Red cell transfusion thresholds in outpatients with myelodysplastic syndromes: Results of a pilot randomized trial RBC-ENHANCE.

BACKGROUND: The optimal hemoglobin (Hb) threshold for red blood cell transfusions in adult patients with myelodysplastic syndromes (MDS) has not been defined. STUDY DESIGN AND METHODS: We conducted a pilot randomized multi-center study of two transfusion algorithms (liberal, to maintain Hb 110-120 g/L, transfuse 2 units if Hb < 105 g/L and 1 unit if Hb 105-110 g/L vs. restrictive, 85-105 g/L, transfuse 2 units when Hgb < 85 g/L). Primary objectives were 70% compliance in maintaining the q2 week hemoglobin within the targeted range and the achievement of a 15 g/L difference in pre-transfusion Hb. Secondary outcomes included measures of quality of life (QOL), iron studies and safety. RESULTS: Twenty-eight patients were randomized between February 2015-2020, 13 to the restrictive arm and 15 to the liberal arm in three tertiary care centers. The compliance was 66% and 45% and the mean pre-transfusion Hb thresholds were 86 (standard deviation [SD] 8) and 98 g/L (SD 10) in the restrictive and liberal arms, (mean difference 11.8 g/L, p < .0001), respectively. Patients in the liberal arm experienced a mean of 3.4 (SD 2.6) more transfusion visits and received a mean of 5.3 (SD 5.5) more units of blood during the 12-week study. Ferritin increased by 1043 (SD 1516) IU/L and 148 (SD 1319) IU/L in the liberal and restrictive arms, respectively. Selected QOL scores were superior pre-transfusion and more patients achieved clinically important improvements in the liberal arm compared with the restrictive arm for selected symptoms and function domains. CONCLUSION: The results establish that policies for transfusion support can be delivered in practice at multiple hospitals, but further research is required to understand the full clinical effects and safety of liberal transfusion policies in MDS outpatients.

Predictors for improvement in patient-reported outcomes: post hoc analysis of a phase 3 randomized, open-label study of eculizumab and ravulizumab in complement inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by uncontrolled terminal complement activation leading to intravascular hemolysis (IVH), thrombosis, and impairments in quality of life (QoL). The aim of this study was to identify the clinical drivers of improvement in patient-reported outcomes (PROs) in patients with PNH receiving the complement component 5 (C5) inhibitors eculizumab and ravulizumab.This post hoc analysis assessed clinical outcomes and PROs from 246 complement inhibitor-naive patients with PNH enrolled in a phase 3 randomized non-inferiority study that compared the C5 inhibitors ravulizumab and eculizumab (study 301; NCT02946463). The variables of interest were lactate dehydrogenase (LDH) levels, a surrogate measure of IVH, and hemoglobin (Hb) levels. PROs were collected using Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) to assess fatigue and QoL, respectively.Improvements in absolute mean LDH levels were significantly associated with improvements in mean FACIT-F score (p = 0.0024) and EORTC QLQ-C30 global health (GH) score (p < 0.0001) from baseline to day 183. Improvements in scores were achieved despite a non-significant increase in Hb levels. To understand the interaction between LDH and Hb, a regression analysis was performed: LDH response with Hb improvements was a significant predictor of improvement in fatigue. The independent effect of improved Hb did not significantly affect FACIT-F or EORTC QLQ-C30 GH scores.These findings suggest that LDH levels are an important determinant of fatigue and QoL outcomes in patients with PNH. CTR: NCT02946463, October 27, 2016.

Pharmacogenetics of Lethal Opioid Overdose: Review of Current Evidence and Preliminary Results from a Pilot Study.

There has been a worldwide substantial increase in accidental opioid-overdose deaths. The aim of this review, along with preliminary results from our pilot study, is to highlight the use of pharmacogenetics as a tool to predict causes of accidental opioid-overdose death. For this review, a systematic literature search of PubMed® between the time period of January 2000 to March 2023 was carried out. We included study cohorts, case-controls, or case reports that investigated the frequency of genetic variants in opioid-related post-mortem samples and the association between these variants and opioid plasma concentrations. A total of 18 studies were included in our systematic review. The systematic review provides evidence of the use of CYP2D6, and to a lower extent, CYP2B6 and CYP3A4/5 genotyping in identifying unexpectedly high or low opioid and metabolite blood concentrations from post-mortem samples. Our own pilot study provides support for an enrichment of the CYP2B6*4-allele in our methadone-overdose sample (n = 41) compared to the anticipated frequency in the general population. The results from our systematic review and the pilot study highlight the potential of pharmacogenetics in determining vulnerability to overdose of opioids.

