Ibrutinib-based therapy reinvigorates CD8+ T cells compared to chemoimmunotherapy: immune monitoring from the E1912 trial.

ABSTRACT: Bruton tyrosine kinase inhibitors (BTKis) that target B-cell receptor signaling have led to a paradigm shift in chronic lymphocytic leukemia (CLL) treatment. BTKis have been shown to reduce abnormally high CLL-associated T-cell counts and the expression of immune checkpoint receptors concomitantly with tumor reduction. However, the impact of BTKi therapy on T-cell function has not been fully characterized. Here, we performed longitudinal immunophenotypic and functional analysis of pretreatment and on-treatment (6 and 12 months) peripheral blood samples from patients in the phase 3 E1912 trial comparing ibrutinib-rituximab with fludarabine, cyclophosphamide, and rituximab (FCR). Intriguingly, we report that despite reduced overall T-cell counts; higher numbers of T cells, including effector CD8+ subsets at baseline and at the 6-month time point, associated with no infections; and favorable progression-free survival in the ibrutinib-rituximab arm. Assays demonstrated enhanced anti-CLL T-cell killing function during ibrutinib-rituximab treatment, including a switch from predominantly CD4+ T-cell:CLL immune synapses at baseline to increased CD8+ lytic synapses on-therapy. Conversely, in the FCR arm, higher T-cell numbers correlated with adverse clinical responses and showed no functional improvement. We further demonstrate the potential of exploiting rejuvenated T-cell cytotoxicity during ibrutinib-rituximab treatment, using the bispecific antibody glofitamab, supporting combination immunotherapy approaches.

Prediction of outcomes for high-count monoclonal B lymphocytosis using an epigenetic and immunogenetic signature.

ABSTRACT: Monoclonal B-cell lymphocytosis (MBL) progresses to chronic lymphocytic leukemia (CLL) requiring therapy at 1% to 5% per year. Improved prediction of progression would greatly benefit individuals with MBL. Patients with CLL separate into 3 distinct epigenetic subtypes (epitypes) with high prognostic significance, and recently the intermediate epitype has been shown to be enriched for high-risk immunoglobulin lambda variable (IGLV) 3-21 rearrangements, impacting outcomes for these patients. Here, we employed this combined strategy to generate the epigenetic and light chain immunoglobulin (ELCLV3-21) signature to classify 219 individuals with MBL. The ELCLV3-21 high-risk signature distinguished MBL individuals with a high probability of progression (39.9% and 71.1% at 5 and 10 years, respectively). ELCLV3-21 improved the accuracy of predicting time to therapy for individuals with MBL compared with other established prognostic indicators, including the CLL international prognostic index (c-statistic, 0.767 vs 0.668, respectively). Comparing ELCLV3-21 risk groups in MBL vs a cohort of 226 patients with CLL revealed ELCLV3-21 high-risk individuals with MBL had significantly shorter time to therapy (P = .003) and reduced overall survival (P = .03) compared with ELCLV3-21 low-risk individuals with CLL. These results highlight the power of the ELCLV3-21 approach to identify individuals with a higher likelihood of adverse clinical outcome and may provide a more accurate approach to classify individuals with small B-cell clones.

Fostering Psychological Safety and Supporting Mental Health Among Cardiovascular Health Care Workers: A Science Advisory From the American Heart Association.

The psychological safety of health care workers is an important but often overlooked aspect of the rising rates of burnout and workforce shortages. In addition, mental health conditions are prevalent among health care workers, but the associated stigma is a significant barrier to accessing adequate care. More efforts are therefore needed to foster health care work environments that are safe and supportive of self-care. The purpose of this brief document is to promote a culture of psychological safety in health care organizations. We review ways in which organizations can create a psychologically safe workplace, the benefits of a psychologically safe workplace, and strategies to promote mental health and reduce suicide risk.

The effect of neighborhood socioeconomic disadvantage on smoking status, quit attempts, and receipt of cessation support among adults with cancer: Results from nine ECOG-ACRIN Cancer Research Group trials.

