Stereotactic ablative body radiotherapy for primary kidney cancer (TROG 15.03 FASTRACK II): a non-randomised phase 2 trial.

BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is a novel non-invasive alternative for patients with primary renal cell cancer who do not undergo surgical resection. The FASTRACK II clinical trial investigated the efficacy of SABR for primary renal cell cancer in a phase 2 trial. METHODS: This international, non-randomised, phase 2 study was conducted in seven centres in Australia and one centre in the Netherlands. Eligible patients aged 18 years or older had biopsy-confirmed diagnosis of primary renal cell cancer, with only a single lesion; were medically inoperable, were at high risk of complications from surgery, or declined surgery; and had an Eastern Cooperative Oncology Group performance status of 0-2. A multidisciplinary decision that active treatment was warranted was required. Key exclusion criteria were a pre-treatment estimated glomerular filtration rate of less than 30 mL/min per 1·73 m2, previous systemic therapies for renal cell cancer, previous high-dose radiotherapy to an overlapping region, tumours larger than 10 cm, and direct contact of the renal cell cancer with the bowel. Patients received either a single fraction SABR of 26 Gy for tumours 4 cm or less in maximum diameter, or 42 Gy in three fractions for tumours more than 4 cm to 10 cm in maximum diameter. The primary endpoint was local control, defined as no progression of the primary renal cell cancer, as evaluated by the investigator per Response Evaluation Criteria in Solid Tumours (version 1.1). Assuming a 1-year local control of 90%, the null hypothesis of 80% or less was considered not to be worthy of proceeding to a future randomised controlled trial. All patients who commenced trial treatment were included in the primary outcome analysis. This trial is registered with ClinicalTrials.gov, NCT02613819, and has completed accrual. FINDINGS: Between July 28, 2016, and Feb 27, 2020, 70 patients were enrolled and initiated treatment. Median age was 77 years (IQR 70-82). Before enrolment, 49 (70%) of 70 patients had documented serial growth on initial surveillance imaging. 49 (70%) of 70 patients were male and 21 (30%) were female. Median tumour size was 4·6 cm (IQR 3·7-5·5). All patients enrolled had T1-T2a and N0-N1 disease. 23 patients received single-fraction SABR of 26 Gy and 47 received 42 Gy in three fractions. Median follow-up was 43 months (IQR 38-60). Local control at 12 months from treatment commencement was 100% (p<0·0001). Seven (10%) patients had grade 3 treatment-related adverse events, with no grade 4 adverse events observed. Grade 3 treatment-related adverse events were nausea and vomiting (three [4%] patients), abdominal, flank, or tumour pain (four [6%]), colonic obstruction (two [3%]), and diarrhoea (one [1%]). No treatment-related or cancer-related deaths occurred. INTERPRETATION: To our knowledge, this is the first multicentre prospective clinical trial of non-surgical definitive therapy in patients with primary renal cell cancer. In a cohort with predominantly T1b or larger disease, SABR was an effective treatment strategy with no observed local failures or cancer-related deaths. We observed an acceptable side-effect profile and renal function after SABR. These outcomes support the design of a future randomised trial of SABR versus surgery for primary renal cell cancer. FUNDING: Cancer Australia Priority-driven Collaborative Cancer Research Scheme.

Draft Genome Sequence of the Yeast Torulaspora quercuum Strain UCD657, Isolated from Soil in Ireland.

Torulaspora quercuum is an ascomycete yeast first isolated in 2009. Here, we present the genome sequence of T. quercuum isolate UCD657, which was isolated from soil in Ireland. This genome is 10.4 Mb and was assembled into 8 chromosome-sized scaffolds of >1 Mb in size, plus a mitochondrial genome scaffold.

Efficacy of Normalisation of Advance Care Planning (NACP) for people with chronic diseases in hospital and community settings: a quasi-experimental study.

