Citations

Abstract Background Two methods combining survival and health-related quality of life (HRQoL) data in glioma trials to calculate the “net clinical benefit” were evaluated: Quality-adjusted effect sizes (QASES) and joint modeling (JM). Methods The net clinical benefit in two trials was calculated as proof of concept for other trials. With the QASES method, effect sizes for differences in progression-free survival (PFS) or overall survival (OS) and HRQoL between the experimental arm and standard treatment arm were calculated, while the relative emphasis placed on survival/HRQoL varied. JM allows simultaneous modeling of HRQoL and OS/PFS. Results In the EORTC 26951 trial, combined radiochemotherapy significantly prolonged OS (difference 11.7 months), but also resulted in more patients experiencing clinically relevant worsening (≥10 points) in appetite loss and nausea/vomiting shortly after treatment. Using QASES, the survival benefit of additional procarbazine, lomustine, and vincristine (PCV) decreased from 42.3 months to 29.5 and 28.2 months when accounting for appetite loss and nausea/vomiting, respectively. JM analyses resulted in a loss of the beneficial effect of additional PCV between 13% and 24% when adjusting for different HRQoL parameters. The EORTC 22033 trial showed no significant PFS difference between radiotherapy or temozolomide alone (46 vs 39 months), nor clinically relevant differences in HRQoL. JM analyses also showed no significant association between PFS and HRQoL scales/items, whereas QASES showed that temozolomide alone was more favorable when considering symptom burden (47–49 instead of 39 months). Conclusions Both methods resulted in different outcomes, but adjusting for the impact of treatment on HRQoL resulted in theoretically reduced survival benefits.

AbstractIntroducing a sensitive and specific peripheral blood flow cytometric assay for Sézary syndrome and mycosis fungoides (SS/MF) requires careful selection of assay design characteristics, and translation into a laboratory developed assay through development/optimization, validation, and continual quality monitoring. As outlined in a previous article in this series, the recommended design characteristics of this assay include at a minimum, evaluation of CD7, CD3, CD4, CD8, CD26, and CD45, analyzed simultaneously, requiring at least a 6 color flow cytometry system, with both quantitative and qualitative components. This article provides guidance from an international group of cytometry specialists in implementing an assay to those design specifications, outlining specific considerations, and best practices. Key points presented in detail are: (a) Pre‐analytic components (reagents, specimen processing, and acquisition) must be optimized to: (i) identify and characterize an abnormal population of T‐cells (qualitative component) and (ii) quantitate the abnormal population (semi/quasi‐quantitative component). (b)Analytic components (instrument set‐up/acquisition/analysis strategy and interpretation) must be optimized for the identification of SS/MF populations, which can vary widely in phenotype. Comparison with expert laboratories is strongly encouraged in order to establish competency. (c) Assay performance must be validated and documented through a validation plan and report, which covers both qualitative and semi/quasi‐quantitative assay components (example template provided). (d) Ongoing assay‐specific quality monitoring should be performed to ensure consistency.

ABSTRACT Background: There is a high prevalence of burnout among health care professionals, but little remains known about burnout and satisfaction with work–life integration (WLI) among advance practice nurses (APNs). Purpose: To evaluate burnout and satisfaction with WLI among APNs compared with other US workers. Methods: A national sample of APNs and a probability-based sample of US workers completed a survey that measured burnout and satisfaction with WLI. Results: Of the 976 (47%) APNs who completed the survey 64% had high personal accomplishment, 36.6% had symptoms of overall burnout, and 60.6% were satisfied with their WLI. In multivariable analysis, work hours (for each additional hour odds ratio [OR] 1.03, 95% confidence interval [CI] 1.02–1.04, p < .001) and working in an outpatient setting (overall p = .03; referent hospital: outpatient, OR 1.80, 95% CI 1.17–2.18; other/unknown, OR 1.41, 95% CI 0.90–2.22, p = .13) were independently associated with having higher odds of burnout. Work hours were also independently associated with lower odds of satisfaction with WLI (for each additional hour OR 0.94, 95% CI 0.94–0.95, p < .001). Advance practice nurses were not more likely to have burnout or have greater struggles with WLI than other workers. Implications for practice: Findings from this study suggest APNs have high levels of personal accomplishment and a favorable occupational health profile. Advance practice nurses do not appear at higher risk of burnout or dissatisfaction with WLI than other US workers.