BACKGROUND: Tobacco use is associated with adverse outcomes among patients diagnosed with cancer. Socioeconomic determinants influence access and utilization of tobacco treatment; little is known about the relationship between neighborhood socioeconomic disadvantage (NSD) and tobacco assessment, assistance, and cessation among patients diagnosed with cancer. METHODS: A modified Cancer Patient Tobacco Use Questionnaire (C-TUQ) was administered to patients enrolled in nine ECOG-ACRIN clinical trials. We examined associations of NSD with (1) smoking status, (2) receiving tobacco cessation assessment and support, and (3) cessation behaviors. NSD was classified by tertiles of the Area Deprivation Index. Associations between NSD and tobacco variables were evaluated using logistic regression. RESULTS: A total of 740 patients completing the C-TUQ were 70% male, 94% White, 3% Hispanic, mean age 58.8 years. Cancer diagnoses included leukemia 263 (36%), lymphoma 141 (19%), prostate 131 (18%), breast 79 (11%), melanoma 69 (9%), myeloma 53 (7%), and head and neck 4 (0.5%). A total of 402 (54%) never smoked, 257 (35%) had formerly smoked, and 81 (11%) were currently smoking. Patients in high disadvantaged neighborhoods were approximately four times more likely to report current smoking (odds ratio [OR], 3.57; 95% CI, 1.69-7.54; p = .0009), and more likely to report being asked about smoking (OR, 4.24; 95% CI, 1.64-10.98; p = .0029), but less likely to report receiving counseling (OR, 0.11; 95% CI, 0.02-0.58; p = .0086) versus those in the least disadvantaged neighborhoods. CONCLUSIONS: Greater neighborhood socioeconomic disadvantage was associated with smoking but less cessation support. Increased cessation support in cancer care is needed, particularly for patients from disadvantaged neighborhoods.

Progression and survival of MBL: a screening study of 10 139 individuals.

Monoclonal B-cell lymphocytosis (MBL) is a common hematological premalignant condition that is understudied in screening cohorts. MBL can be classified into low-count (LC) and high-count (HC) types based on the size of the B-cell clone. Using the Mayo Clinic Biobank, we screened for MBL and evaluated its association with future hematologic malignancy and overall survival (OS). We had a two-stage study design including discovery and validation cohorts. We screened for MBL using an eight-color flow-cytometry assay. Medical records were abstracted for hematological cancers and death. We used Cox regression to evaluate associations and estimate hazard ratios and 95% confidence intervals (CIs), adjusting for age and sex. We identified 1712 (17%) individuals with MBL (95% LC-MBL), and the median follow-up time for OS was 34.4 months with 621 individuals who died. We did not observe an association with OS among individuals with LC-MBL (P = .78) but did among HC-MBL (hazard ratio, 1.8; 95% CI, 1.1-3.1; P = .03). Among the discovery cohort with a median of 10.0 years follow-up, 31 individuals developed hematological cancers with two-thirds being lymphoid malignancies. MBL was associated with 3.6-fold risk of hematological cancer compared to controls (95% CI, 1.7-7.7; P < .001) and 7.7-fold increased risk for lymphoid malignancies (95% CI:3.1-19.2; P < .001). LC-MBL was associated with 4.3-fold risk of lymphoid malignancies (95% CI, 1.4-12.7; P = .009); HC-MBL had a 74-fold increased risk (95% CI, 22-246; P < .001). In this large screening cohort, we observed similar survival among individuals with and without LC-MBL, yet individuals with LC-MBL have a fourfold increased risk of lymphoid malignancies. Accumulating evidence indicates that there are clinical consequences to LC-MBL, a condition that affects 8 to 10 million adults in the United States.

Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial.

