Use of Percutaneous Left Ventricular Assist Device Before Durable Device Implantation in Patients With Cardiac Cachexia: Case Series.

Frailty and malnutrition in patients with heart failure are barriers to durable left ventricular assist device (D-LVAD) support and heart transplantation. Moreover, cachexia in patients with advanced heart failure carries a high mortality risk. There are no guidelines for these patients other than increased caloric intake and rehabilitation. Patients suffering from cardiac cachexia and heart failure may benefit from temporary, percutaneous assist device support to improve the underlying heart disease and reverse the catabolic state. We retrospectively reviewed patients from January 2017 to January 2022. All patients who received Impella support (5.0 or 5.5, Abiomed) before D-LVAD implantation were screened. Those who met the criteria for cardiac cachexia were included. Patient demographics, nutritional and biochemical markers, and survival data were collected. A total of 14 patients were included. The majority of patients were male (85.7%) with ischemic cardiomyopathy (64.3%). Caloric intake, physical strength, and ambulation improved. Prealbumin levels improved from a median of 13.7-18.0 mg/dl ( p < 0.006) while on Impella 5.0 or 5.5 support. All patients survived to discharge and the 6 month follow-up. In conclusion, use of the Impella device improves cardiogenic shock symptoms and, consequently, may improve cachexia status prior to D-LVAD implantation.

Perioperative Impella 5.5 Support for Surgical Aortic Valve Replacement: Pull Back/Push Through Technique, Safeguards, and Pitfalls.

In patients undergoing aortic valve surgery, preoperative reduced left ventricular ejection fraction is not uncommon and is associated with poor outcomes. Mechanical circulatory support (MCS) may be preemptively used in patients presenting with high periprocedural risk. The Impella 5.5 is a percutaneous left ventricular assist device that has been increasingly used in various cardiac surgeries. In this article, we present a step-by-step guide, safeguards, and pitfalls on how to replace the aortic valve and preserve this transaortic MCS device for postoperative support in patients with concomitant aortic valve pathology and left ventricular dysfunction.

Clinical and Economic Benefit of Achieving Disease Control in Psoriatic Arthritis and Ankylosing Spondylitis: A Retrospective Analysis from the OM1 Registry.

BACKGROUND: There is limited evidence on the clinical and economic benefit of achieving disease control in psoriatic arthritis (PsA) and ankylosing spondylitis (AS), thus we aimed to assess the impact of disease control on healthcare resource use (HCRU) and direct medical costs among US patients with PsA or AS over 1 year. METHODS: Data were derived from the US OM1 PsA/AS registries (PsA: 1/2013-12/2020; AS: 01/2013-4/2021) and the Optum Insight Clinformatics® Data Mart to identify adult patients with PsA or AS. Two cohorts were created: with disease control and without disease control. Disease control was defined as modified Disease Activity Index for Psoriatic Arthritis (DAPSA28) ≤ 4 for PsA and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) < 4 for AS. Outcomes were all-cause inpatient, outpatient, and emergency department (ED) visits and associated costs over a 1-year follow-up period. Mean costs per person per year (PPPY) were assessed descriptively and adjusted odds ratios (aOR) with 95% confidence intervals (CI) were estimated for the likelihood of HCRU by logistic regression. RESULTS: The study included 1235 PsA (with disease control: N = 217; without: N = 1018) and 581 AS patients (with disease control: N = 342; without: N = 239). Patients without disease control were more likely to have an inpatient (aOR [95% CI]; PsA: 3.0 [0.9, 10.1]; AS: 7.7 [2.3, 25.1]) or ED (PsA: 1.6 [0.6, 4.2]; AS: 3.5 [1.5, 8.3]) visit than those with disease control. Those without disease control, vs. those with disease control, had greater PPPY costs associated with inpatient (PsA: $1550 vs. $443), outpatient (PsA: $1789 vs. $1327; AS: $2498 vs. $2023), and ED (PsA: $114 vs. $57; AS: $316 vs. $50) visits. CONCLUSIONS: Findings from this study demonstrate lower disease activity among patients with PsA and AS is associated with less HCRU and lower costs over the following year.

Aortic Root Dissection Due to an Automated Fastener Device.

