Bispectral Index monitoring of palliative sedation for home withdrawal of tracheostomy ventilation: A case report.

BACKGROUND: Tracheostomy ventilation in motor neurone disease is an uncommon life-sustaining treatment. Best practice is having a plan for ventilation withdrawal, but the literature to guide practice is limited. Case reports have documented standard doses of opioids and benzodiazepines used for sedation in such cases. CASE: A 49-year-old man was diagnosed with motor neurone disease in 2016. He commenced tracheostomy ventilation in 2018. In 2022 and 2023, planning was undertaken, at the patient's request, for withdrawal of tracheostomy ventilation at home, when he was no longer able to communicate with technology. CASE PLANNING: Planning included Bispectral Index monitoring prior to cessation of ventilation, ensuring this only occurred when deep sedation was achieved. After ventilation withdrawal in 2023, a retrospective review of medications given and his level of sedation on monitoring was undertaken, with family consent. OUTCOME: Ventilation withdrawal was initiated after deep sedation was achieved, 6 h after commencing subcutaneous infusions of morphine, midazolam, clonazepam and phenobarbital. LESSONS: Doses required to achieve acceptable sedation exceeded literature reports. Achieving deep sedation was a longer than expected process. CONCLUSION: More research using an objective measure of sedation is required, as clinical assessment of sedation in this context is compromised.

DNA methylation landscapes in DIPG reveal methylome variability that can be modified pharmacologically.

Background: Diffuse intrinsic pontine glioma (DIPG) is a uniformly lethal brainstem tumor of childhood, driven by histone H3 K27M mutation and resultant epigenetic dysregulation. Epigenomic analyses of DIPG have shown global loss of repressive chromatin marks accompanied by DNA hypomethylation. However, studies providing a static view of the epigenome do not adequately capture the regulatory underpinnings of DIPG cellular heterogeneity and plasticity. Methods: To address this, we performed whole-genome bisulfite sequencing on a large panel of primary DIPG specimens and applied a novel framework for analysis of DNA methylation variability, permitting the derivation of comprehensive genome-wide DNA methylation potential energy landscapes that capture intrinsic epigenetic variation. Results: We show that DIPG has a markedly disordered epigenome with increasingly stochastic DNA methylation at genes regulating pluripotency and developmental identity, potentially enabling cells to sample diverse transcriptional programs and differentiation states. The DIPG epigenetic landscape was responsive to treatment with the hypomethylating agent decitabine, which produced genome-wide demethylation and reduced the stochasticity of DNA methylation at active enhancers and bivalent promoters. Decitabine treatment elicited changes in gene expression, including upregulation of immune signaling such as the interferon response, STING, and MHC class I expression, and sensitized cells to the effects of histone deacetylase inhibition. Conclusions: This study provides a resource for understanding the epigenetic instability that underlies DIPG heterogeneity. It suggests the application of epigenetic therapies to constrain the range of epigenetic states available to DIPG cells, as well as the use of decitabine in priming for immune-based therapies.

Nurses' encounters with patients having end-of-life dreams and visions in an acute care setting - A cross-sectional survey study.

AIM: This study aimed to estimate the proportion of acute care nurses witnessing end-of-life dreams and visions or having these reported by a patient or relative, and to canvass their related attitudes and beliefs. DESIGN: A cross-sectional survey study was conducted from February 2023 to May 2023. SETTING/PARTICIPANTS: Participants were medical and surgical nurses from a 200-bed acute care hospital in metropolitan Australia. RESULTS: Fifty-seven nurses participated from a workforce of 169 (34% response rate), of whom 35 (61%) reported they had encountered end-of-life dreams and visions. The nature of end-of-life dreams and visions encountered was similar to those reported in previous studies by patients and clinicians. Nurses generally held positive attitudes towards end-of-life dreams and visions but identified an unmet need for education and training on this aspect of end-of-life care. CONCLUSION: Our results suggest that nurses in acute care encounter end-of-life dreams and visions in a similar proportion to oncology and long-term care but lower than in palliative care settings. Education and training regarding end-of-life dreams and visions are needed to ensure the provision of comprehensive, patient-centred end-of-life care. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution. IMPACT: Research in sub-acute and long-term care settings suggests that end-of-life dreams and visions are a common accompaniment to the dying process. No research has yet focused on the acute care setting, despite this being the place of death for the majority of people in most high-income countries. This study demonstrates that acute care nurses encounter end-of-life dreams and visions in similar proportions to oncology and long-term care nurses but lower than palliative care nurses. Acute care nurses would benefit from education and training regarding end-of-life dreams and visions to enable the provision of holistic person-centred end-of-life care. REPORTING METHOD: This study was reported using the STROBE Checklist for cross-sectional studies.