Herein, we present the long-term follow-up of the randomized E1912 trial comparing the long-term efficacy of ibrutinib-rituximab (IR) therapy to fludarabine, cyclophosphamide, and rituximab (FCR) and describe the tolerability of continuous ibrutinib. The E1912 trial enrolled 529 treatment-naïve patients aged ≤70 years with chronic lymphocytic leukemia (CLL). Patients were randomly assigned (2:1 ratio) to receive IR or 6 cycles of FCR. With a median follow-up of 5.8 years, median progression-free survival (PFS) is superior for IR (hazard ratio [HR], 0.37; P < .001). IR improved PFS relative to FCR in patients with both immunoglobulin heavy chain variable region (IGHV) gene mutated CLL (HR: 0.27; P < .001) and IGHV unmutated CLL (HR: 0.27; P < .001). Among the 354 patients randomized to IR, 214 (60.5%) currently remain on ibrutinib. Among the 138 IR-treated patients who discontinued treatment, 37 (10.5% of patients who started IR) discontinued therapy due to disease progression or death, 77 (21.9% of patients who started IR) discontinued therapy for adverse events (AEs)/complications, and 24 (6.8% of patients who started IR) withdrew for other reasons. Progression was uncommon among patients able to remain on ibrutinib. The median time from ibrutinib discontinuation to disease progression or death among those who discontinued treatment for a reason other than progression was 25 months. Sustained improvement in overall survival (OS) was observed for patients in the IR arm (HR, 0.47; P = .018). In conclusion, IR therapy offers superior PFS relative to FCR in patients with IGHV mutated or unmutated CLL, as well as superior OS. Continuous ibrutinib therapy is tolerated beyond 5 years in the majority of CLL patients. This trial was registered at www.clinicaltrials.gov as #NCT02048813.

Impact of targeted agents on survival of chronic lymphocytic leukemia patients age >65 relative to age- and sex-matched population.

Pooled analysis of six mature phase 3 trials (RESONATE2, ILLUMINATE, ALLIANCE041202, ELEVATE-TN, CLL14, and GLOW) evaluating Bruton's tyrosine kinase inhibitors (BTKis) and venetoclax-based treatments suggests that these agents have reduced but not completely eliminated the overall survival (OS) gap between elderly chronic lymphocytic leukemia (CLL) patients and the age and sex-matched general population (AGMGP).

Evaluation of Work-Life Integration, Social Isolation, and the Impact of Work on Personal Relationships Among Healthcare CEOs and Administrative Leaders.

GOAL: The objective of this study was to evaluate satisfaction with work-life integration (WLI), social isolation, and the impact of work on personal relationships (IWPR) among senior healthcare operational leaders. METHODS: Between June 7 and June 30, 2021, we performed a national survey of CEOs and other senior healthcare operational leaders in the United States to evaluate their personal work experience. Satisfaction with WLI, social isolation, and IWPR were assessed using standardized instruments. Burnout and professional fulfillment were also assessed using standardized scales. PRINCIPAL FINDINGS: The mean IWPR score on the 0-10 scale was 4.39 (standard deviation was 2.36; higher scores were unfavorable). On multivariable analysis to identify demographic and professional factors associated with the IWPR score, each additional hour worked per week decreased the likelihood of a favorable IWPR score. The IWPR, feeling isolated, and satisfaction with WLI were independently associated with burnout after adjusting for other personal and professional factors. On multivariable analysis, healthcare administrators were more likely than U.S. workers in other fields to indicate work had adversely impacted personal relationships in response to the item "In the past year, my job has contributed to me feeling more isolated and detached from the people who are most important to me." PRACTICAL APPLICATIONS: Experiencing an adverse IWPR is common among U.S. healthcare administrators, who are more likely than the general U.S. working population to indicate their job contributes to isolation and detachment from the people most important to them. Problems with WLI, isolation, and an adverse IWPR are associated with increased burnout and lower professional fulfillment. Intentional efforts by both organizations and administrative leaders are necessary to address the work characteristics and professional norms that erode WLI and result in work adversely impacting personal relationships.

The CLL International Prognostic Index predicts outcomes in monoclonal B-cell lymphocytosis and Rai 0 CLL.

