Our dementia challenge: arise palliative care.

While many of the maladies of the 20th century are steadily coming under control, the march of neurodegenerative disorders continues largely unchecked. Dementias are an exemplar of such disorders; their incidence and prevalence continue to rise, in large part due to a steadily ageing population worldwide. They represent a group of chronic, progressive and, ultimately, fatal neurodegenerative diseases. Dementia has remained therapeutically recalcitrant. It is not a single disease, and because of that, we cannot expect a single panacea. While primary prevention rightly gains prominence, those with established disease currently require a shift in focus from curative intent towards improved quality of life. Enter palliative care. The sheer number and complexity of needs of patients with dementia, from the physical to the psychosocial and spiritual, necessitates the engagement of a wide range of medical disciplines, nursing and allied health professionals. One of those disciplines, as highlighted in the recent Australian Royal Commission into Aged Care Quality and Safety, is palliative care. This paper shall expand upon that role in the overall context of care for those with dementia.

Current nonclinical approaches for immune assessments of immuno-oncology biotherapeutics.

Harnessing the immune system to kill tumors has been revolutionary and, as a result, has had an enormous benefit for patients in extending life and resulting in effective cures in some. However, activation of the immune system can come at the cost of undesirable adverse events such as cytokine release syndrome, immune-related adverse events, on-target/off-tumor toxicity, neurotoxicity and tumor lysis syndrome, which are safety risks that can be challenging to assess non-clinically. This article provides a review of the biology and mechanisms that can result in immune-mediated adverse effects and describes industry approaches using in vitro and in vivo models to aid in the nonclinical safety risk assessments for immune-oncology modalities. Challenges and limitations of knowledge and models are also discussed.

Feasibility, acceptability, and utility of a nurse-led survivorship program for people with metastatic melanoma (MELCARE).

PURPOSE: Immune checkpoint inhibitors (ICIs) and targeted therapy (TT) have improved the survival of people with metastatic melanoma. We assessed the feasibility, acceptability, and utility of a novel model of nurse-led, telehealth-delivered survivorship care (MELCARE) for this survivor group. METHODS: People ≥ 18 years diagnosed with unresectable stage III or stage IV melanoma who were ≥ 6 months post initiation of ICI/TT with a radiological response suggestive of a long-term response to ICI/TT were recruited from a specialist melanoma centre in Australia. All participants received MELCARE, a nurse-led survivorship program involving two telehealth consultations 3 months apart, needs assessment using the Distress Thermometer (DT) and Problem List, and creation of a survivorship care plan. Feasibility, acceptability, and utility were assessed using rates of consent and study completion, time taken to complete each component of MELCARE, the Acceptability of Intervention Measure (AIM), and a customised utility survey. RESULTS: 31/54 (57%) people consented. Participants were male (21, 68%), with a median age of 67 (range: 46-82). Eleven (35%) were receiving/had received ipilimumab and nivolumab and 27 (87%) had ceased treatment. Feasibility was demonstrated with 97% completing MELCARE. Utility was demonstrated on a customised survey and supported by a reduction in the mean DT score (initial: 5.6, SD: 2.9; follow-up: 1.5, SD: 1.2). Acceptability was demonstrated on 3/4 AIM items. CONCLUSION: MELCARE was feasible and acceptable with high levels of utility. However, the consent rate was 57% indicating some people do not require support. Future studies should consider MELCARE's optimal timing, resourcing, and cost-effectiveness.

Temporal changes and risk factors for death from early withdrawal within 12 months of dialysis initiation-a cohort study.

BACKGROUND: Mortality risk is high soon after dialysis initiation in patients with kidney failure, and dialysis withdrawal is a major cause of early mortality, attributed to psychosocial or medical reasons. The temporal trends and risk factors associated with cause-specific early dialysis withdrawal within 12 months of dialysis initiation remain uncertain. METHODS: Using data from the Australia and New Zealand Dialysis and Transplant Registry, we examined the temporal trends and risk factors associated with mortality attributed to early psychosocial and medical withdrawals in incident adult dialysis patients in Australia between 2005 and 2018 using adjusted competing risk analyses. RESULTS: Of 32 274 incident dialysis patients, 3390 (11%) experienced death within 12 months post-dialysis initiation. Of these, 1225 (36%) were attributed to dialysis withdrawal, with 484 (14%) psychosocial withdrawals and 741 (22%) medical withdrawals. These patterns remained unchanged over the past two decades. Factors associated with increased risk of death from early psychosocial and medical withdrawals were older age, dialysis via central venous catheter, late referral and the presence of cerebrovascular disease; obesity and Asian ethnicity were associated with decreased risk. Risk factors associated with early psychosocial withdrawals were underweight and higher socioeconomic status. Presence of peripheral vascular disease, chronic lung disease and cancers were associated with early medical withdrawals. CONCLUSIONS: Death from dialysis withdrawal accounted for >30% of early deaths in kidney failure patients initiated on dialysis and remained unchanged over the past two decades. Several shared risk factors were observed between mortality attributed to early psychosocial and medical withdrawals.

