Citations

Abstract In 2017, 43.9% of US physicians reported symptoms of burnout. Poor electronic health record (EHR) usability and time-consuming data entry contribute to burnout. However, less is known about how modifiable dimensions of EHR use relate to burnout and how these associations vary by medical specialty. Using the KLAS Arch Collaborative’s large-scale nationwide physician (MD/DO) data, we used ordinal logistic regression to analyze associations between self-reported burnout and after-hours charting and organizational EHR support. We examined how these relationships differ by medical specialty, adjusting for confounders. Physicians reporting ≤ 5 hours weekly of after-hours charting were twice as likely to report lower burnout scores compared to those charting ≥6 hours (aOR: 2.43, 95% CI: 2.30, 2.57). Physicians who agree that their organization has done a great job with EHR implementation, training, and support (aOR: 2.14, 95% CI: 2.01, 2.28) were also twice as likely to report lower scores on the burnout survey question compared to those who disagree. Efforts to reduce after-hours charting and improve organizational EHR support could help address physician burnout.

159 Background: Tumour tissue from metastatic castration-resistant prostate cancer (mCRPC) harbors frequent copy number variations (CNVs) in the phosphatidylinositol-3-kinase (PI3K)/Akt-signaling pathway. However, identifying CNVs in plasma cell-free DNA (cfDNA) has proven challenging. With emerging data supporting Akt inhibition in PTEN-deficient mCRPC, cfDNA assays for robustly identifying PI3K/Akt pathway aberrations including CNVs are urgently required. Methods: In this multi-institutional prospective biomarker study, we used the Predicine cfDNA assay, optimised for CNV detection, to perform targeted sequencing in 231 mCRPC patients in two independent cohorts (Australian, n = 78; US, n = 153). Kaplan-Meier survival estimates and multivariable Cox regression analysis were used to assess associations between genomic aberrations and progression-free survival (PFS) and overall survival (OS). Results: PTEN loss and PIK3CA gain were detected in 37% (85/231) and 17% (39/231) of patients, respectively. Poorer outcomes were observed in patients with PI3K/Akt pathway aberrations, including those with dual PTEN loss and PIK3CA gain (HR 2.3, 95% CI 1.2-4.4). Similarly, cumulative CNV burden in the PI3K/Akt and AR pathways (0 vs 1 vs ≥2 CNVs in Australian cohort: median OS 33.5 vs 17.2 vs 9.7 months, p< 0.001; 0 vs 1 vs ≥2 CNVs in US cohort: median OS 35.5 vs 14.3 vs 9.2 months, p< 0.001) was associated with significantly worse clinical outcomes. Notably, 21% (31/146) of PTEN-neutral patients harbored other alterations in the PI3K/Akt pathway. Conclusions: Our cfDNA assay readily detected PI3K/Akt pathway CNVs, with the prevalence of PTEN loss comparable to prior tissue sequencing studies. CNVs in the PI3K/Akt pathway were associated with deleterious clinical outcomes, especially when concurrent with AR gain. Additional PI3K/Akt pathway aberrations were found in approximately one-fifth of PTEN-neutral mCRPC. Collectively, our data demonstrate the potential utility of profiling cfDNA to facilitate and optimize patient selection for treatment with Akt inhibitors in mCRPC. [Table: see text]

Tobacco use is projected to kill 1 billion people in the 21st century. Tobacco Use Disorder (TUD) is one of the most common substance use disorders in the world. Evidence-based treatment of TUD is effective, but treatment accessibility remains very low. A dearth of specially trained clinicians is a significant barrier to treatment accessibility, even within systems of care that implement brief intervention models. The treatment of TUD is becoming more complex and tailoring treatment to address new and traditional tobacco products is needed. The Council for Tobacco Treatment Training Programs (Council) is the accrediting body for Tobacco Treatment Specialist (TTS) training programs. Between 2016 and 2019, n = 7761 trainees completed Council-accredited TTS training programs. Trainees were primarily from North America (92.6%) and the Eastern Mediterranean (6.1%) and were trained via in-person group workshops in medical and academic settings. From 2016 to 2019, the number of Council-accredited training programs increased from 14 to 22 and annual number of trainees increased by 28.5%. Trainees have diverse professional backgrounds and work in diverse settings but were primarily White (69.1%) and female (78.7%) located in North America. Nearly two-thirds intended to implement tobacco treatment services in their setting; two-thirds had been providing tobacco treatment for 1 year or less; and 20% were sent to training by their employers. These findings suggest that the training programs are contributing to the development of a new workforce of TTSs as well as the development of new programmatic tobacco treatment services in diverse settings. Developing strategies to support attendance from demographically and geographically diverse professionals might increase the proportion of trainees from marginalized groups and regions of the world with significant tobacco-related inequities.