The utility of the chronic lymphocytic leukemia-international prognostic index (CLL-IPI) in predicting outcomes of individuals with Rai 0 stage CLL and monoclonal B-cell lymphocytosis (MBL) is unclear. We identified 969 individuals (415 MBL and 554 Rai 0 CLL; median age, 64 years; 65% men) seen at Mayo Clinic between 1 January 2001 and 1 October 2018, and ascertained time to first therapy (TTFT) and overall survival (OS). After a median follow up of 7 years, the risk of disease progression needing therapy was 2.9%/y for MBL (median, not reached) and 5%/y for Rai 0 CLL (median, 10.4 years). Among patients with low, intermediate, and high/very high-risk CLL-IPI risk groups, the estimated 5-year risk of TTFT was 13.5%, 30%, and 58%, respectively, P< .0001 (c-statistic = 0.69); and the estimated 5-year OS was 96.3%, 91.5%, and 76%, respectively, P< .0001 (c-statistic = 0.65). In a multivariable analysis of absolute B-cell count with individual factors of the CLL-IPI, the absolute B-cell count was associated with shorter TTFT (hazard ratio [HR] for each 10 × 109/L increase: 1.31; P< .0001) and shorter OS (HR: 1.1; P = .02). The OS of the entire cohort was similar to that of the age- and sex-matched general population of Minnesota (P = .17), although Rai 0 CLL patients with high and very high-risk CLL-IPI score had significantly shorter OS (P= .01 and P= .0001, respectively). The results of this study demonstrate the ability of CLL-IPI to predict time from diagnosis to first treatment (an end point not affected by therapy) in a large cohort of patients whose only manifestation of disease is a circulating clonal lymphocyte population.

Measurable residual disease does not preclude prolonged progression-free survival in CLL treated with ibrutinib.

E1912 was a randomized phase 3 trial comparing indefinite ibrutinib plus 6 cycles of rituximab (IR) to 6 cycles of fludarabine, cyclophosphamide, and rituximab (FCR) in untreated younger patients with CLL. We describe measurable residual disease (MRD) levels in E1912 over time and correlate them with clinical outcome. Undetectable MRD rates (<1 CLL cell per 104 leukocytes) were 29.1%, 30.3%, 23.4%, and 8.6% at 3, 12, 24, and 36 months for FCR, and significantly lower at 7.9%, 4.2%, and 3.7% at 12, 24, and 36 months for IR, respectively. Undetectable MRD at 3, 12, 24, and 36 months was associated with longer progression-free survival (PFS) in the FCR arm, with hazard ratios (MRD detectable/MRD undetectable) of 4.29 (95% confidence interval [CI], 1.89-9.71), 3.91 (95% CI, 1.39-11.03), 14.12 (95% CI, 1.78-111.73), and not estimable (no events among those with undetectable MRD), respectively. In the IR arm, patients with detectable MRD did not have significantly worse PFS compared with those in whom MRD was undetectable; however, PFS was longer in those with MRD levels <10-1 than in those with MRD levels above this threshold. Our observations provide additional support for the use of MRD as a surrogate end point for PFS in patients receiving FCR. In patients on indefinite ibrutinib-based therapy, PFS did not differ significantly by undetectable MRD status, whereas those with MRD <10-1 tended to have longer PFS, although continuation of ibrutinib would very likely be necessary to maintain treatment efficacy.

Triggering interferon signaling in T cells with avadomide sensitizes CLL to anti-PD-L1/PD-1 immunotherapy.

Cancer treatment has been transformed by checkpoint blockade therapies, with the highest anti-tumor activity of anti-programmed death 1 (PD-1) antibody therapy seen in Hodgkin lymphoma. Disappointingly, response rates have been low in the non-Hodgkin lymphomas, with no activity seen in relapsed/refractory chronic lymphocytic leukemia (CLL) with PD-1 blockade. Thus, identifying more powerful combination therapy is required for these patients. Here, we preclinically demonstrate enhanced anti-CLL activity following combinational therapy with anti-PD-1 or anti-PD-1 ligand (PD-L1) and avadomide, a cereblon E3 ligase modulator (CELMoD). Avadomide induced type I and II interferon (IFN) signaling in patient T cells, triggering a feedforward cascade of reinvigorated T-cell responses. Immune modeling assays demonstrated that avadomide stimulated T-cell activation, chemokine expression, motility and lytic synapses with CLL cells, as well as IFN-inducible feedback inhibition through upregulation of PD-L1. Patient-derived xenograft tumors treated with avadomide were converted to CD8+ T cell-inflamed tumor microenvironments that responded to anti-PD-L1/PD-1-based combination therapy. Notably, clinical analyses showed increased PD-L1 expression on T cells, as well as intratumoral expression of chemokine signaling genes in B-cell malignancy patients receiving avadomide-based therapy. These data illustrate the importance of overcoming a low inflammatory T-cell state to successfully sensitize CLL to checkpoint blockade-based combination therapy.