Evolving pipe joining methods and their association to musculoskeletal symptoms for residential plumbers.

BACKGROUND: Recently the plumbing trade has transitioned from traditional copper piping to flexible plastic piping (PEX) for residential water distribution systems. However, there has been very limited research into the ergonomic implications of the modernized processes. OBJECTIVE: This research documents the physical workload and risks of musculoskeletal disorders (MSDs) with the use of new tools and processes for joining piping. The research also identifies the factors which can facilitate or limit the use of new ergonomically beneficial tools. METHODS: This mixed methods research included workplace observations, interviews, an experiment, a survey of plumbers in residential construction and focus groups with both plumbers and plumbing contractors. RESULTS: Advantages and disadvantages of the various techniques for joining pipes showed that manual crimping has advantages (i.e., productivity and lower cost) that make it desirable for plumbing contractors. Power devices, which were not widely used, have great potential to reduce MSD risks especially if the size and weight of the tools decreases with newer technologies. A continuing barrier is the cost of power equipment. CONCLUSION: The move to provide ergonomically beneficial tools was not as rapid as the willingness to change piping materials. Productivity and costs of tools are barriers to ergonomic interventions.

Examining the relationship between human factors related quality risk factors and work related musculoskeletal disorder risk factors in manufacturing.

This study addresses the relationship between human factors (HF) related quality deficits in manufacturing and work-related musculoskeletal disorder (WMSD) risk factors in production staff. A recent systematic review identified 60 HF-related quality risk factors (QRFs) in manufacturing related to product, process and workstation design stages. We investigate the extent to which these identified QRFs are also WMSD risk factors. Each QRF was examined for its relationship with WMSD using a 0 (no relationship) to 10 (strong relationship) scale rubric. The authors rated each QRF separately and then discussed and adjusted their ratings in a review session. Results showed that average median ratings were the highest for QRFs related to product design (8/10), intermediate for QRFs related to workstation design (7/10) and the lowest for QRFs related to process design (5/10). This emphasises the significant role of HF in system design in reducing both quality deficits and risk of developing WMSDs for manufacturing personnel.Practitioner summary: This study investigates whether human-related risk factors for product quality are also risk factors for work-related musculoskeletal disorders in manufacturing. Results showed a substantial relationship between quality risk factors and WMSD risk factors. This indicates the significant role of human factors in operations design in improving both system performance and human wellbeing.

The Use of Cremation Data for Timely Mortality Surveillance During the COVID-19 Pandemic in Ontario, Canada: Validation Study.

BACKGROUND: Early estimates of excess mortality are crucial for understanding the impact of COVID-19. However, there is a lag of several months in the reporting of vital statistics mortality data for many jurisdictions, including across Canada. In Ontario, a Canadian province, certification by a coroner is required before cremation can occur, creating real-time mortality data that encompasses the majority of deaths within the province. OBJECTIVE: This study aimed to validate the use of cremation data as a timely surveillance tool for all-cause mortality during a public health emergency in a jurisdiction with delays in vital statistics data. Specifically, this study aimed to validate this surveillance tool by determining the stability, timeliness, and robustness of its real-time estimation of all-cause mortality. METHODS: Cremation records from January 2020 until April 2021 were compared to the historical records from 2017 to 2019, grouped according to week, age, sex, and whether COVID-19 was the cause of death. Cremation data were compared to Ontario's provisional vital statistics mortality data released by Statistics Canada. The 2020 and 2021 records were then compared to previous years (2017-2019) to determine whether there was excess mortality within various age groups and whether deaths attributed to COVID-19 accounted for the entirety of the excess mortality. RESULTS: Between 2017 and 2019, cremations were performed for 67.4% (95% CI 67.3%-67.5%) of deaths. The proportion of cremated deaths remained stable throughout 2020, even within age and sex categories. Cremation records are 99% complete within 3 weeks of the date of death, which precedes the compilation of vital statistics data by several months. Consequently, during the first wave (from April to June 2020), cremation records detected a 16.9% increase (95% CI 14.6%-19.3%) in all-cause mortality, a finding that was confirmed several months later with cremation data. CONCLUSIONS: The percentage of Ontarians cremated and the completion of cremation data several months before vital statistics did not change meaningfully during the COVID-19 pandemic period, establishing that the pandemic did not significantly alter cremation practices. Cremation data can be used to accurately estimate all-cause mortality in near real-time, particularly when real-time mortality estimates are needed to inform policy decisions for public health measures. The accuracy of this excess mortality estimation was confirmed by comparing it with official vital statistics data. These findings demonstrate the utility of cremation data as a complementary data source for timely mortality information during public health emergencies.