Minimally invasive aortic valve replacement through a right thoracotomy is frequently performed in patients with aortic valve disease. The Cor-Knot Device (LSI Solutions) is an automated fastener that secures valve sutures. This case report is for a patient who developed postcardiotomy shock during a minimally invasive aortic valve surgery. The patient was found to have an aortic root dissection involving 90% of the aortic root circumference, including bilateral coronary ostia. The autopsy revealed that the aortic damage could be explained by a direct aortic intimal tear from the distal tip of the device shaft. The device was most likely not in perfect apposition to the sewing ring because of the restricted angle and space between the ribs.

Inter-Institutional Collaboration Between Quaternary and Tertiary Hospitals: Cardiac Surgery Impact.

BACKGROUND: An inter-institutional collaboration between a quaternary hospital (QH) with a high volume of cardiac surgery and a community-based, tertiary hospital (TH) with a newly established cardiac surgery program was established. METHODS: We retrospectively reviewed data of patients admitted to the TH between September 2015 and June 2017 for cardiac surgery. The decision to transfer a patient to the QH was based on a Society of Thoracic Surgeon-Predicted Risk of Mortality (STS-PROM) score of ≥ 3%, the potential need for hemodialysis, and other risk factors. The same team of surgeons performed operations at both hospitals. We analyzed the perioperative outcomes of the patients and the referral pattern. RESULTS: A total of 116 patients met eligibility criteria; 105 underwent surgery at the TH, while 11 were transferred to the QH. Among the 11 patients transferred to the QH, eight had a score of  3% (median = 8.2 [IQR 5.7-25.0]). The patients transferred to the QH prior to surgery had a significantly higher STS-PROM score (P = ≤ .001). Overall, the mortality of patients who underwent surgery at the TH was 0.9% (1/105); while surgeries at the QH had a mortality rate of 0% (0/11). CONCLUSION: The collaborative effort between high-volume cardiac surgery programs and emerging community-based hospitals showed acceptable outcomes in perioperative cardiac surgical mortality. Elevated STS-PROM scores (>3%), previous sternotomy and anticipation of coagulopathy, and low left ventricular ejection fraction or dilated ventricles are factors that influenced the need to transfer from a TH to QH.

Oncogenic HSP90 Facilitates Metabolic Alterations in Aggressive B-cell Lymphomas.

HSP90 is critical for maintenance of the cellular proteostasis. In cancer cells, HSP90 also becomes a nucleating site for the stabilization of multiprotein complexes including signaling pathways and transcription complexes. Here we described the role of this HSP90 form, referred to as oncogenic HSP90, in the regulation of cytosolic metabolic pathways in proliferating B-cell lymphoma cells. Oncogenic HSP90 assisted in the organization of metabolic enzymes into non-membrane-bound functional compartments. Under experimental conditions that conserved cellular proteostasis, oncogenic HSP90 coordinated and sustained multiple metabolic pathways required for energy production and maintenance of cellular biomass as well as for secretion of extracellular metabolites. Conversely, inhibition of oncogenic HSP90, in absence of apparent client protein degradation, decreased the efficiency of MYC-driven metabolic reprogramming. This study reveals that oncogenic HSP90 supports metabolism in B-cell lymphoma cells and patients with diffuse large B-cell lymphoma, providing a novel mechanism of activity for HSP90 inhibitors. SIGNIFICANCE: The oncogenic form of HSP90 organizes and maintains functional multienzymatic metabolic hubs in cancer cells, suggesting the potential of repurposing oncogenic HSP90 selective inhibitors to disrupt metabolism in lymphoma cells.

Off-Pump Continuous-Flow Left Ventricular Assist Device Implantation.

Continuous-flow left ventricular assist device implantation is the typical treatment for end-stage heart failure. Improvements in device engineering and technology, surgical experience and technique, and perioperative management have advanced the field, and short-term results approach those of heart transplantation. Further improvements may be achieved by minimizing adverse physiologic effects associated with cardiopulmonary bypass. Therefore, we have developed an off-pump implantation approach for continuous-flow left ventricular assist devices. We detail our surgical technique for off-pump implantation of the HeartWare device.

Predictors of Co-occurring Cardiovascular and Gastrointestinal Disorders among Elderly with Osteoarthritis.

