Treatment Of High-risk Patients Research Articles

Optimal management of asymptomatic carotid stenosis in 2021: the jury is still out. An international, multispecialty, expert review and position statement.

The recommendations of international guidelines for the management of asymptomatic carotid stenosis (ACS) often vary considerably and extend from a conservative approach with risk factor modification and best medical treatment (BMT) alone, to a more aggressive approach with a carotid intervention plus BMT. The aim of the current multispecialty position statement was to reconcile the conflicting views on the topic. A literature review was performed with a focus on data from recent studies. Several clinical and imaging high-risk features have been identified that are associated with an increased long-term ipsilateral ischemic stroke risk in patients with ACS. Such high-risk clinical/imaging features include intraplaque hemorrhage, impaired cerebrovascular reserve, carotid plaque echolucency/ulceration/ neovascularization, a lipid-rich necrotic core, a thin or ruptured fibrous cap, silent brain infarction, a contralateral transient ischemic attack/stroke episode, male patients <75 years and microembolic signals on transcranial Doppler. There is growing evidence that 80-99% ACS indicate a higher stroke risk than 50-79% stenoses. Although aggressive risk factor control and BMT should be implemented in all ACS patients, several high-risk features that may increase the risk of a future cerebrovascular event are now documented. Consequently, some guidelines recommend a prophylactic carotid intervention in high-risk patients to prevent future cerebrovascular events. Until the results of the much-anticipated randomized controlled trials emerge, the jury is still out regarding the optimal management of ACS patients.

Clinical Prioritization of Antispike Monoclonal Antibody Treatment of Mild to Moderate COVID-19

Clinical Prioritization of Antispike Monoclonal Antibody Treatment of Mild to Moderate COVID-19

TCT-375 High Syntax Score and Left Main Percutaneous Coronary Intervention in High-Risk Patients: Long-Term Follow-Up Real-World Experience of a Single Center Without On-Site Cardiac Surgery

TCT-375 High Syntax Score and Left Main Percutaneous Coronary Intervention in High-Risk Patients: Long-Term Follow-Up Real-World Experience of a Single Center Without On-Site Cardiac Surgery

Molecular Imaging in Primary Staging of Prostate Cancer Patients: Current Aspects and Future Trends.

Simple SummaryAccurate primary staging for determining the extent of prostate cancer is crucial for planning treatment in high-risk patients for distant metastases. Recurrence is still common after curative intent therapy, in spite of developments in the clinical nomograms for appropriate pre-treatment screening of patients for selective therapeutic approaches. This is partly due to suboptimal diagnostic performance of standard conventional imaging modalities such as computed tomography and bone scintigraphy. Molecular imaging by means of PET/CT and PET/MRI imaging using novel specific radiotracers might provide more precise staging of disease, allowing for better personalized treatments. This article reviews current developments and future trends for functional hybrid PET-targeted imaging in primary staging of prostate cancer.Accurate primary staging is the cornerstone in all malignancies. Different morphological imaging modalities are employed in the evaluation of prostate cancer (PCa). Regardless of all developments in imaging, invasive histopathologic evaluation is still the standard method for the detection and staging of the primary PCa. Magnetic resonance imaging (MRI) and computed tomography (CT) play crucial roles; however, functional imaging provides additional valuable information, and it is gaining ever-growing acceptance in the management of PCa. Targeted imaging with different radiotracers has remarkably evolved in the past two decades. [111In]In-capromab pendetide scintigraphy was a new approach in the management of PCa. Afterwards, positron emission tomography (PET) tracers such as [11C/18F]choline and [11C]acetate were developed. Nevertheless, none found a role in the primary staging. By introduction of the highly sensitive small molecule prostate-specific membrane antigen (PSMA) PET/CT, as well as recent developments in MRI and hybrid PET/MRI systems, non-invasive staging of PCa is being contemplated. Several studies investigated the role of these sophisticated modalities in the primary staging of PCa, showing promising results. Here, we recapitulate the role of targeted functional imaging. We briefly mention the most popular radiotracers, their diagnostic accuracy in the primary staging of PCa, and impact on patient management.