Natural history of monoclonal B-cell lymphocytosis among relatives in CLL families.

Chronic lymphocytic lymphoma (CLL) has one of the highest familial risks among cancers. Monoclonal B-cell lymphocytosis (MBL), the precursor to CLL, has a higher prevalence (13%-18%) in families with 2 or more members with CLL compared with the general population (5%-12%). Although, the rate of progression to CLL for high-count MBLs (clonal B-cell count ≥500/µL) is ∼1% to 5%/y, no low-count MBLs have been reported to progress to date. We report the incidence and natural history of MBL in relatives from CLL families. In 310 CLL families, we screened 1045 relatives for MBL using highly sensitive flow cytometry and prospectively followed 449 of them. MBL incidence was directly age- and sex-adjusted to the 2010 US population. CLL cumulative incidence was estimated using Kaplan-Meier survival curves. At baseline, the prevalence of MBL was 22% (235/1045 relatives). After a median follow-up of 8.1 years among 449 relatives, 12 individuals progressed to CLL with a 5-year cumulative incidence of 1.8%. When considering just the 139 relatives with low-count MBL, the 5-year cumulative incidence increased to 5.7%. Finally, 264 had no MBL at baseline, of whom 60 individuals subsequently developed MBL (2 high-count and 58 low-count MBLs) with an age- and sex-adjusted incidence of 3.5% after a median of 6 years of follow-up. In a screening cohort of relatives from CLL families, we reported progression from normal-count to low-count MBL to high-count MBL to CLL, demonstrating that low-count MBL precedes progression to CLL. We estimated a 1.1% annual rate of progression from low-count MBL, which is in excess of that in the general population.

Well-Being and Professional Fulfillment in Mohs Surgeons: An Explanatory Sequential Mixed-Method Design Study.

BACKGROUND: There are limited data evaluating specific themes of well-being and professional fulfillment in Mohs surgeons. OBJECTIVE: To identify factors that drive occupational distress and those that promote well-being and professional fulfillment among Mohs surgeons. METHODS: This is an explanatory sequential mixed-method study, using semistructured individual interviews. Common drivers of physician well-being and fulfillment were identified based on the independent assessment of the coding in the interview transcripts. RESULTS: This study reports the following qualitative themes: (1) gratitude for the chosen profession and relationships, (2) unrealistic standards of perfection that may have contributed to past career success but are unattainable and create emotional burden, and (3) ability to practice in a manner aligned with personal values promotes professional fulfillment. CONCLUSION: This study suggests that gratitude, self-compassion, and ability to practice in a manner aligned with personal values promote well-being and professional fulfillment in Mohs surgeons. Notably, we found that unrealistic standards of perfection and personal-organization practice incongruences contribute to burnout.

Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukaemia in patients with TP53 aberrations: a pooled analysis from four clinical trials.