Abstract Proton Bragg peak irradiation has a higher ionizing density than conventional photon irradiation or the entrance of the proton beam profile. Whether targeting the DNA damage response (DDR) could enhance vulnerability to the distinct pattern of damage induced by proton Bragg peak irradiation is currently unknown. Here, we performed genetic or pharmacologic manipulation of key DDR elements and evaluated DNA damage signaling, DNA repair, and tumor control in cell lines and xenografts treated with the same physical dose across a radiotherapy linear energy transfer spectrum. Radiotherapy consisted of 6 MV photons and the entrance beam or Bragg peak of a 76.8 MeV spot scanning proton beam. More complex DNA double-strand breaks (DSB) induced by Bragg peak proton irradiation preferentially underwent resection and engaged homologous recombination (HR) machinery. Unexpectedly, the ataxia-telangiectasia mutated (ATM) inhibitor, AZD0156, but not an inhibitor of ATM and Rad3-related, rendered cells hypersensitive to more densely ionizing proton Bragg peak irradiation. ATM inhibition blocked resection and shunted more DSBs to processing by toxic ligation through nonhomologous end-joining, whereas loss of DNA ligation via XRCC4 or Lig4 knockdown rescued resection and abolished the enhanced Bragg peak cell killing. Proton Bragg peak monotherapy selectively sensitized cell lines and tumor xenografts with inherent HR defects, and the repair defect induced by ATM inhibitor coadministration showed enhanced efficacy in HR-proficient models. In summary, inherent defects in HR or administration of an ATM inhibitor in HR-proficient tumors selectively enhances the relative biological effectiveness of proton Bragg peak irradiation. Significance: Coadministration of an ATM inhibitor rewires DNA repair machinery to render cancer cells uniquely hypersensitive to DNA damage induced by the proton Bragg peak, which is characterized by higher density ionization. See related commentary by Nickoloff, p. 3156

Abstract Acute ischemic stroke is one of the leading causes of disability and mortality worldwide. There have been significant improvements to the treatment of acute ischemic stroke over the past 5 yr, specifically related to strokes caused by large vessel occlusions. Stent retrievers with and without local aspiration and direct aspiration alone have all been demonstrated as viable treatment options for this patient population. This case represents the surgical technique for direct aspiration for the treatment of large vessel occlusion. A 76-yr-old man presented with right-sided weakness and aphasia. His last known normal was 5 h ago. His NIHSS (National Institutes of Health Stroke Scale) was 18. The noncontrast computed tomography (CT) did not show a significant infarct burden and ASPECTS (Alberta Stroke Program Early CT Score) of 9. CT angiogram demonstrated a left M1 occlusion. The patient was not a candidate for tissue plasminogen activator (tPA) because of time to presentation; however, the patient was deemed to be a candidate for emergent thrombectomy. Consent was obtained per institutional guidelines for the emergent procedure and the video recording. The video demonstrates a direct aspiration thrombectomy technique for the treatment of stroke. The patient successfully underwent direct aspiration thrombectomy with a TICI 3 (thrombolysis in cerebral infarction) recanalization.

Abstract Thromboembolic complications during aneurysm coiling are rare, with higher rates noted in ruptured aneurysms as patients are not usually premedicated with dual antiplatelet therapy. 1,2 Management includes a series of escalating strategies, including medical therapy and intra-arterial thrombolysis. 3-6 Additional strategies include mechanical thrombectomy with suction aspiration and stent retrievers. 3 Intracranial stenting can be used as a last resource, especially in ruptured cases given the need for dual antiplatelets to prevent stent thrombosis. 2 We present the case of a 42-yr-old man with a ruptured left internal carotid artery aneurysm with associated intracranial and intraventricular hemorrhage. The patient was initially presented to an outside facility after he was found in bed unable to speak and with right hemiparesis. The patient consented for surgery and underwent external ventricular drain (EVD) placement for the treatment of obstructive hydrocephalus, followed by diagnostic cerebral angiogram and aneurysm coiling. After the deployment of the last coil, control angiogram showed a small filling defect at the interface between the aneurysm neck and the distal vessel. The patient received intravenous heparin for therapeutic ACT and aspirin load. After progressive enlargement of the thrombus, the patient received intra-arterial glycoprotein (GP) IIB/IIIA inhibitors with a microcatheter positioned proximal to the thrombus. As the thrombus mass continued to enlarge, mechanical thrombectomy with an aspiration catheter was performed twice. Follow-up angiogram 20 min after the second aspiration demonstrated near-complete resolution of the thrombus. The patient recovered from his right hemiparesis, and he was discharged to rehabilitation on POD #21.