FDA Approval Summary: Dabrafenib in Combination with Trametinib for BRAFV600E Mutation-Positive Low-Grade Glioma.

On March 16, 2023, the FDA approved dabrafenib in combination with trametinib (Tafinlar, Mekinist; Novartis Pharmaceuticals Corporation) for the treatment of pediatric patients with low-grade glioma (LGG) with a BRAFV600E mutation who require systemic therapy. FDA also approved oral formulations of both drugs suitable for patients who cannot swallow pills. This approval was based on the LGG cohort from study CDRB436G2201 (NCT02684058), a multicenter, open-label trial in which pediatric patients with LGG with a BRAFV600E mutation were randomly assigned 2:1 to dabrafenib plus trametinib (D+T) or carboplatin plus vincristine (C+V). The overall response rate (ORR) by independent review based on Response Assessment in Neuro-oncology LGG (2017) criteria was assessed in 110 patients randomly assigned to D+T (n = 73) or C+V (n = 37). ORR was 47% [95% confidence interval (CI), 35-59] in the D+T arm and 11% (95% CI, 3.0-25) in the C+V arm. Duration of response (DOR) was 23.7 months (95% CI, 14.5-NE) in the D+T arm and not estimable (95% CI, 6.6- NE) in the C+V arm. Progression-free survival (PFS) was 20.1 months (95% CI: 12.8, NE) and 7.4 months (95% CI, 3.6- 11.8) [HR, 0.31 (95% CI, 0.17-0.55); P < 0.001] in the D+T and C+V arms, respectively. The most common (>20%) adverse reactions were pyrexia, rash, headache, vomiting, musculoskeletal pain, fatigue, diarrhea, dry skin, nausea, hemorrhage, abdominal pain, and dermatitis acneiform. This represents the first FDA approval of a systemic therapy for the first-line treatment of pediatric patients with LGG with a BRAFV600E mutation.

Dexmedetomidine for end of life sedation: retrospective cohort comparison study.

OBJECTIVES: Infused sedatives are often utilised to alleviate distress at the end of life. Which sedative best achieves this is unknown. This study compares breakthrough medication requirements of patients treated with the novel agent dexmedetomidine compared with patients treated with standard-care sedatives. METHODS: A retrospective cross-cohort comparison. Two studies of patients at the end of life under sedation at the same palliative care unit, one utilising novel sedatives, and the other standard care were compared. Breakthrough medication requirements were compared using paired t-tests, including opioids, benzodiazepines and anticholinergics. Changes in background infusions were compared. RESULTS: The dexmedetomidine cohort required less breakthrough interventions per day compared with the standard care group, the reduction was significant (2.2 vs 3.9, p=0.003). There was a significant difference in benzodiazepine requirements, with the dexmedetomidine cohort requiring fewer doses per day than the standard care cohort (1.1 vs 0.6, p=0.03). Anticholinergics were more commonly utilised in the standard care cohort but there was no significant difference (p=0.22). Opioid requirements were similar across cohorts with comparable rates of breakthrough use and infusion increases. CONCLUSIONS: This study demonstrates a reduction in breakthrough medication requirements, particularly benzodiazepines, for patients sedated with dexmedetomidine at end of life.

A Phase II Trial of Guadecitabine in Children and Adults with SDH-Deficient GIST, Pheochromocytoma, Paraganglioma, and HLRCC-Associated Renal Cell Carcinoma.