TP53 aberrations [del(17p) or TP53 mutation] predict poor survival with chemoimmunotherapy in patients with chronic lymphocytic leukaemia (CLL). We evaluated long-term efficacy and safety of first-line ibrutinib-based therapy in patients with CLL bearing TP53 aberrations in a pooled analysis across four studies: PCYC-1122e, RESONATE-2 (PCYC-1115/16), iLLUMINATE (PCYC-1130) and ECOG-ACRIN E1912. The pooled analysis included 89 patients with TP53 aberrations receiving first-line treatment with single-agent ibrutinib (n = 45) or ibrutinib in combination with an anti-CD20 antibody (n = 44). All 89 patients had del(17p) (53% of 89 patients) and/or TP53 mutation (91% of 58 patients with TP53 sequencing results available). With a median follow-up of 49·8 months (range, 0·1-95·9), median progression-free survival was not reached. Progression-free survival rate and overall survival rate estimates at four years were 79% and 88%, respectively. Overall response rate was 93%, including complete response in 39% of patients. No new safety signals were identified in this analysis. Forty-six percent of patients remained on ibrutinib treatment at last follow-up. With median follow-up of four years (up to eight years), results from this large, pooled, multi-study data set suggest promising long-term outcomes of first-line ibrutinib-based therapy in patients with TP53 aberrations. Registered at ClinicalTrials.gov (NCT01500733, NCT01722487, NCT02264574 and NCT02048813).

Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia.

BACKGROUND: Data regarding the efficacy of treatment with ibrutinib-rituximab, as compared with standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, in patients with previously untreated chronic lymphocytic leukemia (CLL) have been limited. METHODS: In a phase 3 trial, we randomly assigned (in a 2:1 ratio) patients 70 years of age or younger with previously untreated CLL to receive either ibrutinib and rituximab for six cycles (after a single cycle of ibrutinib alone), followed by ibrutinib until disease progression, or six cycles of chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. The primary end point was progression-free survival, and overall survival was a secondary end point. We report the results of a planned interim analysis. RESULTS: A total of 529 patients underwent randomization (354 patients to the ibrutinib-rituximab group, and 175 to the chemoimmunotherapy group). At a median follow-up of 33.6 months, the results of the analysis of progression-free survival favored ibrutinib-rituximab over chemoimmunotherapy (89.4% vs. 72.9% at 3 years; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.22 to 0.56; P<0.001), and the results met the protocol-defined efficacy threshold for the interim analysis. The results of the analysis of overall survival also favored ibrutinib-rituximab over chemoimmunotherapy (98.8% vs. 91.5% at 3 years; hazard ratio for death, 0.17; 95% CI, 0.05 to 0.54; P<0.001). In a subgroup analysis involving patients without immunoglobulin heavy-chain variable region (IGHV) mutation, ibrutinib-rituximab resulted in better progression-free survival than chemoimmunotherapy (90.7% vs. 62.5% at 3 years; hazard ratio for progression or death, 0.26; 95% CI, 0.14 to 0.50). The 3-year progression-free survival among patients with IGHV mutation was 87.7% in the ibrutinib-rituximab group and 88.0% in the chemoimmunotherapy group (hazard ratio for progression or death, 0.44; 95% CI, 0.14 to 1.36). The incidence of adverse events of grade 3 or higher (regardless of attribution) was similar in the two groups (in 282 of 352 patients [80.1%] who received ibrutinib-rituximab and in 126 of 158 [79.7%] who received chemoimmunotherapy), whereas infectious complications of grade 3 or higher were less common with ibrutinib-rituximab than with chemoimmunotherapy (in 37 patients [10.5%] vs. 32 [20.3%], P<0.001). CONCLUSIONS: The ibrutinib-rituximab regimen resulted in progression-free survival and overall survival that were superior to those with a standard chemoimmunotherapy regimen among patients 70 years of age or younger with previously untreated CLL. (Funded by the National Cancer Institute and Pharmacyclics; E1912 ClinicalTrials.gov number, NCT02048813.).

Establishing Crosswalks Between Common Measures of Burnout in US Physicians.