Abstract Intracranial atherosclerosis disease (IAD) is the cause of stroke in up to 10% of cases. Symptomatic IAD results mainly from hypoperfusion, embolic phenomenon, and occlusion. Treatment consists of conservative management with aggressive medical treatment, surgery, and endovascular therapy. 1,2 This video is about a 62-yr-old male who presented with left-sided hemiparesis and right gaze preference secondary to an acute ischemic stroke in the right middle cerebral artery (MCA) territory treated initially with tissue plasminogen activator (tPA). Head computed tomography (CT) angiography (CTA) revealed occlusion of the extracranial and cavernous segments of the internal carotid artery (ICA). CT perfusion (CTP) showed hypoperfusion in the MCA territory and magnetic resonance imaging (MRI) revealed multifocal, wedge-shaped areas of restricted diffusion in the right hemisphere. During his hospitalization, he experienced worsening of his symptoms in the setting of hypoperfusion (hypotension). The patient underwent a cerebral angiogram with thrombectomy and submaximal angioplasty (SA). Successful revascularization of the right ICA was obtained. No procedure-related complications occurred, and the patient's neurological exam improved. SA can be as efficient and a safer option than conventional angioplasty or angioplasty and stenting for symptomatic IAD. The patient consented for the procedure and for the video production.

PURPOSE Lenalidomide combined with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) (R2CHOP) in untreated diffuse large B-cell lymphoma (DLBCL) has shown promising activity, particularly in the activated B-cell–like (ABC) subtype. Eastern Cooperative Oncology Group (ECOG)-ACRIN trial E1412 was a randomized phase II study comparing R2CHOP versus R-CHOP in untreated DLBCL. PATIENTS AND METHODS Patients with newly diagnosed DLBCL, stage II bulky-IV disease, International Prognostic Index (IPI) ≥ 2, and ECOG performance status ≤ 2 were eligible and randomly assigned 1:1 to R2CHOP versus R-CHOP for six cycles. Tumors were analyzed using the NanoString Lymph2Cx for cell of origin. The primary end point was progression-free survival (PFS) in all patients with the co-primary end point of PFS in ABC-DLBCL. Secondary end points included overall response rate (ORR), complete response (CR) rate, and overall survival (OS). RESULTS Three hundred forty-nine patients were enrolled; 280 patients (145 R2CHOP and 135 R-CHOP) were evaluable: 94 were ABC-DLBCL, 122 germinal center B-cell–like-DLBCL, 18 unclassifiable, and 46 unknowns. Baseline characteristics were well-balanced between arms, and the median age was 66 (range, 24-92); 70% of patients had stage IV disease; 34%, 43%, and 24% had IPI 2, 3, and 4 or 5, respectively. Myelosuppression was more common in the R2CHOP arm. The ORR and CR rate were 92% and 68% in R-CHOP and 97% ( P = .06) and 73% ( P = .43) in the R2CHOP arm, respectively. The median follow-up was 3.0 years; R2CHOP was associated with a 34% reduction in risk of progression or death versus R-CHOP (hazard ratio [HR], 0.66 95% CI, 0.43 to 1.01) and 3-year PFS of 73% versus 61%, one-sided P = .03, and an improvement in OS (83% and 75% at 3 years; HR, 0.67; one-sided P = .05). The PFS HR for R2CHOP was 0.67 for ABC-DLBCL, one-sided P = .1. CONCLUSION In this signal-seeking study, the addition of lenalidomide to R-CHOP (R2CHOP) improved outcomes in newly diagnosed DLBCL including patients with ABC-DLBCL.

Abstract Initially developed for large and giant wide-necked aneurysms of the internal carotid artery, flow diverter devices are now used in almost every location safely and with effectiveness. 1-5 This video demonstrates a unique case of a giant aneurysm of the right petrous internal carotid artery in a 20-yr-old patient. This is an extremely rare location, and most of patients are asymptomatic. 3-6 Signs of compression of the seventh and eight cranial nerves can be present and even Horner syndrome and lower cranial nerves neuropathies. Nevertheless, rupture can lead to epistaxis and otorrhagia, and ultimately to hemorrhagic shock. The patient in the current report was otherwise healthy but presented with lightheadedness and dizziness for 10 d. The patient consented to the procedure. There was no history of major trauma or head and neck infection. A transradial endovascular flow diversion embolization of a giant aneurysm of the petrous internal carotid artery is herein demonstrated in a stepwise manner. A triaxial system was used to deploy 3 overlapping devices. Concepts of J-wire technique, multiple coverage, 1 and the so-called weld technique are emphasized. The role of adjunctive coiling and main reasons for failure are also discussed. 7,8 Brief cases of flow diversion embolization of aneurysms of different morphologies at different locations are used to highlight the importance of assessing vessel wall apposition and follow-up imaging.