences were found with regard to symptom outcomes. CONCLUSIONS: An earlier palliative/supportive care intervention was associated with reduced aggressiveness of therapy, in patients receiving community oncology care. Symptom burden was improved by early palliative/supportive care, independently of the timing of patient referral.

Mindfulness-Based stress reduction in early palliative care for people with metastatic cancer: A mixed-method study.

OBJECTIVES: To explore the impact of a Mindfulness-Based Stress Reduction (MBSR) intervention for people with metastatic cancer integrated in Early Palliative Care (EPC). DESIGN: Mixed-method study. SETTINGS/LOCATION: EPC Service integrated with Oncology Unit, Carpi General Hospital, Italy from January to October 2017. The MBSR intervention took place inside the hospital. SUBJECTS: Study participation was offered to 25 consecutive people referred to the EPC service. INCLUSION CRITERIA: people with metastatic cancer between 18 and 75 years old; informed consent. EXCLUSION CRITERIA: Performance Status <60% according to Karnofsky scale; active psychiatric disorder. 20 patients were included in the study. INTERVENTION: The adapted program consists of 8 meetings for 2.5 h once a week, a 4.5 h session between the 6th and 7th weeks and 0.5 h home practice daily. The following mindfulness practices were included during the training: formal sitting meditation, body scan, light yoga, walking meditation, and Aikido exercises. Participants were provided with materials for home practice. A qualified MBSR instructor conducted the program. Sessions were attended by a clinical psychologist and a physician trained in meditation, together with the palliative nurse as facilitators. OUTCOME MEASURES: Feasibility and acceptability were assessed on 16 participants. In addition, pre-post measures of cancer pain and mood state were collected. Semi-structured, in-depth interviews were conducted on a subset of 8 participants at the end of the study and analysed using the Interpretative-Phenomenological approach. RESULTS: MBSR attendance to meetings and adherence to home practice were 75%. MBSR intervention helped participants to develop an accepting attitude in respect to metastatic cancer disease helping them to face anxiety and cancer pain. MBSR improves self-regulation of mood state engendering feelings of compassion MBSR program supports participants in questioning and reconnecting with their values and spiritual beliefs. CONCLUSIONS: A Mindfulness intervention integrated into EPC setting is feasible, well accepted and could help metastatic cancer patients to control cancer pain together with an opportunity of emotional and spiritual relief.

Scalp Cooling in Daily Clinical Practice for Breast Cancer Patients Undergoing Curative Chemotherapy: A Multicenter Interventional Study.

OBJECTIVE: Chemotherapy-induced alopecia is a common and distressful side effect, especially among breast cancer patients. Scalp cooling (SC) can reduce hair loss during anthracycline- and taxane-based chemotherapy. This study assessed the effectiveness of SC in daily clinical practice in three Italian oncology units. METHODS: From 2014 to 2016, we prospectively included 220 female early-stage breast cancer patients undergoing curative chemotherapy in combination with SC using the Paxman device. Effectiveness was defined as the severity of hair loss according to the Common Terminology Criteria for Adverse Events Version 4.0 as follows: Grade 0, no hair loss; Grade 1, <50% hair loss not requiring a wig; and Grade 2, ≥50% hair loss at each cycle and at completion of chemotherapy. The tolerability and safety were also evaluated. RESULTS: The overall success rate of SC (hair loss Grade 0-1) was 68%. Severe hair loss was avoided in 89% of women receiving taxane-based chemotherapy and in 78% of women receiving both anthracyclines and taxanes. Among women undergoing anthracycline-based chemotherapy, 47% experienced hair preservation. SC was well tolerated, as only 20 patients discontinued SC for reasons other than hair loss. CONCLUSIONS: Our study confirmed that SC provides a reliable chance for breast cancer patients to keep their hair during taxane- and/or anthracycline-based chemotherapy.

Acupuncture As an Integrative Approach for the Treatment of Hot Flashes in Women With Breast Cancer: A Prospective Multicenter Randomized Controlled Trial (AcCliMaT).