Abstract Purpose: Pediatric high-grade glioma (pHGG) diagnosis portends poor prognosis and therapeutic monitoring remains difficult. Tumors release cell-free tumor DNA (cf-tDNA) into cerebrospinal fluid (CSF), allowing for potential detection of tumor-associated mutations by CSF sampling. We hypothesized that direct, electronic analysis of cf-tDNA with a handheld platform (Oxford Nanopore MinION) could quantify patient-specific CSF cf-tDNA variant allele fraction (VAF) with improved speed and limit of detection compared with established methods. Experimental Design: We performed ultra-short fragment (100–200 bp) PCR amplification of cf-tDNA for clinically actionable alterations in CSF and tumor samples from patients with pHGG (n = 12) alongside nontumor CSF (n = 6). PCR products underwent rapid amplicon-based sequencing by Oxford Nanopore Technology (Nanopore) with quantification of VAF. Additional comparison to next-generation sequencing (NGS) and droplet digital PCR (ddPCR) was performed. Results: Nanopore demonstrated 85% sensitivity and 100% specificity in CSF samples (n = 127 replicates) with 0.1 femtomole DNA limit of detection and 12-hour results, all of which compared favorably with NGS. Multiplexed analysis provided concurrent analysis of H3.3A (H3F3A) and H3C2 (HIST1H3B) mutations in a nonbiopsied patient and results were confirmed by ddPCR. Serial CSF cf-tDNA sequencing by Nanopore demonstrated correlation of radiological response on a clinical trial, with one patient showing dramatic multi-gene molecular response that predicted long-term clinical response. Conclusions: Nanopore sequencing of ultra-short pHGG CSF cf-tDNA fragments is feasible, efficient, and sensitive with low-input samples thus overcoming many of the barriers restricting wider use of CSF cf-tDNA diagnosis and monitoring in this patient population.

Abstract Purpose: Intratumorally injected Clostridium novyi-NT (nontoxic; lacking the alpha toxin), an attenuated strain of C. novyi, replicates within hypoxic tumor regions resulting in tumor-confined cell lysis and inflammatory response in animals, which warrants clinical investigation. Patients and Methods: This first-in-human study (NCT01924689) enrolled patients with injectable, treatment-refractory solid tumors to receive a single intratumoral injection of C. novyi-NT across 6 dose cohorts (1 × 104 to 3 × 106 spores, 3+3 dose-escalation design) to determine dose-limiting toxicities (DLT), and the maximum tolerated dose. Results: Among 24 patients, a single intratumoral injection of C. novyi-NT led to bacterial spores germination and the resultant lysis of injected tumor masses in 10 patients (42%) across all doses. The cohort 5 dose (1 × 106 spores) was defined as the maximum tolerated dose; DLTs were grade 4 sepsis (n = 2) and grade 4 gas gangrene (n = 1), all occurring in three patients with injected tumors &gt;8 cm. Other treatment-related grade ≥3 toxicities included pathologic fracture (n = 1), limb abscess (n = 1), soft-tissue infection (n = 1), respiratory insufficiency (n = 1), and rash (n = 1), which occurred across four patients. Of 22 evaluable patients, nine (41%) had a decrease in size of the injected tumor and 19 (86%) had stable disease as the best overall response in injected and noninjected lesions combined. C. novyi-NT injection elicited a transient systemic cytokine response and enhanced systemic tumor-specific T-cell responses. Conclusions: Single intratumoral injection of C. novyi-NT is feasible. Toxicities can be significant but manageable. Signals of antitumor activity and the host immune response support additional studies of C. novyi-NT in humans.

Background and objectives Presymptomatic testing is available for early diagnosis of hereditary autosomal dominant polycystic kidney disease (ADPKD). However, the complex ethical and psychosocial implications can make decision-making challenging and require an understanding of patients’ values, goals and priorities. This study aims to describe patient and caregiver beliefs and expectations regarding presymptomatic testing for ADPKD. Design, setting and participants 154 participants (120 patients and 34 caregivers) aged 18 years and over from eight centres in Australia, France and Korea participated in 17 focus groups. Transcripts were analysed thematically. Results We identified five themes: avoiding financial disadvantage (insecurity in the inability to obtain life insurance, limited work opportunities, financial burden); futility in uncertainty (erratic and diverse manifestations of disease limiting utility, taking preventive actions in vain, daunted by perplexity of results, unaware of risk of inheriting ADPKD); lacking autonomy and support in decisions (overwhelmed by ambiguous information, medicalising family planning, family pressures); seizing control of well-being (gaining confidence in early detection, allowing preparation for the future, reassurance in family resilience); and anticipating impact on quality of life (reassured by lack of symptoms, judging value of life with ADPKD). Conclusions For patients with ADPKD, presymptomatic testing provides an opportunity to take ownership of their health through family planning and preventive measures. However, these decisions can be wrought with tensions and uncertainty about prognostic implications, and the psychosocial and financial burden of testing. Healthcare professionals should focus on genetic counselling, mental health and providing education to patients’ families to support informed decision-making. Policymakers should consider the cost burden and risk of discrimination when informing government policies. Finally, patients are recommended to focus on self-care from an early age.