BACKGROUND: Advance Care Planning (ACP) has emerged to improve end-of-life processes and experiences. However, the available evidence presents the gloomy picture of increasing number of older people living with chronic diseases and the mismatch between their preferences for and the actual place of death. The study aimed to investigate the efficacy of normalisation of an Advance Care Planning (NACP) service delivered by specially trained Registered Nurses (RNs) in hospital and community settings. METHODS: A quasi-experimental study was conducted involving 16 sites (eight hospital and eight community sites) in Australia. Patients who were aged ≥18 years, who had at least one of nine chronic conditions, and who did not have an Advance Care Directive (ACD) were offered the NACP service. ACP was normalised as part of routine service on admission. The intervention, NACP, was a series of facilitated conversations about the components of ACP. The primary outcomes which included the completion of ACDs, and/or appointment of an Enduring Guardian (EG), were assessed in both intervention and control sites at pre and post intervention stages. Numbers of patients who completed an ACD or appointed an EG were described by count (percentage). ACD completion was compared between intervention and control sites using a logistic mixed effects regression model. The model includes fixed effects for treatment group, period, and their interaction, as well as random site level intercepts. Secondary model included potentially confounding variables as covariates, including age, sex and chronic diseases. RESULTS: The prevalence of legally binding ACDs in intervention sites has increased from five to 85 (from 0.85% in pre to 17.6% in post), whereas it has slightly decreased from five to 2 (from 1.2% in pre and to 0.49% in post) in control sites (the difference in these changes being statistically significant p < 0.001). ACD completion rate was 3.6% (n = 4) in LHD1 and 1.2% (n = 3) in LHD2 in hospital whereas it was 53% (n = 26) in LHD1 and 80% (n = 52) in LHD2 in community. CONCLUSIONS: The study demonstrated that NACP service delivered by ACP RNs was effective in increasing completion of ACDs (interaction odds ratio = 50) and was more effective in community than hospital settings. Involvement of various healthcare professionals are warranted to ensure concordance of care. TRIAL REGISTRATION: The study was retrospectively registered with the Australian New Zealand Clinical Trials Registry (Trial ID: ACTRN12618001627246 ) on 03/10/2018. The URL of the trial registry record http://www.anzctr.org.au/trial/MyTrial.aspx.

A cost-consequence analysis of normalised advance care planning practices among people with chronic diseases in hospital and community settings.

BACKGROUND: A growing body of international literature concurs that comprehensive and complex Advance Care Planning (ACP) programs involving specially qualified or trained healthcare professionals are effective in increasing documentation of Advance Care Directives (ACDs), improving compliance with patients' wishes and satisfaction with care, and quality of care for patients and their families. Economic analyses of ACDs and ACP have been more sporadic and inconclusive. This study aimed to contribute to the evidence on resource use associated with implementation of ACP and to inform key decision-makers of the resource implications through the conduct of a cost-consequence analysis of the Normalised Advance Care Planning (NACP) trial. METHODS: The outcomes for the economic evaluation included the number of completed "legally binding" ACDs and the number of completed Conversation Cards (CC). The cost analysis assessed the incremental difference in resource utilisation between Usual Practice and the Intervention. Costs have been categorised into: 1) Contract staff costs; 2) Costs associated with the development of the intervention; 3) Implementation costs; 4) Intervention (delivery) costs; and 5) Research costs. RESULTS: The cost incurred for each completed ACD was A$13,980 in the hospital setting and A$1248 in the community setting. The cost incurred for each completed Conversation Card was A$7528 in the hospital setting and A$910 in the community setting. CONCLUSIONS: The cost-consequence analysis does not support generalisation of the specified intervention within the hospital setting. The trial realised an estimated incremental cost per completed ACD of $1248, within the community setting. This estimate provides an additional benchmark against which decision-makers can assess the value of either 1) this approach towards the realisation of additional completed ACDs; and/or 2) the value of ACP and ACDs more broadly, when this estimate is positioned within the potential health outcomes and downstream health service implications that may arise for people with or without a completed ACD. TRIAL REGISTRATION: The study was retrospectively registered with the Australian New Zealand Clinical Trials Registry (Trial ID: ACTRN12618001627246 ). The URL of the trial registry record.

Prevalence of advance care planning practices among people with chronic diseases in hospital and community settings: a retrospective medical record audit.