BACKGROUND: Physician burnout is often assessed by healthcare organizations. Yet, scores from different burnout measures cannot currently be directly compared, limiting the interpretation of results across organizations or studies. OBJECTIVE: To link common measures of burnout to a single metric in psychometric analyses such that group-level scores from different assessments can be compared. DESIGN: Cross-sectional survey. SETTING: US practices. PARTICIPANTS: A total of 1355 physicians sampled from the American Medical Association Physician Masterfile. MAIN MEASURES: We linked the Stanford Professional Fulfillment Index (PFI) and Mini-Z Single-Item Burnout (MZSIB) scale to the Maslach Burnout Inventory (MBI) in item response theory (IRT) fixed-calibration and equipercentile analyses and created crosswalks mapping PFI and MZSIB scores to corresponding MBI scores. We evaluated the accuracy of the results by comparing physicians' actual MBI scores to those predicted by linking and described the closest cut-point equivalencies across scales linked to the same MBI subscale using the resulting crosswalks. KEY RESULTS: IRT linking produced the most accurate results and was used to create crosswalks mapping (1) PFI Work Exhaustion (PFI-WE) and MZSIB scores to MBI Emotional Exhaustion (MBI-EE) scores and (2) PFI Interpersonal Disengagement (PFI-ID) scores to MBI Depersonalization (MBI-DP) scores. The commonly used MBI-EE raw score cut-point of ≥27 corresponded most closely with respective PFI-WE and MZSIB raw score cut-points of ≥7 and ≥3. The commonly used MBI-DP raw score cut-point of ≥10 corresponded most closely with a PFI-ID raw score cut-point of ≥9. CONCLUSIONS: Our findings allow healthcare organizations using the PFI or MZSIB to compare group-level scores to historical, regional, or national MBI scores (and vice-versa).

Assessing Professional Fulfillment and Burnout Among CEOs and Other Healthcare Administrative Leaders in the United States.

GOAL: The objective of this study was to evaluate the prevalence of burnout and professional fulfillment among healthcare administrative leaders and examine the association between burnout and professional fulfillment and personal and professional characteristics. METHODS: Between June 7 and June 30, 2021, we performed a national survey of CEOs and other senior operational leaders to evaluate their personal work experience. Burnout and professional fulfillment-as well as a sleep-related impairment and self-valuation-were assessed using standardized instruments. PRINCIPLE FINDINGS: Of the 5,994 members of the American College of Healthcare Executives who were sent an invitation to participate, 1,269 (21.2%), including 279 CEOs, submitted usable responses. The mean overall burnout score was 2.71 (range: 0-10), and 33% of participants had burnout scores that fell in the high range (unfavorable). Mean professional fulfillment score was 7.29 (range: 0-10), with 56.6% scoring in the high range (favorable). Burnout and professional fulfillment scores varied by role. On multivariable analysis, sleep-related impairment (OR for each 1-point increase = 1.29, 95% CI [1.19-1.41]; p < .001) and self-valuation (OR for each 1-point increase = 0.63, 95% CI [0.57-0.68]; p < .001) were independently associated with burnout after adjusting for all other variables. APPLICATIONS TO PRACTICE: Results of this study suggest that healthcare leaders had lower burnout and professional fulfillment scores than clinicians. Nonetheless, one third of healthcare leaders had burnout scores that fell in the high range. At the individual level, improved sleep health and self-valuation appear to reduce risk of burnout and promote professional fulfillment.

The Role of Personal Accomplishment in General Surgery Resident Well-being.

OBJECTIVE: To investigate the association of personal accomplishment (PA) with the other subscales, assess its association with well-being outcomes, and evaluate drivers of PA by resident level. BACKGROUND: Most studies investigating physician burnout focus on the emotional exhaustion (EE) and depersonalization (DP) subscales, neglecting PA. Therefore, the role of PA is not well understood. METHODS: General surgery residents were surveyed following the 2019 American Board of Surgery In-Training Examination regarding their learning environment. Pearson correlations of PA with EE and DP were assessed. Multivariable logistic regression models assessed the association of PA with attrition, job satisfaction, and suicidality and identified factors associated with PA by PGY. RESULTS: Residents from 301 programs were surveyed (85.6% response rate, N = 6956). Overall, 89.4% reported high PA, which varied by PGY-level (PGY1: 91.0%, PGY2/3: 87.7%, PGY4/5: 90.2%; P = 0.02). PA was not significantly correlated with EE (r = -0.01) or DP (r = -0.08). After adjusting for EE and DP, PA was associated with attrition (OR 0.60, 95%CI 0.46-0.78) and job satisfaction (OR 3.04, 95%CI 2.45-3.76) but not suicidality (OR 0.72, 95%CI 0.48-1.09). Although the only factor significantly associated with PA for interns was resident cooperation, time in operating room and clinical autonomy were significantly associated with PA for PGY2/3. For PGY4/5s, PA was associated with time for patient care, resident cooperation, and mentorship. CONCLUSION: PA is a distinct metric of resident well-being, associated with job satisfaction and attrition. Drivers of PA differ by PGY level and may be targets for intervention to promote resident wellness and engagement.