PURPOSE: Succinate dehydrogenase (dSDH)-deficient tumors, including pheochromocytoma/paraganglioma, hereditary leiomyomatosis and renal cell cancer-associated renal cell carcinoma (HLRCC-RCC), and gastrointestinal stromal tumors (GIST) without KIT or platelet-derived growth factor receptor alpha mutations are often resistant to cytotoxic chemotherapy, radiotherapy, and many targeted therapies. We evaluated guadecitabine, a dinucleotide containing the DNA methyltransferase inhibitor decitabine, in these patient populations. PATIENTS AND METHODS: Phase II study of guadecitabine (subcutaneously, 45 mg/m2/day for 5 consecutive days, planned 28-day cycle) to assess clinical activity (according to RECISTv.1.1) across three strata of patients with dSDH GIST, pheochromocytoma/paraganglioma, or HLRCC-RCC. A Simon optimal two-stage design (target response rate 30% rule out 5%) was used. Biologic correlates (methylation and metabolites) from peripheral blood mononuclear cells (PBMC), serum, and urine were analyzed. RESULTS: Nine patients (7 with dSDH GIST, 1 each with paraganglioma and HLRCC-RCC, 6 females and 3 males, age range 18-57 years) were enrolled. Two patients developed treatment-limiting neutropenia. No partial or complete responses were observed (range 1-17 cycles of therapy). Biologic activity assessed as global demethylation in PBMCs was observed. No clear changes in metabolite concentrations were observed. CONCLUSIONS: Guadecitabine was tolerated in patients with dSDH tumors with manageable toxicity. Although 4 of 9 patients had prolonged stable disease, there were no objective responses. Thus, guadecitabine did not meet the target of 30% response rate across dSDH tumors at this dose, although signs of biologic activity were noted.

Use of Telemedicine in the Diagnosis of Cervical Spondylotic Myelopathy in a US Veteran During the COVID-19 Pandemic: A Case Report.

Objective: The purpose of this case study was to describe the diagnosis of cervical spondylotic myelopathy through telemedicine during the COVID-19 pandemic. Clinical Features: A 57-year-old male patient was evaluated at a Veterans Affairs chiropractic clinic via video telemedicine for evaluation regarding neck pain and bilateral arm paresthesia. Intervention and Outcome: During the initial evaluation performed by video telemedicine, the doctor of chiropractic was concerned about the possibility of cervical spondylotic myelopathy. This prompted a face-to-face consultation with the patient for further evaluation. The face-to-face evaluation revealed correlating objective findings, including brisk reflexes and transient clonus. Noncontrast magnetic resonance imaging of the cervical spine was performed, which showed evidence of cord compression with associated myelomalacia in the cervical spine at the C4-C5 level. After a neurosurgical consultation, the patient underwent successful anterior cervical decompression and fusion at the C4-C5 level. Conclusion: Chiropractic services through live video telemedicine in conjunction with face-to-face evaluation resulted in a timely neurosurgical consultation and successful decompression of the affected region. In this case, telemedicine facilitated a positive outcome for a patient with cervical spondylotic myelopathy.

End-of-life dreams and visions: A systematic integrative review.

OBJECTIVES: End-of-life dreams and visions (ELDVs) have been reported throughout history. We aimed to synthesize the research literature on ELDVs to determine the proportions of patients, bereaved families, healthcare professionals, and volunteers reporting ELDVs; ELDV content, timing, and interpretation; and any evidence-based approaches to ELDV-related care. METHODS: A systematic review protocol was registered with PROSPERO (CRD4021282929). CINAHL, Medline, Embase, Emcare, and APA PsycInfo were searched for peer-reviewed English language articles reporting qualitative, quantitative, or mixed methods studies that explored reports of ELDVs by patients, bereaved families, healthcare professionals, or volunteers. Synthesis used both meta-analysis and a narrative approach. RESULTS: Of 2,045 papers identified by searches, 22 were included, describing 18 studies in a variety of settings. Meta-analyses indicated that 77% (95% confidence intervals [CIs] 69-84%) of patients (n = 119) reported an ELDV compared with 32% (95% CIs 21-44%) of bereaved relatives (n = 2,444) and that 80% (95% CIs 59-94%) of healthcare professionals (n = 171) reported either witnessing or being told of an ELDV in the preceding 5 years. Studies of volunteers reported 34% (95% CIs 20-48%) (n = 45) either witnessing or being told of an ELDV over their entire period of service, with 49% of volunteers (95% CIs 33-64%) (n = 39) reporting events occurring in the preceding year. ELDVs reported by patients, bereaved families, healthcare professionals, and volunteers were perceived as being a source of comfort. Healthcare professionals and volunteers expressed a need for further education on how to support patients experiencing ELDVs and their families. SIGNIFICANCE OF RESULTS: ELDVs are experienced by the majority of dying patients and need consideration in delivering holistic end-of-life care. Little if any research has been conducted in acute care facilities.

Donor T cell DNMT3a regulates alloreactivity in mouse models of hematopoietic stem cell transplantation.