BACKGROUND: Advance Care Planning (ACP) enables healthcare professionals to embrace the important process where patients think about their values in life and goals for health care, and discuss their future health care preferences with family members for a time when they are not able to make health care decisions. Despite the promotion of ACP last two decades, and well-known benefits of ACP and a written Advance Care Directive (ACD), they are still underutilised in Australia and across the world. Previous studies have provided some insights, however, an uptake of ACP and prevalence of ACDs in community settings is rarely reported. METHODS: The aim of this study was to determine the uptake of ACP and prevalence of ACDs among people with chronic diseases in hospital and community settings. A retrospective medical record audit of eligible patients looking for evidence of ACP was conducted in 16 research sites in eight hospital and eight community care settings. Participants included those who were admitted to one of the research sites, and who were aged 18 years and over with at least one of nine nominated chronic diseases. The primary outcome measures included the number of patients with evidence of ACP through the following practices: completion of an ACD, appointment of an Enduring Guardian (EG), or completion of a resuscitation plan. RESULTS: The overall prevalence of ACD was 2.8% (n = 28) out of 1006 audited records, and only 10 (1%) of them were legally binding. The number of EGs appointed was 39 (3.9%) across the sites. A total of 151 (15.4%) resuscitation plans were found across the eight hospital sites. 95% (n = 144) of the resuscitation plans indicated 'Not-for-resuscitation'. CONCLUSIONS: The uptake of ACP is very low. Current medical recording system reveals the challenges in ACP lie in the process of storage, access and execution of the ACDs. Given that having an ACD or Enduring Guardian in place is only useful if the treating physician knows how and where to access the information, it has implications for policy, information system, and healthcare professionals' education. TRIAL REGISTRATION: The study was retrospectively registered with the Australian New Zealand Clinical Trials Registry (Trial ID: ACTRN12618001627246 ). The URL of the trial registry record http://www.anzctr.org.au/trial/MyTrial.aspx.

Bidirectional Ventricular Tachycardia in a Patient With Fulminant Myocarditis Secondary to Cardiac Sarcoidosis Mimicking Giant Cell Myocarditis.

Differentiating between sarcoidosis and giant cell myocarditis (GCM) based on clinical presentation is difficult. We present the case of a 57-year-old woman who was initially diagnosed with GCM based on endomyocardial biopsy. The patient was refractory to standard management for GCM and went on to develop bidirectional ventricular tachycardia, a finding suggestive of sarcoidosis. Unfortunately, the patient eventually needed cardiac transplantation. The explanted heart demonstrated cardiac sarcoidosis. Bidirectional ventricular tachycardia has not been demonstrated in GCM, and its presence may help in distinguishing between GCM and cardiac sarcoidosis.

La distinction entre la sarcoïdose et la myocardite à cellules géantes (MCG) fondée sur le tableau clinique est difficile. Nous présentons le cas d'une femme de 57 ans qui avait initialement reçu un diagnostic de MCG à la suite de la biopsie endomyocardique. Comme la MCG diagnostiquée chez la patiente était réfractaire à la prise en charge thérapeutique habituelle, elle a continué à souffrir de tachycardie ventriculaire bidirectionnelle, un signe évocateur de sarcoïdose. Malheureusement, la patiente a finalement eu besoin d'une transplantation cardiaque. Le cœur explanté a démontré une sarcoïdose cardiaque. Bien que la tachycardie ventriculaire bidirectionnelle n'ait pas été démontrée lors de MCG, sa présence peut aider à distinguer la MCG de la sarcoïdose cardiaque.

Canadian Cardiovascular Society/Canadian Cardiac Transplant Network Position Statement on Heart Transplantation: Patient Eligibility, Selection, and Post-Transplantation Care.

Significant practice-changing developments have occurred in the care of heart transplantation candidates and recipients over the past decade. This Canadian Cardiovascular Society/Canadian Cardiac Transplant Network Position Statement provides evidence-based, expert panel recommendations with values and preferences, and practical tips on: (1) patient selection criteria; (2) selected patient populations; and (3) post transplantation surveillance. The recommendations were developed through systematic review of the literature and using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. The evolving areas of importance addressed include transplant recipient age, frailty assessment, pulmonary hypertension evaluation, cannabis use, combined heart and other solid organ transplantation, adult congenital heart disease, cardiac amyloidosis, high sensitization, and post-transplantation management of antibodies to human leukocyte antigen, rejection, cardiac allograft vasculopathy, and long-term noncardiac care. Attention is also given to Canadian-specific management strategies including the prioritization of highly sensitized transplant candidates (status 4S) and heart organ allocation algorithms. The focus topics in this position statement highlight the increased complexity of patients who undergo evaluation for heart transplantation as well as improved patient selection, and advances in post-transplantation management and surveillance that have led to better long-term outcomes for heart transplant recipients.

Stroke risk and atrial mechanical dysfunction in cardiac amyloidosis.