Retrospective study of non-natural manners of death in Ontario: Effects of the COVID-19 pandemic and related public health measures.

BACKGROUND: The effects of the COVID-19 pandemic on non-natural manners of death in Ontario is not known. Understanding the indirect consequences of the pandemic and related public health measures (i.e. lockdown) fills a vital need to inform best practice in public health and guide policy decisions. METHODS: The Office of the Chief Coroner and the Ontario Forensic Pathology Service (OCC-OFPS) investigate sudden and unexpected deaths in the province of Ontario. The number of homicides, suicides, and accidental deaths (non-natural deaths=77,655) were extracted from the centralized Coroner's Information System database (total deaths=197,966), across four provincially defined stages of lockdown related to the COVID-19 pandemic (March 17 to December 31, 2020), and crude rates (per 100,000 people) were compared to the previous eleven years. FINDINGS: There was no major change to the rate of homicides during 2020 compared to 2009-2019 (RR 1⋅1, 95% CI 0⋅95-1⋅2; p=0⋅19; estimated annual effect=21 more deaths in 2020). The rate of suicides also did not show an overall major change in 2020 (RR 1⋅02, 95% CI 0⋅96-1⋅1; p=0⋅50; estimated annual effect=27 more deaths in 2020). However, during the first stage of lockdown (Stage 0), there was a decrease in the rate of suicides compared to all combinations of recent years from 2013 onwards (RRs 0⋅82-0⋅86, combined 95% CI 0⋅69-0⋅99; max p=0⋅039; estimated effect of 30 less deaths in Stage 0). There was an excess of over 1,500 accidental drug-related deaths that occurred during 2020 (RR 2⋅5, 95% CI 2⋅4-2⋅7; p<0⋅001). This finding held up to 'interrupted time series' robustness testing, indicating that 2020 had substantially more drug-related deaths, even when accounting for the linear increasing trend over time. Although motor vehicle collision associated fatalities appeared to decrease slightly in 2020 (RR 0⋅89, 95% CI 0⋅81-0⋅96; p=0⋅0039; estimated annual effect of 78 less deaths), we could not conclude any lockdown-associated effect, particularly when compared to 2019 (RR 0⋅26, 95% CI 0⋅75-1⋅1; p=0⋅26). INTERPRETATION: In Ontario, the short-term effects of the COVID-19 pandemic did not greatly increase homicide or suicide rates, nor decrease motor vehicle collision fatality rates; however, the longer-term impact of the pandemic remains to be elucidated and ongoing vigilance is warranted in the event that other trends emerge. Accidental drug-related fatalities substantially increased during all stages of the lockdown, marking an urgent need for consideration in policy. These results highlight the vital role of death investigation systems in providing high quality and timely data to inform public health recommendations.

Genome-wide analysis reveals the genetic stock structure of hoki (Macruronus novaezelandiae).

The assessment of the genetic structuring of biodiversity is crucial for management and conservation. This is particularly critical for widely distributed and highly mobile deep-water teleosts, such as hoki (Macruronus novaezelandiae). This species is significant to Maori people and supports the largest commercial fishery in New Zealand, but uncertainty about its stock structure presents a challenge for management. Here, we apply a comprehensive genomic analysis to shed light on the demographic structure of this species by (1) assembling the genome, (2) generating a catalogue of genome-wide SNPs to infer the stock structure and (3) identifying regions of the genome under selection. The final genome assembly used short and long reads and is near complete, representing 93.8% of BUSCO genes, and consisting of 566 contigs totalling 501 Mb. Whole-genome re-sequencing of 510 hoki sampled from 14 locations around New Zealand and Australia, at a read depth greater than 10×, produced 227,490 filtered SNPs. Analyses of these SNPs were able to resolve the stock structure of hoki into two genetically and geographically distinct clusters, one including the Australian and the other one all New Zealand locations, indicating genetic exchange between these regions is limited. Location differences within New Zealand samples were much more subtle (global F ST  = 0.0006), and while small and significant differences could be detected, they did not conclusively identify additional substructures. Ten putative adaptive SNPs were detected within the New Zealand samples, but these also did not geographically partition the dataset further. Contemporary and historical N e estimation suggest the current New Zealand population of hoki is large yet declining. Overall, our study provides the first genomic resources for hoki and provides detailed insights into the fine-scale population genetic structure to inform the management of this species.