A COMPARATIVE OBSERVATIONAL STUDY OF PROGNOSTIC FACTOR SCORES TO PREDICT MORBIDITY AND MORTALITY IN PATIENTS OF PERFORATED PEPTIC ULCER

Background: Perforation is one of the common complication of peptic ulcer disease which is associated with signicant morbidity and mortality. It is a disease which needs emergent surgical intervention. Accurate and early identication of high-risk patients with Perforated Peptic Ulcer is important for risk stratication. Here, we calculate the three prognostic factor scores, (i) The Boey Score, (ii) The Peptic ulcer perforation (PULP) score, and (iii) The quick sequential organ failure assessment (q-SOFA) score, preoperatively to predict postoperative outcome. Aims &amp; Objective: The aim of the study is to identify patients with an increased risk of adverse outcome, so that we can target the level of perioperative monitoring and treatment in high-risk patients. Also, to determine and compare the ability of three prognostic factor scores to predict morbidity and mortality in patients of Perforated Peptic Ulcer. Methods: Aprospective comparative observational study was conducted comprising of 92 patients with conrmed perforated peptic ulcer (PPU) attending the emergency ward of Department of General Surgery between February 2019 to July 2020. After conrmation of diagnosis, risk stratication according to the three prognostic factor scores (Boey score, PULP score, and q-SOFA score) was done. Acomparison was made between each score through calculation of positive predictive value (PPV) and negative predictive value (NPV). We used receiver operating characteristics (ROC) curve in my study to estimate the predictive ability of each scoring system. Results: The study include 92 patients. Female 41.3% and Male 58.7%. The mean age was 45.38 years. The most common site of PPU was the rst part of duodenum - D1 (64.1%). The most common operative procedure done was the Grahm's patch repair. The morbidity rate was 28.3%. Overall mortality rate was 10.9%. The AUROC for morbidity prediction was 0.791 for Boey score, 0.918 for PULP score, and 0.61 for q-SOFAscore. The AUROC for mortality prediction was 0.829 for Boey score, 0.865 for PULPscore, and 0.602 for q-SOFAscore. Conclusion:Boey score and PULP score helps in accurate and early identication of PPU patients with an increased risk of adverse outcome. q-SOFA score cannot signicantly predict morbidity and mortality in PPU patients. Overall, PULP score performs best but Boey score is crude and simple to calculate and is used to assess the patient rapidly

Acute Complex Endovascular Aortic Repair - Off-the-shelf vs. Surgeon-modified Stent Grafts

Treatment of complex abdominal and thoracoabdominal aortic aneurysms is challenging. Open surgical repair is a high-risk operation, especially in emergency cases. Endovascular aneurysm repair with a patient-specific custom-made stent graft in patients with symptomatic or ruptured complex aortic aneurysms is not possible, due to the manufacturing time required. In such cases, alternative endovascular techniques can be used. The "off-the-shelf" and "surgeon-modified" stent grafts are valid options for the endovascular treatment of complex aneurysms in urgent and emergent patients. The former are standardised commercially manufactured fenestrated or branched stent grafts, which are available off-the-shelf with an anatomical feasibility in 50 - 80% of the patients. The "surgeon-modified" stent grafts refer to a technique, in which a commercially available stent graft is modified by the surgeon under sterile conditions directly before the implantation, in order to add the required fenestrations, scallops and/or branches. The modification takes approximately 60 - 120 min and haemodynamic stability of the patient is mandatory. Because of the off-label use of the commercial stent graft, detailed patient consent about the modification complications and risks should be performed whenever possible. A comparison of results on mortality and morbidity between "off-the-shelf" and "surgeon-modified" stent grafts has been published, although a direct comparison would be unfair for several reasons (different design, lack of extensive outcomes reports, long learning curve and different modification techniques). The "surgeon-modified" and "off-the-shelf" fenestrated/branched stent grafts are used in the treatment of high-risk patients with symptomatic or contained ruptured complex aneurysms. The outcomes of the two techniques are good, although the long-term durability of the former should be further investigated.

Robotic Surgery for Non-Small Cell Lung Cancer Treatment in High-Risk Patients.