End-stage kidney disease: The last 12 months.

BACKGROUND: Chronic kidney disease (CKD) is increasingly prevalent in Australia's ageing population. Over the past decade, there has been growing recognition that dialysis does not benefit every patient with end-stage kidney disease (ESKD). Patients with advanced age, significant comorbidities and poor functional status may not gain a survival benefit with dialysis when compared with being managed conservatively. These developments have implications for general practitioners (GPs). A further development has been the emergence of renal supportive care, a patient-centred approach that integrates the principles of palliative care into nephrology. OBJECTIVE: The aim of this article is to outline salient aspects in the care of patients with ESKD. DISCUSSION: Salient aspects throughout the trajectory of ESKD are discussed, including symptoms of CKD, relevant management, prognostication, advance care planning discussions and end-of-life care. The role of the GP is vital, and it is recommended that GPs are involved early in a patient's CKD trajectory.

What Matters? Palliative Care, Ethics, and the COVID-19 Pandemic.

As is often the case in clinical ethics, the discourse in COVID-19 has focused primarily on difficult and controversial decision-making junctures such as how to decide who gets access to intensive care resources if demand outstrips supply. However, the lived experience of COVID-19 raises less controversial but arguably more profound moral questions around what it means to look after each other through the course of the pandemic and how this translates in care for the dying. This piece explores the interface between the pandemic, ethics, and the role of palliative care. We argue that the ethical discourse should be broader, and that the principles that underly the discipline of palliative care provide a solid ethical foundation for the care of all patients through the coronavirus pandemic.

Cancer Rehabilitation and Palliative Care-Exploring the Synergies.

With perpetual research, management refinement, and increasing survivorship, cancer care is steadily evolving into a chronic disease model. Rehabilitation physicians are quite accustomed to managing chronic conditions, yet, cancer rehabilitation remains unexplored. Palliative care physicians, along with rehabilitationists, are true generalists, who focus on the whole patient and their social context, in addition to the diseased organ system. This, together with palliative care's expertise in managing the panoply of troubling symptoms that beset patients with malignancy, makes them natural allies in the comprehensive management of this patient group from the moment of diagnosis. This article will explore the under-recognized and underused parallels and synergies between the two specialties as well as identifying potential challenges and areas for future growth.

Impact of Renal Supportive Care on Symptom Burden in Dialysis Patients: A Prospective Observational Cohort Study.

CONTEXT: Symptom burden is a strong predictor of reduced health-related quality of life and survival in patients with end-stage kidney disease. Renal supportive care (RSC) is a comprehensive approach shown to benefit symptoms in nondialysis conservatively managed patients, although its role in dialysis patients has not been reported. OBJECTIVES: This study aimed to investigate the impacts of RSC intervention on symptoms in dialysis patients. METHODS: Dialysis patients who were referred to an RSC clinic for symptom control between April 2010 and December 2017 were followed prospectively. Symptoms were scored using the Integrated Palliative care Outcomes Scale-Renal Inventory. Change in symptoms was analyzed at three visits and at final RSC visit within the study period. Correlation and linear regression were used to assess for effect modifiers. RESULTS: A total of 127 dialysis patients attended the RSC clinic for symptom management. Median age was 74 years, 62% males, median dialysis vintage was 2.2 years, and median-modified Charlson Comorbidity Index was 7. Mean combined physical and emotional symptom score at baseline was 17.5 (SD 9.6), the most overwhelming/severe symptoms being difficulty sleeping (35%), pain (31%), lack of energy (31%), poor mobility (24%), and itch (22%). Eighty patients had follow-up to at least three RSC visits (median 3.1 months). There was significant improvement in combined physical and emotional symptom score during three clinic visits (18.1 vs. 14.2; mean change -3.8; 95% CI -5.7 to -1.9; P < 0.001), with greatest improvement in symptom scores for the five most severe symptoms (each P < 0.001). Follow-up of these 80 patients to final RSC visit (median 13.0 months) showed sustained reduction in mean combined physical and emotional symptom score (18.1 vs. 14.4; mean change -3.7; 95% CI -5.6 to -1.7; P < 0.001). These changes occurred without change in dialysis delivery. CONCLUSION: RSC intervention that focuses on symptom control and patient-centered care is associated with improved total and individual symptom burden in dialysis patients. This supports a role for RSC as a management adjunct in these patients.

