Citations

Abstract 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.

AbstractData comparing outcomes in prostate cancer and factors affecting treatment choice are sparse. To inform the design of a comparative effectiveness clinical trial, we engaged patients in developing a 28‐question survey about decision making on treatment and research participation and dispersed it among men greater than or equal to 50 years of age. The 1046 respondents ranked long‐term clinical outcomes as most important in making treatment decisions, specific functional outcomes as slightly less important, and duration, location, and cost of treatment as least important. Treatment choice was strongly impacted by side effect profile. Responses to whether the subject would agree to participation in a randomized trial between two types of radiation with minimal differences in outcomes were “yes” in 15%, “no” in 39%, and “undecided” in 46%. Responses to whether the subject would agree to participation in a randomized trial between two treatment durations with similar outcomes were yes in 36%, no in 24%, and undecided in 40%. Findings suggest many potential patients have strong treatment preferences and are averse to randomization, particularly when outcomes of importance may be affected. Patient engagement in study design and novel nonrandomized trial designs may offer a path to increase clinical trial success.

SummaryInstitutional database search (1999–2020) for acute myeloid leukaemia (AML) identified 109 cases of myeloid sarcoma (MS), of which 19 were isolated and presented de novo. The latter displayed longer survival (median 78 months), compared to MS with synchronous intramedullary AML (n = 32; median 16 months) and de novo AML without MS (n = 729; median 22 months; P = 0·13). However, the difference in survival was no longer apparent after accounting for bone marrow cytogenetic risk status (P = 0·67). Treatment‐induced MS tumour resolution was not affected by the presence of intramedullary disease (P = 0·61). The current study clarifies the prognosis of de novo isolated MS, in the context of AML.

Background: While concerns about the safety and procedural success of radial, as opposed to femoral, access for PCI have largely been abated, the association of radial access with patients’ health status recovery has not been explored. To address this gap in knowledge, we compared the symptoms, physical function and quality of life 1 year after PCI in patients treated with radial, as compared with femoral, access. Methods: This is a 10-center study of PCI, in whom 48 of 139 (35%) interventionalists used both radial and femoral approaches between 2009-2010. A total 2628 patients without prior CABG were interviewed and followed for one year. The previously validated Seattle Angina Questionnaire (SAQ) was used to assess disease-specific health status and the EQ-5D was used to quantify generic quality of life. Clinical characteristics and health status outcomes were compared between 296 radial and 2332 femoral PCI procedures. Results: Radial access was used in 11.2% of patients. No demographic (age, gender, race) or clinical factors (e.g. BMI, smoking, diabetes, hypertension, renal disease or prior cardiac history) were associated with radial use, except for an increased use among those with PAD (10.5% radial vs. 6.8% femoral, p=0.022) but reduced use among those with prior PCI (38.3% vs. 32.1%, p=0.037). There was no difference in health status outcomes based on SAQ angina frequency and quality of life, or the EQ-5D at baseline, 6 months or one year (table). Conclusion: In this multi-center observational registry, there was no association of radial access with long-term health status outcomes. These data suggest that there are no offsetting concerns about patients’ long-term health status benefits to counterbalance the peri-procedural safety benefits of a radial approach.

Background: Whether patients with STEMI with longer times from symptom onset to hospital presentation are less likely to be treated with any reperfusion therapy or treated with less urgency resulting in longer door-to-balloon and door-to-needle times is not known. The relationship between delay in hospital presentation and the quality of reperfusion therapy for patients with STEMI has not been examined Methods: We constructed 3 cohorts of STEMI patients to analyze use of any reperfusion (n=440,398), door-to-balloon time (n=67,207), and door-to-drug time (n=183,441) as a function of delay in hospital presentation. We constructed multivariable generalized linear models for each outcome to estimate the associations between delay in hospital presentation adjusted for all patient and hospital characteristics. Results: In adjusted analysis, longer times from symptom onset to hospital presentation was associated with lower use of any reperfusion therapy (p<0.0001 for trend). For early presenters with times of ≤1 hour, >1 to 2 hours, and >2 to 3 hours, 77%, 77%, and 73% of patients received any reperfusion therapy, respectively, and late presenters with times >9 to 10 hours, >10 to 11 hours, and >11 to 12 hours were treated with any reperfusion therapy in 53%, 50%, and 46%, respectively. Delay in hospital presentation was associated with longer drug-to-balloon and door-to-drug times (p<0.0001 for trend). For time intervals of ≤ 1 hour, >1 to 2 hours, >2 to 3 hours, >9 to 10 hours, >10 to 11 hours, and >11 to 12 hours, patients with STEMI were treated with door-to-balloon times of 99, 101, 106, 123, 125, and 123 minutes respectively. For delay time intervals of ≤ 1 hour, >1 to 2 hours, >2 to 3 hours, >9 to 10 hours, >10 to 11 hours, and >11 to 12 hours, patients were treated with door-to-drug times of 32, 34, 36, 46, 44, and 46 minutes, respectively. Conclusions: Longer time from symptom onset to hospital presentation has important implications for subsequent treatment and was associated with lower use of any reperfusion therapy and longer door-to-balloon and door-to-drug times. Longer delay in hospital presentation is associated with worse system performance for reperfusion therapy quality and represents an opportunity to improve quality of care for STEMI patients.