Robotic-assisted pulmonary resection has greatly increased over the last few years, yet data on the application of robotic surgery in high-risk patients are still lacking. The objective of this study is to evaluate the perioperative outcomes in ASA III-IV patients who underwent robotic-assisted lung resection for NSCLC. Between January 2010 and December 2017, we retrospectively collected the data of 148 high-risk patients who underwent lung resection for NSCLC via a robotic approach at our institution. For this study, the prediction of operative risk was based on the ASA-PS score, considering patients in ASA III and IV classes as high-risk patients: of the 148 high-risk patients identified, 146 patients were classified as ASA III (44.8%) and two as ASA IV (0.2%). Possible prognostic factors were also analysed. The average hospital stay was 6 days (8–30). Post-operative complications were observed in 87 (58.8%) patients. Patients with moderate/severe COPD developed in 33 (80.5%) cases post-operative complications, while elderly patients in 25 (55%) cases, with a greater incidence of high-grade complications. No difference was observed when comparing the data of obese and non-obese patients. Robotic surgery appears to be associated with satisfying post-operative results in ASA III-IV patients. Both marginal respiratory function and advanced age represent negative prognostic factors. Due to its safety and efficacy, robotic surgery can be considered the treatment of choice in high-risk patients.

Applying User-Centered Design to Develop Practical Strategies that Address Overuse in Primary Care.

Engaging patients and frontline clinicians in re-designing clinical care is essential for improving care delivery in a complex clinical environment. This study sought to assess an innovative user-centered design approach to improving clinical care quality, focusing on the use cases of de-intensifying non-beneficial care within the following areas: (1) de-intensifying diabetes treatment in high-risk patients; (2) stopping screening for carotid artery stenosis in asymptomatic patients; and (3) stopping colorectal cancer screening in average-risk, older adults. The user-centered design approach, consisting of patient and patient-clinician charrettes (defined as intensive workshops where key stakeholders collaborate to develop creative solutions to a specific problem) and participant surveys, has been described previously. Following the charrettes, we used inductive coding to identify and categorize themes emerging from the de-intensification ideas prioritized by participants as well as facilitator notes and audio recordings from the charrettes. Thirty-five patients participated in the patient design charrettes, generating 134 unique de-intensification ideas and prioritizing 32, which were then distilled into six patient-generated principles of de-intensification by the study team. These principles provided a starting point for a subsequent patient-clinician charrette. In this follow-up charrette, 9 patients who had participated in an earlier patient design charrette collaborated with 7 clinicians to generate 63 potential de-intensification solutions. Six of these potential solutions were developed into multi-faceted, fully operationalized de-intensification strategies. The de-intensification strategies that patients and clinicians prioritized and operationalized during the co-design charrette process were detailed and multi-faceted. Each component of a strategy had a rationale based on feasibility, practical considerations, and ways of overcoming barriers. The charrette-based process may be a useful way to engage clinicians and patients in developing the complex and multi-faceted strategies needed to improve care delivery.

Targeting the methyltransferase SETD8 impairs tumor cell survival and overcomes drug resistance independently of p53 status in multiple myeloma