The effects of secondary iron overload and iron chelation on a radiation-induced acute myeloid leukemia mouse model.

BACKGROUND: Patients with myelodysplastic syndrome (MDS) require chronic red blood cell (RBC) transfusion due to anemia. Multiple RBC transfusions cause secondary iron overload and subsequent excessive generation of reactive oxygen species (ROS), which leads to mutations, cell death, organ failure, and inferior disease outcomes. We hypothesize that iron loading promotes AML development by increasing oxidative stress and disrupting important signaling pathways in the bone marrow cells (BMCs). Conversely, iron chelation therapy (ICT) may reduce AML risk by lowering iron burden in the iron-loaded animals. METHODS: We utilized a radiation-induced acute myeloid leukemia (RI-AML) animal model. Iron overload was introduced via intraperitoneal injection of iron dextran, and iron chelation via oral gavage of deferasirox. A total of 86 irradiated B6D2F1 mice with various levels of iron burden were monitored for leukemia development over a period of 70 weeks. The Kaplan-Meier estimator was utilized to assess AML free survival. In addition, a second cohort of 30 mice was assigned for early analysis at 5 and 7 months post-irradiation. The BMCs of the early cohort were assessed for alterations of signaling pathways, DNA damage response and gene expression. Statistical significance was established using Student's t-test or ANOVA. RESULTS: Iron loading in irradiated B6D2F1 mice accelerated RI-AML development. However, there was a progressive decrease in AML risk for irradiated mice with increase in iron burden from 7.5 to 15 to 30 mg. In addition, ICT decreased AML incidence in the 7.5 mg iron-loaded irradiated mice, while AML onset was earlier for the 30 mg iron-loaded irradiated mice that received ICT. Furthermore, analysis of BMCs from irradiated mice at earlier intervals revealed accelerated dysregulation of signaling pathways upon iron loading, while ICT partially mitigated the effects. CONCLUSIONS: We concluded that iron is a promoter of leukemogenesis in vivo up to a peak iron dose, but further iron loading decreases AML risk by increasing cell death. ICT can partially mitigate the adverse effects of iron overload, and to maximize its benefit this intervention should be undertaken prior to the development of extreme iron overload.

Intracellular ROS profile in hematopoietic progenitors of MDS patients: association with blast count and iron overload.

Objectives: Reactive oxygen species (ROS) are under scrutiny as a participant in the pathophysiology of myelodysplastic syndrome (MDS) and the progression of MDS to acute myeloid leukemia (AML). Measurement of intracellular ROS (iROS) is particularly important since iROS is a direct indicator of cellular health and integrity.Methods: We developed a technique to measure standardize iROS (siROS) level in lymphocytes and bone marrow (BM) CD34+ hematopoietic progenitors using the fluorescent probe dichlorofluorescein (DCF). We then quantified the siROS in 38 consecutive BM specimens from 27 MDS patients over the course of 10 months. Disease outcome of these patients were also assessed.Results: High serum ferritin, high blast count and poor IPSS were associated with inferior survival and AML progression in this cohort. High blast MDS patients had lower siROS in their BM CD34+ cells than those of low blast patients, consistent with increased reliance on glycolysis and enhanced ROS defense in high blast MDS. We also observed narrower siROS distribution in the BM CD34+ cells of high blast patients, suggesting that loss of heterogeneity in ROS content accompanies the clonal evolution of MDS. Furthermore, we observed a strong correlation between CD34+ cells siROS and serum ferritin level in high blast patients. In one case, iron chelation therapy (ICT) resulted in parallel decreases in serum ferritin and CD34+ cells siROS.Conclusion: Our findings established the siROS profile in early hematopoietic cells of MDS patients and its relationship with blast count and iron overload.

One-year outcomes from a phase 3 randomized trial of ravulizumab in adults with paroxysmal nocturnal hemoglobinuria who received prior eculizumab.