41 Background: Provider experience and physician burnout has been recognized as a critical issue in medicine. Ontario, Canada has a single payer cancer system run by Ontario Health (Cancer Care Ontario) with a mandate covering system level planning and delivery of cancer services, funding, and quality improvement. As part of a larger provincial initiative to address clinician burnout, we examined the prevalence and drivers of burnout in practicing physician oncologists in Ontario. Methods: In November-December 2019, surgical, medical, hematological, and radiation oncologists in Ontario were invited to complete an anonymous online survey to assess burnout and its drivers. Burnout prevalence was assessed through the Maslach Burnout Inventory – Human Services Survey for Medical Personnel (MBI-HSS MP). Data on demographic, workplace, engagement, and practice profiles were collected. Logistic regression modeling was conducted to assess key variables associated with “high” burnout using a common definition of high scores on the MBI subscales of emotional exhaustion (EE) (> 27) and/or depersonalization (DP) (>10). Results: Response rate to the survey was 44% (n=418) with 72% reporting high levels of burnout. Mean scores for EE (30.7, SD 12.1) and DP (9.9, SD 6.7) were consistent with high burnout. Participants endorsed known drivers of burnout including: 1) a poor culture of wellness at work (e.g., not comfortable talking to leadership (72%), 2) inefficiencies of practice (e.g. feeling insufficient documentation time (67%)) and 3) personal resilience (e.g. not feeling they are contributing professionally in ways they value (21%)). Age (<45yrs) (OR: 2.15), poor/marginal control over workload (OR: 4.42), feeling used/unappreciated (OR: 2.63), working atmosphere that feels hectic/chaotic (OR: 2.68), and insufficient time for documentation requirements (OR: 2.52) significantly impacted the odds of high burnout in the regression model (p<0.05). Conclusions: The high rate of burnout among oncology physicians in a single payer public cancer system in Ontario is concerning for the wellbeing of providers, patients and system sustainability. Drivers important for maintaining a culture of wellness and efficiency of practice will require local, regional and provincial health policy to improve. Next steps will include raising awareness with provincial initiatives/policy to address key burnout drivers, and examining the impact of working under pandemic conditions (Covid-19) on oncologist burnout.

Purpose To evaluate the relationship between help-seeking concerns and attitudes and burnout among residents. Method In 2019, all residents across the 4 Mayo Clinic sites were surveyed. The survey included 2 items from the Maslach Burnout Inventory, an item from the National Comorbidity Survey Replication about likelihood of seeking professional help for a serious emotional problem, and items developed to explore residents’ help-seeking behaviors and concerns. Multivariable logistic regression was conducted for each outcome variable and included age, gender, specialty, postgraduate year, site, and burnout. Results Of the 1,146 residents to whom surveys were sent, 762 (66.5%) responded. Nearly half (342/747, 45.8%) were concerned about negative consequence to their career if they went on medical leave, and one-third (247/753, 32.8%) were reluctant to seek professional help for a serious emotional concern. Of the 437 residents who had never attended a personal health appointment during scheduled work, 34.6% (151) thought it would be difficult to tell a supervising physician they needed to miss work due to a scheduled appointment. On multivariable analysis, burnout was independently associated with reporting it would be difficult to tell a supervising physician of a need to attend an appointment (odds ratio [OR] 2.32; 95% confidence interval [CI] 1.46, 3.67; P < .001), being concerned about negative consequence to their career if they went on medical leave (OR 2.09; 95% CI 1.49, 2.93; P < .001), and reluctance to seek professional care for a serious emotional problem (OR 1.65; 95% CI 1.17, 2.34; P = .004). Conclusions Barriers to self-care and help-seeking are common among residents and may be worse among those with burnout. Strategies to reduce stigma and promote a culture of well-being are needed.

AbstractObjectivesThe purpose of this study was to investigate the influence of simulated reduced‐dose three‐dimensional angiography (3DA) on the accuracy and precision of linear measurements derived from 3DA datasets.BackgroundThree‐dimensional angiography is performed during X‐ray guided interventional procedures to aid diagnosis and inform treatment strategies for children and adults with congenital heart disease. However, 3DA contributes substantially to patient radiation dose and may lead to an increased radiation‐induced cancer risk.MethodsReduced‐dose patient 3DA images were simulated by adding quantum noise to the 2D projection angiograms, then reconstructing the projection angiograms into the 3DA dataset. Dose reduction in the range 33–72% was simulated. Five observers performed 46 vessel diameter measurements along prespecified axes within 23 vessel segments from 11 patient 3DA datasets. Statistical tests were performed to assess the influence of radiation dose reduction on the accuracy and precision of vessel diameter measurements.ResultsVessel diameter measurements were in the range 5.9– 22.7 mm. Considering all vessel segments and observers, the influence of dose level on the accuracy of diameter measurements was in the range 0.02 – 0.15 mm (p .05–.8). Interobserver variability increased modestly with vessel diameter, but was not influence by dose level (p = .52). The statistical test for observer recall bias was negative (p = .51).ConclusionsSimulated dose reduction up to 72% did not affect the accuracy or precision of the diameter measurements acquired from 3DA images. These findings may embolden 3DA radiation dose reduction for pediatric and congenital heart disease patients.