BackgroundMultiple myeloma (MM) is a malignancy of plasma cells that largely remains incurable. The search for new therapeutic targets is therefore essential. In addition to a wide panel of genetic mutations, epigenetic alterations also appear as important players in the development of this cancer, thereby offering the possibility to reveal novel approaches and targets for effective therapeutic intervention.ResultsHere, we show that a higher expression of the lysine methyltransferase SETD8, which is responsible for the mono-methylation of histone H4 at lysine 20, is an adverse prognosis factor associated with a poor outcome in two cohorts of newly diagnosed patients. Primary malignant plasma cells are particularly addicted to the activity of this epigenetic enzyme. Indeed, the inhibition of SETD8 by the chemical compound UNC-0379 and the subsequent decrease in histone H4 methylation at lysine 20 are highly toxic in MM cells compared to normal cells from the bone marrow microenvironment. At the molecular level, RNA sequencing and functional studies revealed that SETD8 inhibition induces a mature non-proliferating plasma cell signature and, as observed in other cancers, triggers an activation of the tumor suppressor p53, which together cause an impairment of myeloma cell proliferation and survival. However, a deadly level of replicative stress was also observed in p53-deficient myeloma cells treated with UNC-0379, indicating that the cytotoxicity associated with SETD8 inhibition is not necessarily dependent on p53 activation. Consistent with this, UNC-0379 triggers a p53-independent nucleolar stress characterized by nucleolin delocalization and reduction of nucleolar RNA synthesis. Finally, we showed that SETD8 inhibition is strongly synergistic with melphalan and may overcome resistance to this alkylating agent widely used in MM treatment.ConclusionsAltogether, our data indicate that the up-regulation of the epigenetic enzyme SETD8 is associated with a poor outcome and the deregulation of major signaling pathways in MM. Moreover, we provide evidences that myeloma cells are dependent on SETD8 activity and its pharmacological inhibition synergizes with melphalan, which could be beneficial to improve MM treatment in high-risk patients whatever their status for p53.

Vroegtijdige opsporing van voorstadia van een anaal carcinoom bij hiv-seropositieve patiënten

Early detection of precursor lesions of anal cancer in HIV-seropositive patients Although anal cancer is rare in the overall population, its incidence is increasing in the last decades. Especially HIV-seropositive patients have an increased risk of developing anal squamous cell carcinoma (SCC), mainly because of the high prevalence of high-grade anal intraepithelial neoplasia (AIN) among these patients. High-grade AIN is a precursor lesion for anal SCC associated with human papillomavirus (HPV) infection. Despite the lack of direct evidence demonstrating that AIN identification reduces the risk of anal cancer, experts think that screening and treatment of high-risk patients will prevent the disease. This article aims to review the current literature about AIN and discusses the screening options, including digital rectal examination, anal cytology and high-resolution anoscopy.

25553 Suicide risk among melanoma and nonepithelial skin cancer patients: A Surveillance, Epidemiology, and End Results analysis

Cutaneous neoplasm diagnoses involve the stigma of cancer and cognitive effects of a visible dermatologic disease, leading to potential mental distress. The study queried the Surveillance, Epidemiology, and End Results 18 database with data from 2000 to 2016 for eligible cases of melanoma and non-epithelial skin cancers (ie, Merkel cell carcinoma, dermatofibrosarcoma, sebaceous adenocarcinoma, etc) with death by suicide determined via cause of death recode variable. Standardized mortality ratios were calculated for skin cancer patients and factors associated with risk of suicide determined by Fine-Gray proportional hazards regression model. The study included 225,739 melanoma and 15,277 nonepithelial skin cancer patients, with 332 suicides and 26 suicides in the respective cohorts. Skin cancer patients had an increased risk of suicide compared to the general population (SMR 1.14, 95% CI 1.02-1.28), with the subgroups of melanoma (SMR 1.15, 95% CI 1.03-1.29), elderly (SMR 1.24, 1.03-1.49), unmarried (SMR 1.76, 1.43-2.14), regional stage (SMR 2.41, 95% CI 1.75-3.25), and distant stage (SMR 2.97, 95% CI 1.36-5.64) having high standardized mortality ratios, while nonepithelial skin cancer was not associated with an increased risk of suicide (SMR 1.02, 95% CI 0.63-1.59). The study highlights increased risk and risk factors of suicide amongst skin cancer patients and is the first study, based on literature review, to include analysis of nonepithelial skin cancer patients. The study contributes to understanding of the association between skin cancers and suicide, which is crucial to develop better screening and interventions for high-risk patients.

Cost-utility of a first-trimester screening strategy versus the standard of care for nulliparous women to prevent pre-term pre-eclampsia in Belgium.