Objective: To identify the leading predictors of co-occurring cardiovascular or gastrointestinal disorders (CV-GID) in a real-world cohort of elderly with osteoarthritis (OA). Method: An observational retrospective cohort study using data from Optum's deidentified Clinformatics® Data Mart was conducted. Elderly with OA were identified in 2015 and were followed for two years to identify co-occurring CV-GID including ischemic heart disease, stroke, heart failure, dyspepsia, gastroesophageal reflux disorder, and peptic ulcer disease. Random Forest (RF) and Partial Dependence Plots (PDP) were used to identify the leading predictors of CV-GID and to examine their associations. Multivariable logistic regression was also used to examine the association of the leading predictors with CV-GID. Results: Our study cohort consisted of 45,385 elderly with OA (mean age 76.0 years). CV-GID were present in 59% of elderly. Using RF, age was found to be the strongest predictor of CV-GID followed by cardiac arrhythmia, duration of opioid use, number of orthopedist or physical therapy visits, number of intra-articular corticosteroid injections, polypharmacy, duration of non-selective nonsteroidal anti-inflammatory drugs or oral corticosteroids, and hypertension. The PDPs demonstrated that higher age, cardiac arrhythmia, longer durations of opioid or oral corticosteroids, higher number of physical therapy visits or intra-articular corticosteroid use, polypharmacy, and hypertension were associated with a higher risk of CV-GID. Conclusion: CV-GIDs are common among elderly with OA and can be predicted based on certain clinical factors. Machine learning methods with PDPs can be used to improve the interpretability and inform decision-making.

Use of a Minimally Invasive Approach to Correct Diffuse External Compression of the Left Ventricular Assist Device Outflow Graft.

Left ventricular assist devices (LVADs) implanted into patients with heart failure sometimes develop insufficient forward flow due to malfunction of the outflow graft. One increasingly seen source of outflow graft malfunction is the development of external compression of the outflow graft (ECOG) due to the accumulation of material between the flexible outflow graft and the relatively rigid overlying Gore-Tex tubular graft. When there is segmental ECOG, a percutaneous approach with outflow graft stent placement is the treatment of choice. However, we have encountered cases with diffuse ECOG for which surgery appeared to be a superior choice. We, therefore, developed a minimally invasive surgical approach in which a mini-thoracotomy, rather than redo-sternotomy, is combined with unroofing of the Gore-Tex graft and subsequent evacuation of the organized hematoma. We describe this technique in two patients with diffuse ECOG in whom we found the method to be simple, relatively rapid, and very effective.

A systematic review and meta-analysis of physical activity interventions among colorectal cancer survivors.

With the growing number of colorectal cancer survivors (CRCS), theory-based, high-quality physical activity (PA) interventions are needed to promote quality and quantity of life. This systematic review and meta-analysis synthesized theory-based PA interventions among CRCS. Using PubMed, PsyINFO, CINAHL, MEDLINE, SportDiscus, and Cochrane databases, studies including CRCS participants, a PA outcome, a behavioral theory/model or behavior change techniques (BCTs), and randomized research design were identified. Two reviewers coded BCT, intervention reproducibility (Template for Intervention Description and Replication-TIDier), risk of bias, and quality of evidence. From an initial screen of 1,328 articles, 10 RCTs met our inclusion criteria. The Transtheoretical Model (n = 3), Social Cognitive Theory (n = 3), and Theory of Planned Behavior (n = 2) were the most used theories. "Goal setting (behavior)" (n = 10), "goal setting (outcome)" (n = 10), "action planning" (n = 9), and "problem solving" (n = 9) were the most commonly used BCTs. Intervention modalities were primarily print material based (n = 4) and telephone counseling (n = 4). Findings demonstrated that theory-based PA interventions are successful at increasing PA among CRCS as meta-analysis evidenced a small effect size of 0.26. TDier items 3, 9, and 12 hindered intervention replicability. Lack of blinding and bias in the measurement of outcomes by assessors resulted in serious bias. In-depth theoretical applications are needed for PA interventions that minimize bias and improve outcomes measurement. Intervention adherence and fidelity, as well as theoretical construct measurement pre- and post-intervention, will enhance the behavioral research enterprise. PROSPERO registration: CRD42019142816.

Deadly combination of Vaping-lnduced lung injury and Influenza: case report.