DNA methyltransferase 3a (DNMT3a) is an important part of the epigenetic machinery that stabilizes patterns of activated T cell responses. We hypothesized that donor T cell DNMT3a regulates alloreactivity after allogeneic blood and marrow transplantation (allo-BMT). T cell conditional Dnmt3a KO mice were used as donors in allo-BMT models. Mice receiving allo-BMT from KO donors developed severe acute graft-versus-host disease (aGVHD), with increases in inflammatory cytokine levels and organ histopathology scores. KO T cells migrated and proliferated in secondary lymphoid organs earlier and demonstrated an advantage in trafficking to the small intestine. Donor T cell subsets were purified after BMT for whole-genome bisulfite sequencing (WGBS) and RNA-Seq. KO T cells had global methylation similar to that of WT cells, with distinct, localized areas of hypomethylation. Using a highly sensitive computational method, we produced a comprehensive profile of the altered epigenome landscape. Hypomethylation corresponded with changes in gene expression in several pathways of T cell signaling and differentiation. Additionally, Dnmt3a-KO T cells resulted in superior graft-versus-tumor activity. Our findings demonstrate a critical role for DNMT3a in regulating T cell alloreactivity and reveal pathways that control T cell tolerance. These results also provide a platform for deciphering clinical data that associate donor DNMT3a mutations with increased GVHD, decreased relapse, and improved survival.

Vascular progenitors generated from tankyrase inhibitor-regulated naïve diabetic human iPSC potentiate efficient revascularization of ischemic retina.

Here, we report that the functionality of vascular progenitors (VP) generated from normal and disease-primed conventional human induced pluripotent stem cells (hiPSC) can be significantly improved by reversion to a tankyrase inhibitor-regulated human naïve epiblast-like pluripotent state. Naïve diabetic vascular progenitors (N-DVP) differentiated from patient-specific naïve diabetic hiPSC (N-DhiPSC) possessed higher vascular functionality, maintained greater genomic stability, harbored decreased lineage-primed gene expression, and were more efficient in migrating to and re-vascularizing the deep neural layers of the ischemic retina than isogenic diabetic vascular progenitors (DVP). These findings suggest that reprogramming to a stable naïve human pluripotent stem cell state may effectively erase dysfunctional epigenetic donor cell memory or disease-associated aberrations in patient-specific hiPSC. More broadly, tankyrase inhibitor-regulated naïve hiPSC (N-hiPSC) represent a class of human stem cells with high epigenetic plasticity, improved multi-lineage functionality, and potentially high impact for regenerative medicine.

Breakthrough Medication in Unresponsive Palliative Care Patients: Indications, Practice, and Efficacy.

CONTEXT: An unresponsive patient's need and their response to breakthrough medication is determined by clinical assessment and/or observational measures. How closely these methods match the patient's experience is unknown. OBJECTIVES: Determine the efficacy and effectiveness of breakthrough medication in unresponsive patients and the perception of patient comfort made by nurses and family. METHODS: A prospective study of breakthrough medication in unresponsive patients. The Richmond Agitation-Sedation Scale (RASS) and Patient Comfort Score (PCS) were compared with time-matched Bispectral Index (BIS) Scores. The effects of opioid vs. opioid + benzodiazepine breakthroughs and the relation between synchronous nurse and family measurements of the PCS were evaluated. Analysis of variance and paired t-tests were used for BIS analyses and nonparametric Mann-Whitney tests for RASS and PCS. RESULTS: Significant reductions at 30 and 60 minutes after breakthrough medication were noted for BIS (P < 0.0004), RASS (P = 0.043 and 0.004, respectively), and PCS (P < 0.0004). A direct comparison of the effect of opioid breakthrough medication vs. opioid plus benzodiazepine revealed no significant difference (BIS, P = 0.512; RASS, P = 0.195; PCS, P = 0.119). Of the 157 synchronous nurse and family measures of patient comfort, families rated patient discomfort significantly higher than nurses (P < 0.0004). CONCLUSION: This study provides additional evidence for the efficacy and effectiveness of breakthrough medication and the merit of observational measures in determining a patient's response. The onset of action is evident at 30 minutes after injection. Family assessment of patient comfort may be more nuanced than that of nurses, and they not uncommonly rate patient discomfort higher than nurses.

Correlation Between Observational Scales of Sedation and Comfort and Bispectral Index Scores.