To assess the cost-effectiveness of the Fetal Medicine Foundation (FMF) combined first-trimester pre-eclampsia (PE) screening algorithm, coupled with low-dose aspirin treatment in high-risk patients, compared to the standard of care (SOC; screening based on maternal risk factors) for nulliparous pregnancies in Belgium. A decision analytic model was used to estimate the costs and outcomes for patients screened using the SOC and for those using the FMF screening algorithm, from the Belgian payers' perspective. Where possible, the probabilities and associated costs at each decision point were calculated based on published literature and public databases. Cost-effectiveness was assessed using an incremental cost-effectiveness ratio. One-way sensitivity analyses were performed to assess the impact of independent variations in each model parameter. A probabilistic sensitivity analysis was used to estimate the impact of the overall uncertainty of the model on the estimated cost-effectiveness. Considering an estimated 51,309 pregnancies in nulliparous women in Belgium per year, the FMF screening algorithm resulted in fewer cases of pre-term PE compared with the SOC (479 versus 816 cases) and a cost saving of €28.67 per patient. The outcome in quality-adjusted life-years was similar for both screening approaches (FMF screening algorithm 1.8521 versus SOC 1.8518). The FMF screening algorithm was cost-saving and more effective in 99.4% of simulations. The FMF screening algorithm coupled with early intervention using low-dose aspirin has the potential to prevent an additional 337 cases of pre-term PE per year compared with the current SOC in this population, along with a cost saving.

MINI OPCAB Mammary to LAD and Optimal Medical Treatment in High Risk Patients with Multivessel Coronary Disease Long Term Results

MINI OPCAB Mammary to LAD and Optimal Medical Treatment in High Risk Patients with Multivessel Coronary Disease Long Term Results

MINI OPCAB Mammary to LAD and Optimal Medical Treatment in High Risk Patients with Multivessel Coronary Disease Long Term Results

MINI OPCAB Mammary to LAD and Optimal Medical Treatment in High Risk Patients with Multivessel Coronary Disease Long Term Results

Five-year treat-to-target outcomes after methotrexate induction therapy with or without other csDMARDs and temporary glucocorticoids for rheumatoid arthritis in the CareRA trial

ObjectivesTo compare outcomes of different treatment schedules from the care in early rheumatoid arthritis (CareRA) trial over 5 years.MethodsPatients with RA completing the 2-year CareRA randomised controlled trial were eligible...

Laboratory parameters related to severe disease and death in SARS-CoV-2 pneumonia: Retrospective analysis.

The clinical evolution of coronavirus disease 2019 (COVID‐19) is highly variable and hospitalized patients can rapidly develop conditions requiring oxygen support, intensive care unit (ICU) or high dependency unit (HDU) care. Early identification of high‐risk patients is mandatory. We retrospectively collected the medical history, symptoms, radiological, and laboratory findings of COVID‐19 patients hospitalized between February and April 2020. Laboratory data were collected at the first, last, and middle times of hospitalization. We used arterial oxygen partial pressure and fractional inspired oxygen ratio (P/F) to evaluate respiratory status. Outcomes considered were death and ICU/HDU admission. We used the χ 2 or Fisher's exact test to examine differences between categorical variables. Continuous variables were analyzed using the Wilcoxon matched pairs signed‐ranks test and Mann–Whitney test sample test. Of 71 patients admitted, 92% had interstitial pneumonia, and 17% an unfavorable outcome. Negative predictors were age, cerebrovascular disease, obesity, and chronic obstructive pulmonary disease. Baseline P/F was strongly associated with all outcomes. Markers linked to immunological dysregulation like elevated neutrophil‐to‐lymphocyte ratio exhibited prognostic significance over time. A validated prognostic score comprehensive of all these conditions for early staging and management of COVID‐19 patients is urgently needed. Further studies are desirable to evaluate whether laboratory tests can target early treatment in high‐risk patients.

Results of Register in Patients with Acute Coronary Syndrome and Atrial Fibrillation Receiving Rivaroxaban.