Ravulizumab every 8 weeks showed non-inferiority to eculizumab every 2 weeks in a 26-week, phase 3, randomized controlled trial in adults with paroxysmal nocturnal hemoglobinuria (PNH) who were clinically stable on eculizumab (NCT03056040). We report results from the first 26 weeks of the extension period in which patients continued ravulizumab (n = 96) or switched from eculizumab to ravulizumab (n = 95). At week 52, mean (SD) lactate dehydrogenase levels increased 8.8% (29%) with ravulizumab-ravulizumab and 5.8% (27%) with eculizumab-ravulizumab from primary evaluation period baseline. During the extension period, four patients (ravulizumab-ravulizumab, n = 3; eculizumab-ravulizumab, n = 1) experienced breakthrough hemolysis, but none associated with serum free C5 ≥ 0.5 µg/mL. Mean Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores remained stable through week 52. During the extension period, proportions of patients avoiding transfusion remained stable (ravulizumab-ravulizumab, 86.5%; eculizumab-ravulizumab, 83.2%); 81.2% and 81.1%, respectively, had stabilized hemoglobin. All patients maintained serum free C5 levels < 0.5 µg/mL. Adverse events were generally similar between groups, and rates were lower in the extension period. Adults with PNH on stable eculizumab therapy who received ravulizumab over 52 weeks experienced durable efficacy, with consistent efficacy in patients who received eculizumab during the primary evaluation period and then switched to ravulizumab. Ravulizumab was well tolerated.

One-year efficacy and safety of ravulizumab in adults with paroxysmal nocturnal hemoglobinuria naïve to complement inhibitor therapy: open-label extension of a randomized study.

BACKGROUND: Ravulizumab, the only long-acting complement C5 inhibitor for adults with paroxysmal nocturnal hemoglobinuria (PNH), demonstrated non-inferiority to eculizumab after 26 weeks of treatment in complement inhibitor-naïve patients during a phase III randomized controlled trial. We present open-label extension results with up to 52 weeks of treatment. METHODS: Patients assigned to ravulizumab every 8 weeks (q8w) or eculizumab every 2 weeks during the randomized primary evaluation period received ravulizumab q8w during the 26-week extension. Efficacy endpoints were lactate dehydrogenase (LDH) normalization, transfusion avoidance, breakthrough hemolysis (BTH), LDH levels, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, and stabilized hemoglobin. Serum free C5 levels and safety were assessed. Outcomes as of the data cut-off (4 September 2018) were summarized using descriptive statistics. RESULTS: Overall, 124 patients continued ravulizumab, and 119 switched from eculizumab to ravulizumab. During the extension, 43.5% and 40.3% of patients in the ravulizumab-ravulizumab and eculizumab-ravulizumab arms, respectively, achieved LDH normalization; 76.6% and 67.2% avoided transfusion. BTH decreased in the eculizumab-ravulizumab arm; no events were associated with free C5 ⩾0.5 µg/mL while receiving ravulizumab. Overall, 73.4% and 65.5% of patients in the ravulizumab-ravulizumab and eculizumab-ravulizumab arms, respectively, achieved stabilized hemoglobin. Similar proportions of patients achieved ⩾3-point improvement in FACIT-Fatigue at week 52 (ravulizumab-ravulizumab, 64.5%; eculizumab-ravulizumab, 57.1%). All patients maintained free C5 <0.5 µg/mL during the ravulizumab extension, including those who experienced C5 excursions ⩾0.5 µg/mL while receiving eculizumab during the primary evaluation period. Adverse events were comparable between groups and decreased over time. CONCLUSION: In adult, complement inhibitor-naïve patients with PNH, ravulizumab q8w for up to 52 weeks demonstrated durable efficacy and was well tolerated, with complete and sustained free C5 inhibition and a decreased incidence of BTH with no events associated with loss of free C5 control. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02946463.

Patient preferences and quality of life implications of ravulizumab (every 8 weeks) and eculizumab (every 2 weeks) for the treatment of paroxysmal nocturnal hemoglobinuria.