Current guidelines recommend cardiac resynchronization therapy (CRT-D) in appropriate patients undergoing ICD implantation. However, not all physicians who implant ICDs are trained to perform CRT-D. We examined the ICD Registry to assess whether use of CRT-D implantation varied by physician certification. We determined the certification of 2128 physicians who had submitted >=10 cases between April 2006 and June 2007. We excluded patients with a prior ICD, an epicardial lead, or aged ≤18 years, leaving 111,293 patients. Physicians were grouped into mutually exclusive categories reflecting highest current certification- Electrophysiology (EP), Cardiovascular Disease (CVD), Thoracic Surgery (TS), Internal Medicine (IM), Heart Rhythm Society alternative pathway (HRS), and Other. Patients were considered eligible for CRT-D if they met the following criteria: QRS duration >=120ms, LVEF ≪26>35%, and NYHA Class III-IV. We examined crude rates of CRT-D across physician categories and developed a logistic regression model to assess the association of physician certification and CRT-D implantation. Candidate variables included demographics, cardiac status, comorbidities, and physician volume. Odds ratios were converted to relative risks. 35,851 patients met all three eligibility criteria for CRT-D, and 28,932 (80.7%) had a CRT-D implanted. EP physicians implanted the majority of CRT-D (73.6%), with fewer CRT-D placed by CVD (20.6%), TS (0.9%), IM (0.8%), HRS (1.1%), or Other (3.1%). The crude rate of CRT-D implantation was highest among EP physicians and lower in all other categories: EP- 83.1%, CVD-75.8%, TS- 57.9%, IM- 76.5%, HRS- 77.1%, Other- 73.5% (p<0.001). In multivariable analysis, CVD and TS physicians were less likely to implant CRT-D in eligible patients compared with EP physicians (EP: Ref; CVD: RR 0.92 (0.90 – 0.94); TS: RR 0.76 (0.71– 0.85)). CRT-D rates were comparable for other physician groups (IM RR 0.95 (0.87–1.01); HRS: RR 0.97 (0.90 –1.02); Other RR 0.97 (0.93–1.00)). Among eligible patients, use of CRT-D varies by physician certification. Given the benefits of CRT-D, clinicians should consider referring eligible patients to physicians with familiarity and expertise in CRT-D implantation.

AbstractBackgroundDespite the unprecedented success of ibrutinib in lymphoma therapy, the development of ibrutinib resistance due to acquired BTK or PLCγ2 mutations has become a new clinical problem. However, not all resistance is mediated by these mutations and these mechanisms are poorly understood due to a lack of study tools that truly recapitulate this clinical scenario.MethodsWe established a novel patient‐derived ibrutinib‐resistant mantle cell lymphoma (MCL) line named MCIR1. Using immunological, molecular, and cytogenetic approaches, we comprehensively characterized MCIR1 and further demonstrated its utility in the study of resistance mechanisms and treatments to overcome this resistance.ResultsWe show that MCIR1 is a bona fide ibrutinib‐resistant MCL cell line with normal BTK‐/PLCγ2 but ibrutinib‐resistant ERK1/2 and AKT1 signaling. RNA‐Seq analysis revealed a robust non‐canonical NF‐kB signaling that drives the ibrutinib resistance. We also demonstrate the potential utility of a MCIR1‐based cell and mouse model for the discovery of new treatments to overcome BTK inhibitor resistance.ConclusionsWe have established the first patient‐derived ibrutinib‐resistant MCL cell line MCIR1 that lacks BTK or PLCγ2 mutations but exhibits a hyperactive non‐canonical NF‐kB pathway. We further demonstrate its utility in the discovery and validation of new drugs to overcome this resistance.

Disruption of metabolic homeostasis at the organismal level can cause metabolic syndrome associated with obesity. The role of adipose tissue in cancer has been investigated over the last several decades with many studies implicating obesity as a risk factor for the development of cancer. Adipose tissue contains a diverse array of immune cell populations that promote metabolic homeostasis through a tightly controlled balance of pro- and anti-inflammatory signals. During obesity, pro-inflammatory cell types infiltrate and expand within the adipose tissue, exacerbating metabolic dysfunction. Some studies have now shown that the intracellular metabolism of immune cells is also deregulated by the lipid-rich environment in obesity. What is not fully understood, is how this may influence cancer progression, metastasis, and anti-tumor immunity. This review seeks to highlight our current understanding of the effect of adipose tissue on immune cell function and discuss how recent results offer new insight into the role that adipose tissue plays in cancer progression and anti-tumor immunity.