Retrospective chart review to assess domains of quality of death (recognition of dying, appropriate limitations, symptom monitoring, anticipatory prescribing) of patients dying in the acute hospital under the care of a nephrology service with renal supportive care support over time.

AIM: To explore the quality of deaths in an acute hospital under a nephrology service at two teaching hospitals in Sydney with renal supportive care services over time. METHODS: Retrospective chart review of all deaths in the years 2004, 2009 and 2014 at St George Hospital (SGH) and in 2014 at the Concord Repatriation General Hospital. Domains assessed were recognition of dying, invasive interventions, symptom assessment, anticipatory prescribing, documentation of spiritual needs and bereavement information for families. End-of-life care plan (EOLCP) use was also evaluated at SGH. RESULTS: Over 90% of patients were recognized to be dying in all 3 years at SGH. Rates of interventions in the last week of life were low and did not differ across the 3 years. There was a significant increase in the prescription of anti-psychotic, anti-emetic and anti-cholinergic medication over the years at SGH. Use of EOLCP was significantly higher at SGH, and their use improved several quality domains. Of all deaths, 68% were referred to palliative care at SGH and 33% at Concord Repatriation General Hospital (not significant). Cessation of observations and non-essential medications and documentation of bereavement information given to families was low across both sites in all years, although this significantly improved when EOLCP were used. CONCLUSION: While acute teams are good at recognizing dying, they need support to care for dying patients. The use of EOLCP in acute services can facilitate improvements in caring for the dying. Renal supportive care services need time to become embedded in the culture of the acute hospital.

Access to Pain Management as a Human Right.

The concept of access to pain management as a human right has gained increasing currency in recent years. Commencing as individual advocacy, it was later embraced by the disciplines of pain medicine and palliative care and by mainstream human rights organizations.Today, United Nations and regional human rights bodies have accepted the concept and incorporated it into key human rights reports, reviews, and standards. We review the foundations in law of this right and the obligations that flow from it to governments. We analyze the nature and content of the obligation in the context of acute, chronic nonmalignant and cancer pain.Finally, we examine this right in light of the twin crises of inadequate access to pain management and the opioid crisis in the United States and other nations.

Multidisciplinary management of motor neurone disease.

BACKGROUND: Motor neurone disease (MND) is the term for a group of progressive, debilitating, neurodegenerative disorders that affect various aspects of a patient's life, including speech, swallowing, breathing and limb function. OBJECTIVE: This review outlines the common symptoms and issues in MND and the latest available treatment options. A multidisciplinary approach to MND, involving the general practitioner (GP) and rehabilitation, palliative care and allied health services, is discussed. DISCUSSION: The complexity of care for patients with MND and their families is best managed using a multidisciplinary team approach, with the GP as an important member of that team. The biopsychosocial care model discussed can improve the quality of life for patients and carers, as well as the life expectancy of patients with MND.

"The Poor Mystery of My body": The Sanctity of the Human in Illness and Death.

Respect for the human body is a fundamental principle of health care. This article examines a selection of the work of three Polish poets who lived through the agonies of World War II. The author reflects on the lessons that can be drawn from their work for clinical care, including Palliative Care, the dignity of the human person and the nature of suffering.

Generation and characterization of a high affinity anti-human FcRn antibody, rozanolixizumab, and the effects of different molecular formats on the reduction of plasma IgG concentration.

Rozanolixizumab (UCB7665), a humanized high-affinity anti-human neonatal Fc receptor (FcRn) monoclonal antibody (IgG4P), has been developed to reduce pathogenic IgG in autoimmune and alloimmune diseases. We document the antibody isolation and compare rozanolixizumab with the same variable region expressed in various mono-, bi- and trivalent formats. We report activity data for rozanolixizumab and the different molecular formats in human cells, FcRn-transgenic mice, and cynomolgus monkeys. Rozanolixizumab, considered the most effective molecular format, dose-dependently and selectively reduced plasma IgG concentrations in an FcRn-transgenic mouse model (no effect on albumin). Intravenous (IV) rozanolixizumab dosing in cynomolgus monkeys demonstrated non-linear pharmacokinetics indicative of target-mediated drug disposition; single IV rozanolixizumab doses (30 mg/kg) in cynomolgus monkeys reduced plasma IgG concentration by 69% by Day 7 post-administration. Daily IV administration of rozanolixizumab (initial 30 mg/kg loading dose; 5 mg/kg daily thereafter) reduced plasma IgG concentrations in all cynomolgus monkeys, with low concentrations maintained throughout the treatment period (42 days). In a 13-week toxicology study in cynomolgus monkeys, supra-pharmacological subcutaneous and IV doses of rozanolixizumab (≤ 150 mg/kg every 3 days) were well tolerated, inducing sustained (but reversible) reductions in IgG concentrations by up to 85%, with no adverse events observed. We have demonstrated accelerated natural catabolism of IgG through inhibition of IgG:FcRn interactions in mice and cynomolgus monkeys. Inhibition of FcRn with rozanolixizumab may provide a novel therapeutic approach to reduce pathogenic IgG in human autoimmune disease. Rozanolixizumab is being investigated in patients with immune thrombocytopenia (NCT02718716) and myasthenia gravis (NCT03052751).