Burnout and Professional Fulfillment in Early and Early-Mid-Career Breast Surgeons.

BACKGROUND: Prior work has shown that burnout among breast surgeons is prevalent and highest in those earlier in their clinical practice career. Therefore, we sought to better understand and identify specific contributors to early-career breast surgeon burnout. METHODS: We analyzed data from our 2017 survey of members of the American Society of Breast Surgeons. The 16-items of the Professional Fulfillment Index were used in determining overall burnout and professional fulfillment scores. Multivariable regressions were performed to evaluate factors related to overall burnout and professional fulfillment. RESULTS: The mean overall burnout score was 1.23 (0-4 scale; higher score unfavorable) for surgeons in practice < 5 years, compared with 1.39 for surgeons in practice 5-9 years and 1.22 for those in practice ≥ 10 years. The mean professional fulfillment score was 2.71 (0-4 scale; higher score favorable) for surgeons in practice < 5 years, 2.66 for surgeons in practice 5-9 years, and 2.67 for surgeons in practice ≥ 10 years. Multivariable analysis showed that burnout was positively correlated with ≥ 60 work hours per week in the group practicing for < 5 years, and dedicating less than full time to breast surgery in the group in practice 5-9 years. Professional fulfillment was negatively associated with single relationship status in surgeons practicing < 5 years, and dedicating less than full time to breast surgery for those in practice 5-9 years. CONCLUSION: Our study suggests that breast surgeons who have been in practice for 5-9 years have particularly high overall burnout rates and additional support focused on this group of breast surgeons may be needed.

Developmental subtypes assessed by DNA methylation-iPLEX forecast the natural history of chronic lymphocytic leukemia.

Alterations in global DNA methylation patterns are a major hallmark of cancer and represent attractive biomarkers for personalized risk stratification. Chronic lymphocytic leukemia (CLL) risk stratification studies typically focus on time to first treatment (TTFT), time to progression (TTP) after treatment, and overall survival (OS). Whereas TTFT risk stratification remains similar over time, TTP and OS have changed dramatically with the introduction of targeted therapies, such as the Bruton tyrosine kinase inhibitor ibrutinib. We have shown that genome-wide DNA methylation patterns in CLL are strongly associated with phenotypic differentiation and patient outcomes. Here, we developed a novel assay, termed methylation-iPLEX (Me-iPLEX), for high-throughput quantification of targeted panels of single cytosine guanine dinucleotides from multiple independent loci. Me-iPLEX was used to classify CLL samples into 1 of 3 known epigenetic subtypes (epitypes). We examined the impact of epitype in 1286 CLL patients from 4 independent cohorts representing a comprehensive view of CLL disease course and therapies. We found that epitype significantly predicted TTFT and OS among newly diagnosed CLL patients. Additionally, epitype predicted TTP and OS with 2 common CLL therapies: chemoimmunotherapy and ibrutinib. Epitype retained significance after stratifying by biologically related biomarkers, immunoglobulin heavy chain mutational status, and ZAP70 expression, as well as other common prognostic markers. Furthermore, among several biological traits enriched between epitypes, we found highly biased immunogenetic features, including IGLV3-21 usage in the poorly characterized intermediate-programmed CLL epitype. In summary, Me-iPLEX is an elegant method to assess epigenetic signatures, including robust classification of CLL epitypes that independently stratify patient risk at diagnosis and time of treatment.