BACKGROUND: E-cigarette and vaping use-associated acute lung injury (EVALI) has been recently recognized as a complication in individuals who use vaping devices. Another consideration is that EVALI may have an adverse influence on the outcome of intercurrent respiratory infections. We document this deadly combination in the case of a young man who had EVALI and simultaneous 41 Influenza-A infection leading to severe Acute Respiratory Distress Syndrome (ARDS). CASE PRESENTATION: A 27-year-old male with a history of tobacco and vaping use was admitted to hospital after two weeks of flu-like symptoms, diarrhea and vomiting. A chest x-ray was consistent with multifocal pneumonia, and microbiological tests were positive for Influenza-A and methicillin-sensitive Staphalacoccus aureus (MSSA). Bronchoscopy provided evidence of acute inhalational injury. After admission, he acutely decompensated with severe hypoxia and hypotension; he required intubation, sedation and vasopressors. He developed sepsis with acute kidney failure, liver failure, biventricular systolic dysfunction and severe rhabdomyolysis. He was placed on veno-venous (VV) extracorporeal membrane oxygenation (ECMO) initially and later changed to Veno-Arterial (VA) ECMO. Nevertheless, the patient continued to deteriorate, and he expired two weeks after admission. CONCLUSION: This case documents that EVALI can act as a major factor leading a respiratory infection to progress into severe ARDS with a fatal outcome.

Axillary Access TAVR: Entrapment of a Transcatheter Aortic Valve in the Innominate Artery With Aortic Dissection.

Non-femoral transcatheter aortic valve replacement (TAVR) is indicated when peripheral vascular disease is diagnosed. We describe the "double-stick" technique via the axillary artery. During the procedure, the pigtail coiled around the TAVR system. While retracting the TAVR sheath, the seam along system split dislodging the valve from the balloon. The valve was entrapped in the innominate artery, and an aortic dissection required surgery. With the double-stick technique, friction and resistance between the pigtail and delivery system must be avoided. Pre-procedural planning and early identification is paramount. Smaller and more seamless delivery systems may reduce risk for dissection and entrapment.

Healthcare Expenditures Associated with Persistent Opioid use Among Adults with Chronic Non-Cancer Pain Conditions: A Retrospective Cohort Study.

Persistent opioid use in adults with chronic non-cancer pain (CNCP) conditions may lead to high economic burden due to adverse events associated with opioids. The objective of our study was to estimate the healthcare expenditures associated with persistent opioid use among adults with CNCP from both payer and patient perspectives. A retrospective cohort study using data from the Medical Expenditure Panel Survey (2012-2015) was undertaken. Patients with persistent, intermittent, and no opioid use in the baseline year were identified and their healthcare expenditures in the follow-up year were examined after controlling for potential confounders. In all, 7,286 adults with CNCP matching our inclusion criteria were identified: 14%, 16%, and 70% reported persistent, intermittent, and no opioid use, respectively. Persistent and intermittent opioid use were associated with additional $4,412 ($12,468 vs $8,056; P < .001) and $1,607 ($9,663 vs $8,056; P = .004), respectively, in total healthcare expenditures compared to no opioid use. Moreover, persistent opioid use was associated with high out-of-pocket burden compared to no opioid use (adjusted odds ratio, 1.44; 95% confidence interval, 1.09-1.89). Our study shows that both payers and patients bear the brunt of economic burden of persistent opioid use. Alternative cost-effective strategies for pain management for this group of patients are needed.

Germline Lysine-Specific Demethylase 1 (LSD1/KDM1A) Mutations Confer Susceptibility to Multiple Myeloma.

Given the frequent and largely incurable occurrence of multiple myeloma, identification of germline genetic mutations that predispose cells to multiple myeloma may provide insight into disease etiology and the developmental mechanisms of its cell of origin, the plasma cell (PC). Here, we identified familial and early-onset multiple myeloma kindreds with truncating mutations in lysine-specific demethylase 1 (LSD1/KDM1A), an epigenetic transcriptional repressor that primarily demethylates histone H3 on lysine 4 and regulates hematopoietic stem cell self-renewal. In addition, we found higher rates of germline truncating and predicted deleterious missense KDM1A mutations in patients with multiple myeloma unselected for family history compared with controls. Both monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma cells have significantly lower KDM1A transcript levels compared with normal PCs. Transcriptome analysis of multiple myeloma cells from KDM1A mutation carriers shows enrichment of pathways and MYC target genes previously associated with myeloma pathogenesis. In mice, antigen challenge followed by pharmacologic inhibition of KDM1A promoted PC expansion, enhanced secondary immune response, elicited appearance of serum paraprotein, and mediated upregulation of MYC transcriptional targets. These changes are consistent with the development of MGUS. Collectively, our findings show that KDM1A is the first autosomal-dominant multiple myeloma germline predisposition gene providing new insights into its mechanistic roles as a tumor suppressor during post-germinal center B-cell differentiation.Significance: KDM1A is the first germline autosomal dominant predisposition gene identified in multiple myeloma and provides new insights into multiple myeloma etiology and the mechanistic role of KDM1A as a tumor suppressor during post-germinal center B-cell differentiation. Cancer Res; 78(10); 2747-59. ©2018 AACR.