Current strategies in the non-clinical safety assessment of biologics: New targets, new molecules, new challenges.

Nonclinical safety testing of biopharmaceuticals can present significant challenges to human risk assessment with these innovative and often complex drugs. Emerging topics in this field were discussed recently at the 2016 Annual US BioSafe General Membership meeting. The presentations and subsequent discussions from the main sessions are summarized. The topics covered included: (i) specialty biologics (oncolytic virus, gene therapy, and gene editing-based technologies), (ii) the value of non-human primates (NHPs) for safety assessment, (iii) challenges in the safety assessment of immuno-oncology drugs (T cell-dependent bispecifics, checkpoint inhibitors, and costimulatory agonists), (iv) emerging therapeutic approaches and modalities focused on microbiome, oligonucleotide, messenger ribonucleic acid (mRNA) therapeutics, (v) first in human (FIH) dose selection and the minimum anticipated biological effect level (MABEL), (vi) an update on current regulatory guidelines, International Council for Harmonization (ICH) S1, S3a, S5, S9 and S11 and (vii) breakout sessions that focused on bioanalytical and PK/PD challenges with bispecific antibodies, cytokine release in nonclinical studies, determining adversity and NOAEL for biologics, the value of second species for toxicology assessment and what to do if there is no relevant toxicology species.

'To die with dignity': an update on Palliative Care.

Significant developments have occurred in the discipline of palliative care in the modern era. This paper shall explore those developments, challenge some widely held misconceptions about the role and daily practice of the discipline, highlight the growing recognition of the role of palliative care in non-malignant diseases, briefly discuss innovations in symptom management and reflect on the underlying principles, maturation and challenges faced by the discipline.

Nutrition in Renal Supportive Care: Patient-driven and flexible.

Renal Supportive Care is an alternative treatment pathway in advanced chronic kidney disease that is being increasingly adopted, particularly in the elderly. Renal Supportive Care uses principles of palliative care and has been developed to enhance the care for dialysis patients with a high symptom burden and those being managed on a non-dialysis pathway. Nutrition management is often an under-recognized component of care and can play an important role in improving patients' quality of life to reduce symptom burden, support physical function and independence and provide appropriate counselling to patients and their families to ensure the goals of Renal Supportive Care are met. Nutrition interventions need to target patient and treatment goals, with frequent monitoring to ensure patient needs are being met. This review outlines available literature on this topic and suggests some practical ways in which nutrition can be enhanced for these patients.

In vitro assays supporting the safety assessment of immunomodulatory monoclonal antibodies.

Many monoclonal antibodies (mAbs) licensed for human use or in clinical development for cancer and autoimmune disease directly interact with the immune system. These immunomodulatory mAbs have an inherent risk of adverse immune-mediated drug reactions, including infusion reactions, cytokine storms, immunosuppression and autoimmunity. A thorough understanding of the potential for immunotoxicity of a mAb is required to support administration to humans. This review will highlight the key role of in vitro assays in defining the immunopharmacology, immunotoxicity and immunogenicity of mAbs. A wide range of in vitro tests with multiple formats of different complexity can be utilized to characterize i) the antibody-binding domains of the mAb, such as on-target binding and downstream pharmacological effects (e.g. immunosuppression, immune activation, cytokine release) in both humans and animal species used for toxicology studies and off-target binding; ii) Fc-dependent effects such as Fc-mediated cellular activation (e.g. of leukocytes, platelets) and cytokine release, complement activation; and iii) product-related factors (sequence, physical-chemical properties and impurities) that can impact both pharmacological activity and immunogenicity potential of a mAb. These assays can be crucial to the selection of mAbs with an optimum balance of safety and efficacy, in defining whether a mAb is a high risk molecule, and together with animal data, can inform human safe starting doses and escalation schemes.