CONTEXT: When palliative care patients enter the phase of unconsciousness preceding death, it is standard practice to initiate or continue a subcutaneous infusion of an opioid plus or minus a sedative. The doses are determined somewhat empirically and adjustments are based on clinical assessment and observational measures of sedation and comfort. Following reports that these observational measures could be misleading, this study assesses their validity by comparing them with an objective measure of sedation, the Bispectral Index Score (BIS). OBJECTIVE: The objective of this study was to determine the validity of the Richmond Agitation and Sedation Scale (RASS) and the Patient Comfort Score (PCS) in assessing sedation and comfort in unconscious patients. METHODS: Forty eligible and consenting patients were monitored from the onset of unconsciousness (unresponsiveness) until death. Measures of sedation (RASS) and comfort (PCS) were made by the attending nurse every four hours. Correlation coefficients examined the relationship between fourth hourly RASS and PCS and time-matched BISs. RESULTS: A significant correlation was found between RASS and BIS and PCS and BIS. Sedation and comfort scores were concentrated at the lower end of the respective scales, whereas time-matched BISs were widely scattered with scores ranging from near full awareness to deep sedation. CONCLUSIONS: Compared with BIS, both RASS and PCS appear to be relatively blunt instruments at the lower end of their respective scales. Due caution should be taken interpreting and making clinical decisions based solely on the RASS and PCS and, by extension, other observational measures of patient comfort and sedation.

Epigenetic reprogramming and re-differentiation of a Ewing sarcoma cell line.

Developmental reprogramming techniques have been used to generate induced pluripotent stem (iPS) cells from both normal and malignant cells. The derivation of iPS cells from cancer has the potential to provide a unique scientific tool to overcome challenges associated with the establishment of cell lines from primary patient samples and a readily expandable source of cells that may be used to model the initial disease. In the current study we developmentally reprogrammed a metastatic Ewing sarcoma (EWS) cell line to a meta-stable embryonic stem (ES)-like state sharing molecular and phenotypic features with previously established ES and iPS cell lines. EWS-iPS cells exhibited a pronounced drug resistant phenotype despite persistent expression of the oncogenic EWS-FLI1 fusion transcript. This included resistance to compounds that specifically target downstream effector pathways of EWS-FLI1, such as MAPK/ERK and PI3K/AKT, which play an important role in EWS pathogenesis. EWS-iPS cells displayed tumor initiation abilities in vivo and formed tumors exhibiting characteristic Ewing histopathology. In parallel, EWS-iPS cells re-differentiated in vitro recovered sensitivity to molecularly targeted chemotherapeutic agents, which reiterated pathophysiological features of the cells from which they were derived. These data suggest that EWS-iPS cells may provide an expandable disease model that could be used to investigate processes modulating oncogenesis, metastasis, and chemotherapeutic resistance in EWS.

An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia.

To define the mutation spectrum in non-Down syndrome acute megakaryoblastic leukemia (non-DS-AMKL), we performed transcriptome sequencing on diagnostic blasts from 14 pediatric patients and validated our findings in a recurrency/validation cohort consisting of 34 pediatric and 28 adult AMKL samples. Our analysis identified a cryptic chromosome 16 inversion (inv(16)(p13.3q24.3)) in 27% of pediatric cases, which encodes a CBFA2T3-GLIS2 fusion protein. Expression of CBFA2T3-GLIS2 in Drosophila and murine hematopoietic cells induced bone morphogenic protein (BMP) signaling and resulted in a marked increase in the self-renewal capacity of hematopoietic progenitors. These data suggest that expression of CBFA2T3-GLIS2 directly contributes to leukemogenesis.

The genetic basis of early T-cell precursor acute lymphoblastic leukaemia.

Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell acute lymphoblastic leukaemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating lesions disrupting haematopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1 and EP300) and histone-modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of recurrent mutation including DNM2, ECT2L and RELN. The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL.

The impact of unrelieved patient suffering on palliative care nurses.

AIM: to describe the impact of unrelieved patient suffering on nurses working with palliative care patients. DESIGN: This was a qualitative descriptive design using semi-structured interviews. SAMPLE: nine experienced palliative care nurses were interviewed. RESULTS: nurses acknowledged that the term 'suffering' generally was not used in the workplace. The nurses identified that only a small group of patients died with suffering that could be classified as 'unrelieved' but that the impact of these patients' suffering on themselves was enormous. Nurses describe the impact in terms of perceptions of suffering (difficult situation), feelings (helplessness, distress, feelings of failure), bearing the burden (alcohol consumption, headaches) and effects on their relationship with family. The nurses identified several factors that increased the personal impact of unrelieved patient suffering. The most important strategy for ameliorating the impact of unrelieved patient suffering was informal support from work colleagues. CONCLUSION: the nurses' stories indicate that the personal impact of unrelieved patient suffering could be reduced through acknowledgement of this suffering and better formal and informal support mechanisms.