BACKGROUND: Eculizumab has transformed management of paroxysmal nocturnal hemoglobinuria (PNH) since its approval. However, its biweekly dosing regimen remains a high treatment burden. Ravulizumab administered every 8 weeks demonstrated noninferiority to eculizumab in two phase 3 trials. In regions where two PNH treatment options are available, it is important to consider patient preference. OBJECTIVE: The aim of this study was to assess patient preference for ravulizumab or eculizumab. METHODS: Study 302s (ALXN1210-PNH-302s) enrolled PNH patients who participated in the extension period of phase 3 study ALXN1210-PNH-302. In the parent study, eculizumab-experienced adult PNH patients received ravulizumab or eculizumab during a 26-week primary evaluation period. All patients in the extension period received ravulizumab. In study 302s, patient treatment preference was evaluated using an 11-item PNH-specific Patient Preference Questionnaire (PNH-PPQ©). Of 98 patients, 95 completed PNH-PPQ© per protocol for analysis. RESULTS: Overall, 93% of patients preferred ravulizumab whereas 7% of patients either had no preference (6%) or preferred eculizumab (1%) (P < 0.001). For specific aspects of treatment, ravulizumab was preferred (in comparison to no preference or eculizumab) on infusion frequency (98% vs. 0% vs. 2%), ability to plan activities (98% vs. 0% vs. 2%), and overall quality of life (88% vs. 11% vs. 1%), among other aspects. Most participants selected frequency of infusions as the most important factor determining preference (43%), followed by overall quality of life (23%). CONCLUSION: This study shows that a substantial proportion of patients preferred ravulizumab over eculizumab and provides an important patient perspective on PNH treatment when there is more than one treatment option.

Pharmacokinetic and pharmacodynamic effects of ravulizumab and eculizumab on complement component 5 in adults with paroxysmal nocturnal haemoglobinuria: results of two phase 3 randomised, multicentre studies.

Ravulizumab, a novel long-acting complement component 5 (C5) inhibitor administered every 8 weeks (q8w), was non-inferior to eculizumab for all efficacy outcomes in two randomised, open-label, phase 3 trials in C5 inhibitor-naïve (Study 301) and eculizumab-experienced (Study 302) adult patients with paroxysmal nocturnal haemoglobinuria (PNH). This pre-specified analysis characterised ravulizumab pharmacokinetics (PK), pharmacodynamics (PD; free C5 levels), and PD differences between medications (Study 301, n = 246; Study 302, n = 195). Ravulizumab PK parameters were determined using non-compartmental analysis. Serum free C5 was quantified with a Gyros-based fluorescence assay (ravulizumab) and an electrochemiluminescence ligand-binding assay (eculizumab). Ravulizumab PK parameters were numerically comparable in both studies; the median time to maximum concentrations ranged from 2·3 to 2·8 and 2·3 to 2·6 h in studies 301 and 302, respectively. Ravulizumab steady-state serum concentrations were achieved immediately after the first dose and sustained throughout treatment. For ravulizumab, the mean (SD) post hoc terminal elimination half-life was 49·7 (8·9) days. Serum free C5 concentrations <0·5 µg/ml were achieved after the first ravulizumab dose and sustained throughout treatment in both studies. In a minority of patients, free C5 concentrations <0·5 µg/ml were not consistently achieved with eculizumab in either study. Ravulizumab q8w was more consistent in providing immediate, complete, sustained C5 inhibition than eculizumab every-2-weeks in patients with PNH.

Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study.

This phase 2 study was designed to compare systemic decitabine exposure, demethylation activity, and safety in the first 2 cycles with cedazuridine 100 mg/decitabine 35 mg vs standard decitabine 20 mg/m2 IV. Adults with International Prognostic Scoring System intermediate-1/2- or high-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) were randomized 1:1 to receive oral cedazuridine/decitabine or IV decitabine in cycle 1, followed by crossover to the other treatment in cycle 2. All patients received oral cedazuridine/decitabine in subsequent cycles. Cedazuridine and decitabine were given initially as separate capsules in a dose-confirmation stage and then as a single fixed-dose combination (FDC) tablet. Primary end points: mean decitabine systemic exposure (geometric least-squares mean [LSM]) of oral/IV 5-day area under curve from time 0 to last measurable concentration (AUClast), percentage long interspersed nuclear element 1 (LINE-1) DNA demethylation for oral cedazuridine/decitabine vs IV decitabine, and clinical response. Eighty patients were randomized and treated. Oral/IV ratios of geometric LSM 5-day AUClast (80% confidence interval) were 93.5% (82.1-106.5) and 97.6% (80.5-118.3) for the dose-confirmation and FDC stages, respectively. Differences in mean %LINE-1 demethylation between oral and IV were ≤1%. Clinical responses were observed in 48 patients (60%), including 17 (21%) with complete response. The most common grade ≥3 adverse events regardless of causality were neutropenia (46%), thrombocytopenia (38%), and febrile neutropenia (29%). Oral cedazuridine/decitabine (100/35 mg) produced similar systemic decitabine exposure, DNA demethylation, and safety vs decitabine 20 mg/m2 IV in the first 2 cycles, with similar efficacy. This study is registered at www.clinicaltrials.gov as #NCT02103478.