Amyloidosis is associated with poor prognosis, and patients with cardiac involvement have especially poor outcomes. Cardiac amyloidosis leads to higher rates of atrial arrhythmia and an increased risk of intracardiac thrombus formation. However, atrial mechanical dysfunction due to protein deposition in amyloidosis may lead to thrombus formation in the absence of atrial arrhythmia. We present a 42-year-old male patient with familial transthyretin amyloidosis who suffered an embolic stroke that originated from a left atrial appendage thrombus in the absence of any documented atrial fibrillation. This case highlights atrial mechanical dysfunction in patients with cardiac amyloidosis and the need to better stratify thrombotic risk in this population with integration of echocardiographic parameters and transesophageal echocardiography.

Study protocol to investigate the efficacy of normalisation of Advance Care Planning (ACP) for people with chronic diseases in acute and community settings: a quasi-experimental design.

BACKGROUND: Advanced care planning (ACP) is a process that involves thinking about what medical care one would like should individuals be seriously ill and cannot communicate decisions about treatment for themselves. The literature indicates that ACP leads to increased satisfaction from both patients and healthcare professionals. Despite the well-known benefits of ACP, it is still underutilised in Australia. METHODS: The aim of this study is to investigate the effects of normalising ACP in acute and community settings with the use of specially trained normalisation agents. This is a quasi-experimental study, involving 16 sites (8 intervention and 8 control) in two health districts in Australia. A minimum of total 288 participants will be recruited (144 intervention, 144 control). We will train four registered nurses as normalisation agents in the intervention sites, who will promote and facilitate ACP discussions with adult patients with chronic conditions in hospital and community settings. An audit of the prevalence of ACP and Advanced Care Directives (ACDs) will be conducted before and after the 6-month intervention period at the 16 sites to assess the effects of the ACP service delivered by these agents. We will also collect interview and survey data from patients and families who participate, and healthcare professionals who are involved in this service to capture their experiences with ACP. DISCUSSION: This study will potentially contribute to better patient outcomes with their health care services. Completion of ACDs will allow patients to express their wishes for care and receive the care that they wish for, as well as ease their family from the burden of making difficult decisions. The study will contribute to development of a new best practice model to normalise ACP that is sustainable and transferable in the processes of: 1) initiation of conversation; 2) discussion of important issues; 3) documentation of the wishes; 4) storage of the documented wishes; and 5) access and execution of the documented wishes. The study will generate new evidence on the challenges, strategies and benefits of normalising ACP into practice in acute and community settings. TRIAL REGISTRATION: This project has been approved by the Hunter New England Human Research Ethics Committee (Approval No. 17/12/13/4.16). It has also been retrospectively registered on 3 October 2018 with the Australian New Zealand Clinical Trials Registry (Trial ID: ACTRN12618001627246 ). This study will operate in accordance with the National Health and Medical Research Council's National Statement on Ethical Conduct in Human Research (2007) and the CPMP/ICH Note for Guidance on Good Clinical Practice.

Association between cytokines and functional, hemodynamic parameters, and clinical outcomes in pulmonary arterial hypertension.

To assess the relationship of cytokines with functional and clinical outcomes in pulmonary arterial hypertension (PAH). Endothelial dysfunction and vascular inflammation are characteristic of PAH. We investigated whether markers of angiogenesis and inflammation associated with functional, hemodynamic parameters, and clinical outcomes in PAH. PAH patients (n = 206) were pooled from two clinical trials: TRUST-1 and FREEDOM-C2. Baseline and post-treatment cytokine levels were correlated to baseline clinical and hemodynamic parameters, were assessed in clinical subgroups, and were associated with clinical outcomes. In 206 patients (mean age = 48 years; 74% women) with WHO group-1 PAH, most cytokine levels were higher in those with 6-min walking distance (6MWD) < median (335 m) vs. those above median, including Ang-1 (11.9 ± 10.1 vs. 5.9 ± 6.0 ng/mL), Ang-2 (14.3 ± 11.8 vs. 12.2 ± 11.2 ng/mL), and MMP-9 (221 ± 262.3 vs. 119 ± 171 ng/mL). Baseline 6MWD inversely correlated with Ang-1 (r = -0.27, P < 0.0001), Ang-2 (r = -0.20, P = 0.004), and MMP-9 (r = -0.27, P < 0.0001). MMP-9 levels differed significantly by NYHA functional class ( P = 0.001) suggesting an association between MMP-9 and subjective PAH severity. Mean Ang-2 levels were higher in those with baseline right atrial pressure (RAP) > 15 mmHg compared to those with RAP < 15 mmHg (23,841 vs. 11,020 pg/mL). Baseline RAP was associated with change in MMP-9 levels (r = -0.53, P = 0.03). Finally, baseline Ang-1, VEGF and MMP-9 levels were associated with risk of death and hospitalization at 16-week follow-up. Inflammatory cytokines and vascular angiogenesis markers are associated with baseline functional, hemodynamic parameters in PAH, and predict death and hospitalization. Larger prospective studies are needed to confirm the utility of cytokines in PAH.