Metabolomic Profiling Reveals Cellular Reprogramming of B-Cell Lymphoma by a Lysine Deacetylase Inhibitor through the Choline Pathway.

Despite the proven clinical antineoplastic activity of histone deacetylase inhibitors (HDACI), their effect has been reported to be lower than expected in B-cell lymphomas. Traditionally considered as "epigenetic drugs", HDACI modify the acetylation status of an extensive proteome, acting as general lysine deacetylase inhibitors (KDACI), and thus potentially impacting various branches of cellular metabolism. Here, we demonstrate through metabolomic profiling of patient plasma and cell lines that the KDACI panobinostat alters lipid metabolism and downstream survival signaling in diffuse large B-cell lymphomas (DLBCL). Specifically, panobinostat induces metabolic adaptations resulting in newly acquired dependency on the choline pathway and activation of PI3K signaling. This metabolic reprogramming decreased the antineoplastic effect of panobinostat. Conversely, inhibition of these metabolic adaptations resulted in superior anti-lymphoma effect as demonstrated by the combination of panobinostat with a choline pathway inhibitor. In conclusion, our study demonstrates the power of metabolomics in identifying unknown effects of KDACI, and emphasizes the need for a better understanding of these drugs in order to achieve successful clinical implementation.

Short-Term Experience with Off-Pump Versus On-Pump Implantation of the HeartWare Left Ventricular Assist Device.

Implantation of left ventricular assist devices while avoiding cardiopulmonary bypass (CPB) may decrease bleeding and improve postoperative recovery. To understand the effectiveness of this approach, we reviewed the charts of 26 patients who underwent HeartWare left ventricular assist device (HVAD) implantation without use of CPB (off-CPB group) and 22 patients who had HVAD implanted with CPB (CPB group) with an emphasis on the 30 day postoperative period. Preoperatively, both groups had similar demographic, functional, and hemodynamic characteristics. Off-CPB patients had significantly shorter surgery times than CPB patients, 188.5 (161.5-213.3) min versus 265.0 (247.5-299.5) min, respectively; p < 0.001. Blood transfusion requirements during surgery and within the postoperative 48 hour period were significantly lower in the off-CPB group than in the CPB group (odds ratio: 5.9; 95% confidence interval: 1.1-31.1, p = 0.042). Compared with the CPB group, the off-CPB group patients had a shorter intubation time, 21 (17.4-48.5) hours versus 41 (20.6-258.4) hours; p = 0.042. Intensive care unit stay was 7.0 (4.75-13.5) days for off-CPB versus 10.0 (6.0-19.0) days for CPB (p = 0.256). The off-CPB approach allows HVAD to be implanted quickly with significantly less perioperative bleeding and transfusion requirements and facilitates postoperative rehabilitation.

Combinatorial epigenetic therapy in diffuse large B cell lymphoma pre-clinical models and patients.