PURPOSE: To determine the effectiveness of acupuncture for the management of hot flashes in women with breast cancer. PATIENTS AND METHODS: We conducted a pragmatic, randomized controlled trial comparing acupuncture plus enhanced self-care versus enhanced self-care alone. A total of 190 women with breast cancer were randomly assigned. Random assignment was performed with stratification for hormonal therapy; the allocation ratio was 1:1. Both groups received a booklet with information about climacteric syndrome and its management to be followed for at least 12 weeks. In addition, the acupuncture group received 10 traditional acupuncture treatment sessions involving needling of predefined acupoints. The primary outcome was hot flash score at the end of treatment (week 12), calculated as the frequency multiplied by the average severity of hot flashes. The secondary outcomes were climacteric symptoms and quality of life, measured by the Greene Climacteric and Menopause Quality of Life scales. Health outcomes were measured for up to 6 months after treatment. Expectation and satisfaction of treatment effect and safety were also evaluated. We used intention-to-treat analyses. RESULTS: Of the participants, 105 were randomly assigned to enhanced self-care and 85 to acupuncture plus enhanced self-care. Acupuncture plus enhanced self-care was associated with a significantly lower hot flash score than enhanced self-care at the end of treatment (P < .001) and at 3- and 6-month post-treatment follow-up visits (P = .0028 and .001, respectively). Acupuncture was also associated with fewer climacteric symptoms and higher quality of life in the vasomotor, physical, and psychosocial dimensions (P < .05). CONCLUSION: Acupuncture in association with enhanced self-care is an effective integrative intervention for managing hot flashes and improving quality of life in women with breast cancer.

Differentiation-dependent lysine 4 acetylation enhances MEF2C binding to DNA in skeletal muscle cells.

Myocyte enhancer factor 2 (MEF2) proteins play a key role in promoting the expression of muscle-specific genes in differentiated muscle cells. MEF2 activity is regulated by the association with several transcriptional co-factors and by post-translational modifications. In the present report, we provide evidence for a novel regulatory mechanism of MEF2C activity, which occurs at the onset of skeletal muscle differentiation and is based on Lys4 acetylation. This covalent modification results in the enhancement of MEF2C binding to DNA and chromatin. In particular, we report that the kinetic parameters of MEF2/DNA association change substantially upon induction of differentiation to give a more stable complex and that this effect is mediated by Lys4 acetylation. We also show that Lys4 acetylation plays a prominent role in the p300-dependent activation of MEF2C.

Low-density lipoprotein (LDL) receptor/transferrin fusion protein: in vivo production and functional evaluation as a potential therapeutic tool for lowering plasma LDL cholesterol.

A soluble form of human low-density lipoprotein receptor (LDL-R) fused in frame with rabbit transferrin (LDL-Rs(hu)/Tf(rab)) is assessed in vivo as a therapeutic tool for lowering plasma LDL cholesterol. The cDNA encoding LDL-Rs(hu)/Tf(rab) is expressed in mice, using a hydrodynamics-based gene transfer procedure. The transgene is transcribed in the liver of transduced animals and the corresponding protein is secreted into the bloodstream. Circulating LDL-Rs(hu)/Tf(rab) binds LDL specifically, thus indicating that it is correctly processed through the cellular compartments in vivo. More importantly, the expression of LDL-Rs(hu)/Tf(rab) allows the removal of injected human (125)I-labeled LDL ((123)I-LDL) from the bloodstream of transduced CD1 mice, which show faster LDL plasma clearance, anticipating by approximately 90 min the same clearance value observed in control animals. A similar effect is observed in transduced LDL-R(-/-) mice, in which the clearance of injected human LDL depends solely on the presence of circulating LDL-Rs(hu) /Tf(rab). In these animals the extent of plasma LDL clearance is directly related to the concentration of LDL-Rs(hu)/Tf(rab) in the blood. Finally, LDL-Rs(hu)/Tf(rab) does not alter the pattern of LDL organ distribution: in transduced animals, as well as in control animals, liver and bladder are the predominantly labeled organs after (123)I-LDL injection. However, LDL-Rs(hu)/Tf(rab) has a quantitative effect on LDL tissue deposition: in treated animals LDL-Rs(hu)/Tf(rab) determines an increase in radioactivity in the liver at early times after (123)I-LDL injection and a progressive labeling of the bladder, starting 20 min after injection.

Role of pleckstrin homology domain in regulating membrane targeting and metabolic function of insulin receptor substrate 3.

The insulin receptor phosphorylates insulin receptor substrate (IRS) proteins on multiple tyrosine residues that act as docking sites to recruit a number of downstream signaling molecules. Here we show that IRS3 is localized both at the plasma membrane and in the nucleus. Interestingly, the nuclear localization of the protein is restricted to specific regions involved in mRNA processing and known as speckles. By using different truncated versions of the protein, we demonstrate that the pleckstrin homology (PH) domain is involved in IRS3 localization at the level of both plasma membrane and nucleus. To our knowledge this is the first report of a PH domain responsible for a nuclear targeting of the host protein. By site-directed mutagenesis, we identify residues within the PH domain critical for proper localization of IRS3. Mutations within the PH domain preventing IRS3 intracellular localization result in an inhibition of IRS3-induced glucose uptake. We conclude that the PH domain is required for IRS3 intracellular localization and, furthermore, that it has a key role in metabolic functions of IRS3. In particular, our data suggest that IRS3 intracellular localization at the plasma membrane and in the nucleus is the result of two different cooperative mechanisms both involving the PH domain.