Aim To evaluate outcomes in patients with acute coronary syndrome and atrial fibrillation who receive rivaroxaban and the patients' compliance with the antithrombotic therapy.Material and methods The study was performed from October 2017 through December 2019 and included 129 patients. Events between the discharge from the hospital and 12 months of follow-up were recorded. The primary endpoint was development of major, minor or requiring medical attention bleeding according to the TIMI scale. The secondary endpoint was a combination of recurrent myocardial infarction, nonfatal acute ischemic cerebrovascular disease, nonfatal systemic embolism, stent thrombosis, and cardiovascular mortality.Results 32 (24.8%) patients early terminated the antiplatelet treatment and 22 (17.1%) patients terminated the rivaroxaban treatment. 26 (20.2 %) patients had hemorrhagic complications. The highest incidence of hemorrhage was observed within the first 2 months after the discharge. None of the bleedings was fatal. Composite endpoint events were observed in 24 (18.6 %) patients, including 14 (10.9 %) who died from cardiovascular causes.Conclusion The compliance with the antiplatelet therapy was insufficient. The incidence of hemorrhagic complications was relatively high; minor and requiring medical attention hemorrhages mostly contributed to the structure of these complications. The observed incidence of recurrent ischemic events associated with a high mortality presents a more serious problem compared to hemorrhagic complications of the combination antiplatelet therapy and warrants a more aggressive tactics of the antiplatelet treatment in high-risk patients.

Urothelial Carcinoma in The Era of Immune Checkpoint Inhibitors

Bladder cancer is the seventh most frequent cancer worldwide. The majority of patients present with nonmuscle invasive disease, while 20% of the patients are diagnosed with muscle-invasive bladder cancer. The treatment of nonmuscle invasive disease is endoscopic resection followed by intravesical adjuvant treatment for high risk patients. The standard treatment of localized muscle-invasive disease is neoadjuvant chemotherapy followed by radical cystectomy. Platinum-based chemotherapy is the first-line treatment in locally advanced or metastatic urothelial carcinoma. Immune checkpoint inhibitors have been approved for the treatment of metastatic urothelial carcinoma as second-line treatment or first-line in platinum-ineligible patients. Recently, pembrolizumab have been approved in bacillus Calmette-Guérin (BCG)-refractory nonmuscle invasive bladder cancer. This review summarizes the current evidence concerning immunotherapy in the treatment of urothelial carcinoma.

Lung Cancer Strategist Program: A novel care delivery model to improve timeliness of diagnosis and treatment in high-risk patients

IntroductionThe diagnosis and treatment of lung cancer is challenged by complex diagnostic pathways and fragmented care that can lead to care disparities for vulnerable patients. MethodsA multi-institutional, multidisciplinary conference was convened to address the complexity of lung cancer care particularly in patients at high-risk for treatment delay. The resulting care delivery model, called the Lung Cancer Strategist Program (LCSP), was led by a thoracic-trained advanced practice provider (APP) with emphasis on expedited surgery and early oncologic consultation in the assessment of a newly diagnosed suspicious lung nodule. We performed a retrospective review to evaluate care efficiency and oncologic outcomes in the first 100 LCSP patients compared to 100 concurrent patients managed via routine surgical referral. ResultsIn the 78 LCSP and 41 routine referral patients managed via nodule surveillance, LCSP patients had a shorter time from suspicious finding to work-up (3 vs. 26 days, p < 0.001) and to surveillance decision (12.5 vs. 39 days, p < 0.001). In the 22 LCSP and 59 routine referral patients treated for intrathoracic malignancy, LCSP patients had fewer hospital visits (4 vs 6, p < 0.001), clinicians seen (1.5 vs. 2, p = 0.08), and diagnostic studies (4 vs 5, p = 0.01) with a shorter time to diagnosis (30.5 vs. 48 days, p = 0.02) and treatment (40.5 vs. 68.5 days, p = 0.02). ConclusionsPatient triage through a thoracic-trained APP in consultation with surgical, medical, and radiation oncology facilitates rapid assessment of benign versus malignant lesions with reduced time to diagnosis and treatment, even among patients at high-risk for treatment delay.