A case of ruptured sinus of Valsalva aneurysm and reversible flow-induced pulmonary hypertension.

Pulmonary hypertension (PH) in adults with congenital heart disease (CHD) and significant systemic-to-pulmonary shunting is a significant cause of morbidity and mortality. Its pathophysiology is incompletely understood, but involves a flow-induced pulmonary arteriopathy characterized by endothelial cell dysfunction and vascular remodeling that alters pulmonary arterial vasoreactivity. There is a paucity of literature linking PH with left-to-right shunting due to ruptured sinus of Valsalva aneurysms (SOVA). We present a unique case of reversible, flow-associated PH due to a ruptured congenital right SOVA fistulizing into the right atrium (RA), with emphasis on non-invasive and invasive assessment of pulmonary hemodynamics before and after surgical intervention.

Transradial-Guided Percutaneous Transaxillary Intra-aortic Balloon Pump Insertion.

Axillary access for an intra-aortic balloon pump allows patients with advanced heart failure (HF) to sit upright and ambulate while waiting for destination therapy or bridging to heart transplantation. We describe the combination of radial access for positioning a 4F pigtail catheter to allow axillary angiography and provide a target for a micropuncture needle entry point in a fully anticoagulated patient with advanced HF.

Phosphodiesterase type 5 inhibitor to riociguat transition is associated with hemodynamic and symptomatic improvement in pulmonary hypertension.

Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. We studied the clinical and hemodynamics effects of transitioning 12 pulmonary hypertension patients from Phosphodiesterase type 5 inhibitor (PDE5i) to riociguat, and demonstrated a significant increase in cardiac index, fall in pulmonary vascular resistance, and improvement in functional class with this switch. Switch from PDE5i to riociguat appeared to be safe and fairly well tolerated in most patients.

Hemodynamic monitoring in heart failure and pulmonary hypertension: From analog tracings to the digital age.

Hemodynamic monitoring has long formed the cornerstone of heart failure (HF) and pulmonary hypertension diagnosis and management. We review the long history of invasive hemodynamic monitors initially using pulmonary artery (PA) pressure catheters in the hospital setting, to evaluating the utility of a number of implantable devices that can allow for ambulatory determination of intracardiac pressures. Although the use of indwelling PA catheters has fallen out of favor in a number of settings, implantable devices have afforded clinicians an opportunity for objective determination of a patient's volume status and pulmonary pressures. Some devices, such as the CardioMEMS and thoracic impedance monitors present as part of implantable cardiac defibrillators, are supported by a body of evidence which show the potential to reduce HF related morbidity and have received regulatory approval, whereas other devices have failed to show benefit and, in some cases, harm. Clearly these devices can convey a considerable amount of information and clinicians should start to familiarize themselves with their use and expect further development and refinement in the future.

Repair of UVB-induced DNA damage is reduced in melanoma due to low XPC and global genome repair.

UVB exposure leads to DNA damage, which when unrepaired induces C>T transitions. These mutations are found throughout the melanoma genome, particularly in non-transcribed regions. The global genome repair (GGR) branch of nucleotide excision repair (NER) is responsible for repairing UV-induced DNA damage across non-transcribed and silent regions of the genome. This study aimed to examine the relationship between UVB and GGR in melanoma. DNA repair capacity and relative expression of NER in melanocytes and melanoma cell lines before and after treatment with UVB was quantified. Transcript expression from 196 melanomas was compared to clinical parameters including solar elastosis and whole transcriptome data collected. Melanoma cell lines showed significantly reduced DNA repair when compared to melanocytes, most significantly in the S phase of the cell cycle. Expression of GGR components XPC, DDB1 and DDB2 was significantly lower in melanoma after UVB. In the melanoma tumours, XPC expression correlated with age of diagnosis and low XPC conferred significantly poorer survival. The same trend was seen in the TCGA melanoma dataset. Reduced GGR in melanoma may contribute to the UV mutation spectrum of the melanoma genome and adds further to the growing evidence of the link between UV, NER and melanoma.