BACKGROUND: Refractory and/or relapsed diffuse large B cell lymphoma (RR-DLBCL) patients are incurable with conventional chemotherapy due to the aggressiveness and the chemorefractory state of these tumors. DNA hypermethylation and histone deacetylation are two major epigenetic modifications by which aggressive DLBCL maintain their oncogenic state. We have previously reported that DNA methyltransferase inhibitors (DNMTI) affect RR-DLBCL growth and improve chemosensitivity. Here, we hypothesized that the combination of DNMTI with histone deacetylase inhibitor (HDI) would be an active and feasible therapeutic strategy in RR-DLBCL. Thus, we evaluated the anti-lymphoma activity of the HDI vorinostat (VST) in combination with the DNMTI azacitidine (AZA) or decitabine (DAC) in pre-clinical models of RR-DLBCL, and we determined the feasibility of the combination by conducting a phase Ib trial in RR-DLBCL patients. RESULTS: Concurrent combination of DNMTI and HDI resulted in synergistic anti-lymphoma effect toward RR-DLBCL cells in vitro and in vivo, with no significant toxicity increase. In a phase Ib trial, a total of 18 patients with a median of three prior therapies were treated with four different dose levels of AZA and VST. The most common toxicities were hematological, followed by gastrointestinal and metabolic. The clinical benefit was low as only one subject had a partial response and three subjects had stable disease. Interestingly, two of the seven patients that received additional chemotherapy post-study achieved a complete response and three others had a significant clinical benefit. These observations suggested that the combination might have a delayed chemosensitization effect that we were able to confirm by using in vitro and in vivo models. These studies also demonstrated that the addition of VST does not improve the chemosensitizing effect of DAC alone. CONCLUSIONS: Our data supports the strategy of epigenetic priming by employing DNMTI in RR-DLBCL patients in order to overcome resistance and improve their outcomes.

Combinatorial targeting of nuclear export and translation of RNA inhibits aggressive B-cell lymphomas.

Aggressive double- and triple-hit (DH/TH) diffuse large B-cell lymphomas (DLBCLs) feature activation of Hsp90 stress pathways. Herein, we show that Hsp90 controls posttranscriptional dynamics of key messenger RNA (mRNA) species including those encoding BCL6, MYC, and BCL2. Using a proteomics approach, we found that Hsp90 binds to and maintains activity of eIF4E. eIF4E drives nuclear export and translation of BCL6, MYC, and BCL2 mRNA. eIF4E RNA-immunoprecipitation sequencing in DLBCL suggests that nuclear eIF4E controls an extended program that includes B-cell receptor signaling, cellular metabolism, and epigenetic regulation. Accordingly, eIF4E was required for survival of DLBCL including the most aggressive subtypes, DH/TH lymphomas. Indeed, eIF4E inhibition induces tumor regression in cell line and patient-derived tumorgrafts of TH-DLBCL, even in the presence of elevated Hsp90 activity. Targeting Hsp90 is typically limited by counterregulatory elevation of Hsp70B, which induces resistance to Hsp90 inhibitors. Surprisingly, we identify Hsp70 mRNA as an eIF4E target. In this way, eIF4E inhibition can overcome drug resistance to Hsp90 inhibitors. Accordingly, rational combinatorial inhibition of eIF4E and Hsp90 inhibitors resulted in cooperative antilymphoma activity in DH/TH DLBCL in vitro and in vivo.

Selective targeting of BCL6 induces oncogene addiction switching to BCL2 in B-cell lymphoma.

The BCL6 oncogene plays a crucial role in sustaining diffuse large B-cell lymphomas (DLBCL) through transcriptional repression of key checkpoint genes. BCL6-targeted therapy kills lymphoma cells by releasing these checkpoints. However BCL6 also directly represses several DLBCL oncogenes such as BCL2 and BCL-XL that promote lymphoma survival. Herein we show that DLBCL cells that survive BCL6-targeted therapy induce a phenomenon of "oncogene-addiction switching" by reactivating BCL2-family dependent anti-apoptotic pathways. Thus, most DLBCL cells require concomitant inhibition of BCL6 and BCL2-family members for effective lymphoma killing. Moreover, in DLBCL cells initially resistant to BH3 mimetic drugs, BCL6 inhibition induces a newly developed reliance on anti-apoptotic BCL2-family members for survival that translates in acquired susceptibility to BH3 mimetic drugs ABT-737 and obatoclax. In germinal center B cell-like (GCB)-DLBCL cells, the proteasome inhibitor bortezomib and the NEDD inhibitor MLN4924 post-transcriptionally activated the BH3-only sensitizer NOXA thus counteracting the oncogenic switch to BCL2 induced by BCL6-targeting. Hence our study indicates that BCL6 inhibition induces an on-target feedback mechanism based on the activation of anti-apoptotic BH3 members. This oncogene-addition switching mechanism was harnessed to develop rational combinatorial therapies for GCB-DLBCL.