Assessing Preferences for Rare Disease Treatment: Qualitative Development of the Paroxysmal Nocturnal Hemoglobinuria Patient Preference Questionnaire (PNH-PPQ©).

PURPOSE: To develop a patient preference questionnaire (PPQ) assessing eculizumab and ravulizumab treatment for paroxysmal nocturnal hemoglobinuria (PNH). PATIENTS AND METHODS: The development of the PNH-PPQ© was consistent with Food and Drug Administration guidelines for patient-reported outcome measure development, and included 1) a targeted literature review; 2) PNH expert clinician input on treatment preferences; 3) review of existing qualitative data on the PNH treatment and disease experience; 4) concept elicitation interviews with 8 PNH patients who received eculizumab and/or ravulizumab; 5) translatability review; and 6) cognitive debriefing with 5 patients. Interview participants were recruited through a United Kingdom PNH patient advocacy group and a Canadian clinical site involved in clinical trial ALXN1210-PNH-302. RESULTS: Six themes were identified as most relevant to the PNH treatment experience from the concept elicitation interviews: disease symptoms (n=8/8); treatment frequency (n=7/8); quality of life impact of treatment/disease (n=7/8); treatment burden (n=7/8); treatment efficacy (n=5/8); and treatment side effects (n=5/8). An initial list of 88 preference questions was reduced to 11 highly relevant and non-redundant questions reflecting the 6 themes. Cognitive interview participants unanimously agreed that the PNH-PPQ instructions were clear; response options were understandable, easy to use, and provided enough choices; and the questions captured the factors that inform treatment preferences. DISCUSSION: When new drugs have similar efficacy to existing medications, documenting patient preferences is important for confirming patient benefit from the new medication. Understanding what matters most to patients is essential for delivering patient-centered care and may play a particularly significant role in treatment decision making. The availability of such a tool may be especially important as new orphan drugs are developed and patients with rare diseases have more than one treatment option to consider. CONCLUSION: The PNH-PPQ provides a patient-centered approach for evaluating preferences for the treatment of PNH. The PNH-PPQ has subsequently assessed patient preference in the clinical trial sub-study ALXN1210-PNH-302s.

Does urethral length affect continence outcomes following robot assisted laparoscopic radical prostatectomy (RALP)?

BACKGROUND: Post-operative urinary incontinence is a significant concern for patients choosing to undergo a radical prostatectomy (RP) for treatment of prostate cancer. The aim of our study was to determine the effect of pre-operative MUL on 12 month continence outcomes in men having robot-assisted laparoscopic prostatectomy (RALP). METHODS: We use the South Australian Prostate Cancer Clinical Outcomes Collaborative (SA-PCCOC) database, to identify 602 patients who had undergone RALP by a high volume surgeon. Only patients who received an assessment and education by a specialist pelvic floor physiotherapist, had completed EPIC questionnaires before treatment and did not have radiotherapy treatment within 12 months of surgery were included. MUL measurements were taken from pre-operative magnetic resonance imaging (MRI) scans. The short-form version of the Expanded Prostate Cancer Index Composite (EPIC-26) was used to measure continence outcomes. Continence was defined as 100/100 in the EPIC-26 Urinary Continence domain score. RESULTS: The observed median MUL in this study was 14.6 mm. There was no association between MUL and baseline continence. MUL was associated with continence at 12 months post RALP (OR 1.13, 95% CI 1.03-1.21, p = 0.0098). In men who were continent before surgery, MUL was associated with return to continence at 12 months after RALP (OR 1.15, 1.05-1.28, p = 0.006). MUL was also associated with change in continence after surgery (ß = 1.22, p = 0.002). CONCLUSIONS: MUL had no effect on baseline continence but had a positive and significant association with continence outcomes over 12 months post RALP.