A ROR1 Bispecific T Cell Engager for the Treatment of Chronic Lymphocytic Leukaemia Demonstrates Enhanced Function Following Ibrutinib Treatment

ROR1 is expressed on a range of solid and haematological malignancies, including chronic lymphocytic leukaemia, mantle cell lymphoma and a subset of acute lymphoblastic lymphoma, making it an attractive therapeutic target. In keeping with this, ROR1 CAR T cells and a ROR1 antibody, are being investigated as novel treatments [NCT02222688, NCT02776917 & NCT02706392]. BiTEs are small, 55kDa antibody based therapeutics composed of two single chain variable fragments (scFv) linked in tandem by a flexible linker. One scFv binds to tumour antigens and the other to the CD3 complex, bringing target cells and T cells in close proximity, facilitating formation of cytotoxic synapses and resulting in target cell death. We have generated a fully humanised ROR1 BiTE which unlike conventional antibodies recruits and utilises the inherent cytotoxic potential of polyclonal resident T cells and does not require ex vivo cell manipulation. We therefore investigated the potential of a ROR1 BiTE for the treatment of CLL.We first assessed the efficacy of our ROR1 BiTE against SKW6.4, Jeko1 and Kasumi-2 haematological cell lines which are ROR1 positive, confirming significant cytotoxicity even at low concentrations of 1ng/ml (Figure 1A). To demonstrate in vivo potential, mice were injected with SKW6.4 cells and disease established before treatment with T cells and 5 days of ROR1 BiTE or control PBS therapy. BiTE treated animals had improved survival compared to the control cohort (50 days vs 18 days), despite only a single infusion of T cells (Figure 1B).We next assessed the potential of the BiTE to target primary CLL cells: allogeneic healthy donor T cells were co-cultured with CLL cells (3:1 effector:target ratio) in the presence of ROR1 BiTE with resultant decrease in CLL viability at 24 hours (Mean CLL survival 32%, Figure 1C). In contrast, we saw minimal cytotoxicity in co-cultures of autologous patient T cells and CLL cells with ROR1 BiTE under identical conditions (Mean CLL survival 92%, Figure 1D). We hypothesised this was secondary to the previously described multifactorial T cell dysfunction in CLL.Ibrutinib, the first in class Bruton's tyrosine kinase inhibitor, demonstrates impressive efficacy in front line and relapsed/refractory CLL patients including those with high risk 17p deletion. In addition, it modulates the tumour micro-environment, skews T cells to a Th1 phenotype, reduces PD-1 expression and reverses pseudo-exhaustion. In view of this, we isolated T cells from patients receiving Ibrutinib and cultured them with autologous CLL cells and demonstrated significantly enhanced cytotoxicity compared to patients not exposed to Ibrutinib (Mean CLL survival 43% vs 85%, p=0.012) (Figure 1E). This cohort included patients who had failed multiple prior lines of therapy and/or 17p deleted cases. Ibrutinib treatment was also associated with markedly enhanced secretion of a range of pro-inflammatory mediators including IFNγ and TNFα (Figure 1F). To ensure this effect was not due to Ibrutinib increasing sensitivity of CLL cells to a ROR1 BiTE, we analysed matched samples from 2 patients pre and post treatment. Post Ibrutinib T cells demonstrated enhanced killing, irrespective of the CLL cells exposure to Ibrutinib, confirming enhanced T cell function as the driving force of improved BiTE mediated cytotoxicity (Figure 1G).Taken together, we demonstrate the potential of a ROR1 BiTE to target haematological malignancies and highlight for CLL, the clinical context in which BiTEs are used is critical for effective responses. Baseline T cell dysfunction in untreated or relapsed CLL patients will likely limit efficacy, whilst Ibrutinib treatment allows for improved T cell effector function. In keeping with this CD19 CAR T cells demonstrate superior expansion, function and persistence when generated from CLL patients on Ibrutinib, confirming a global positive immunomodulatory role. Other small molecule inhibitors may improve T cell function by reducing tumour bulk but Ibrutinib inhibits other tyrosine kinases including ITK, which may play a role in T cell modulation. Despite Ibrutinib monotherapy being effective, patients often have a low level disease burden and minimal residual disease is rarely achieved. BiTE treatment for high risk patients in this situation represents a rational option to deepen responses. Overall, our data supports the assessment of our ROR1 BiTE in the post Ibrutinib setting for CLL. [Display omitted] DisclosuresGohil:UCL Business: Patents & Royalties. Nathwani:UCL Business: Patents & Royalties. Della Peruta:UCL Business: Patents & Royalties.