Treatment Of High-risk Patients Research Articles

Deep Learning Analyses of Brain MRI to Identify Sustained Attention Deficit in Treated Obstructive Sleep Apnea: A Pilot Study.

Persistent sustained attention deficit (SAD) after continuous positive airway pressure (CPAP) treatment is a source of quality of life and occupational impairment in obstructive sleep apnea (OSA). However, persistent SAD is difficult to predict in patients initiated on CPAP treatment. We performed secondary analyses of brain magnetic resonance (MR) images in treated OSA participants, using deep learning, to predict SAD. 26 middle-aged men with CPAP use of more than 6 hours daily and MR imaging were included. SAD was defined by psychomotor vigilance task lapses of more than 2. 17 participants had SAD and 9 were without SAD. A Convolutional Neural Network (CNN) model was used for classifying the MR images into +SAD and -SAD categories. The CNN model achieved an accuracy of 97.02±0.80% in classifying MR images into +SAD and -SAD categories. Assuming a threshold of 90% probability for the MR image being correctly classified, the model provided a participant-level accuracy of 99.11±0.55% and a stable image level accuracy of 97.45±0.63%. Deep learning methods, such as the proposed CNN model, can accurately predict persistent SAD based on MR images. Further replication of these findings will allow early initiation of adjunctive pharmacologic treatment in high-risk patients, along with CPAP, to improve quality of life and occupational fitness. Future augmentation of this approach with explainable artificial intelligence methods may elucidate the neuroanatomical areas underlying persistent SAD to provide mechanistic insights and novel therapeutic targets.

Role of Adjuvant Treatment in High-risk Patients Following Resection for Gallbladder Cancer.

To identify prognostic factors for surgically resected gallbladder cancer (GBC). Medical records of 66 patients with GBC undergoing potentially curative resection between 2001 and 2017 were retrospectively reviewed. After a median follow-up of 39.9 months (range=0.5-216.4 months), 22 locoregional recurrences and 25 distant metastases occurred. Adjuvant radiotherapy and adjuvant chemotherapy failed to prove efficacy in all patient groups. In patients with stage III-IV GBC, adjuvant chemotherapy showed a marginally positive effect on locoregional control (p=0.064), and was significantly beneficial for overall survival (p=0.040), and adjuvant treatment improved both locoregional control and overall survival (p=0.029 and p=0.005, respectively). On multivariate analysis, a negative resection margin was a significant prognostic factor for superior local control, and disease-free and overall survival (p=0.003, p=0.010 and p=0.005, respectively) and adjuvant treatment was associated with improved overall survival (p=0.018). Adjuvant treatment is recommended for patients with stage III-IV GBC following curative surgical resection.

Rockall score in Upper Gastrointestinal Bleeding: Risk stratification and prognostic outcome

Background: Early risk stratification of patients with upper gastrointestinal bleeding (UGIB) is of utmost importance for a favourable patient outcome. It ensures patient triaging into the appropriate level of care, avoiding unnecessary and prolonged hospitalisations on one end and rapid identification of high-risk patients for emergent management on the other. Methods: This prospective observational study was carried out on 150 patients who met the inclusion criteria. Demographic data, baseline lab parameters, Rockall scores, endoscopic interventions, re-bleeding, duration of hospital stay and mortality were recorded. Based on the Rockall scores, patients were divided as low, moderate and high risk. Results: Variceal bleeding was the most common cause of UGIB (34%). The need for therapeutic endoscopy, risk of re-bleeding and duration of hospital stay were proportional to the severity of the risk as per Rockall score (p-value < 0.01). Among the study subjects, one patient in high-risk category expired. Conclusion: Rockall scoring system helps in the risk stratification of UGIB patients and hence early intervention in high-risk patients. Higher scores are associated with poor patient outcomes.

Clinico-biological features of T-cell acute lymphoblastic leukemia with fusion proteins

T-cell acute lymphoblastic leukemias (T-ALL) represent 15% of pediatric and 25% of adult ALL. Since they have a particularly poor outcome in relapsed/refractory cases, identifying prognosis factors at diagnosis is crucial to adapting treatment for high-risk patients. Unlike acute myeloid leukemia and BCP ALL, chromosomal rearrangements leading to chimeric fusion-proteins with strong prognosis impact are sparsely reported in T-ALL. To address this issue an RT-MPLA assay was applied to a consecutive series of 522 adult and pediatric T-ALLs and identified a fusion transcript in 20% of cases. PICALM-MLLT10 (4%, n = 23), NUP214-ABL1 (3%, n = 19) and SET-NUP214 (3%, n = 18) were the most frequent. The clinico-biological characteristics linked to fusion transcripts in a subset of 235 patients (138 adults in the GRAALL2003/05 trials and 97 children from the FRALLE2000 trial) were analyzed to identify their prognosis impact. Patients with HOXA trans-deregulated T-ALLs with MLLT10, KMT2A and SET fusion transcripts (17%, 39/235) had a worse prognosis with a 5-year EFS of 35.7% vs 63.7% (HR = 1.63; p = 0.04) and a trend for a higher cumulative incidence of relapse (5-year CIR = 45.7% vs 25.2%, HR = 1.6; p = 0.11). Fusion transcripts status in T-ALL can be robustly identified by RT-MLPA, facilitating risk adapted treatment strategies for high-risk patients.

A Novel Nomogram for Early Identification and Intervention in Colorectal Cancer Patients at Risk for Malnutrition.

Malnutrition is under-recognized in cancer patients and can lead to poor treatment outcomes. We aim to develop an outpatient-focused score based on the Malnutrition Screening Tool (MST) to help identify colorectal cancer (CRC) profiles at high risk for malnutrition. 506 CRC patients during initial outpatient oncology consultation at our tertiary referral outpatient oncology clinic completed the MST. Objective and subjective data were collected through chart review. Data gathered are as follows: demographics, anthropometrics, laboratory values, patient-reported symptoms, MST score, cancer history, performance status, socioeconomic status, and Charlson Comorbidity. Predictors of malnutrition were identified by logistic regression. Receiver operating curve (ROC), area under the curve (AUC), and our model's predictability were determined. Significant predictors of malnutrition are as follows: younger age (20-39 vs >40 years) (P = .007), normal-to-low body mass index at presentation (P = .019), Eastern Cooperative Oncology Group classification 2-3 (P = .012), metastatic disease (P = .046), albumin <3.0g/dL (P = .033), fatigue (P < .001), and change in stool/bowel habits (P = .002). In our derived malnutrition score, risk of malnutrition increased from 11% for score 0, to 100% for scores 9-10. Receiver operating curve showed AUC .745 (95% CI, .697-.793). An outpatient clinic-derived malnutrition score obtained from objective and patient-reported variables may facilitate identification of CRC patients at highest risk for malnutrition. Rapid identification and intervention in high-risk patients may improve treatment recovery, therapy tolerance, and quality of life. Our tool requires external validation before application in clinical practice.

291 Ticagrelor monotherapy after percutaneous coronary intervention in high-risk patients with prior myocardial infarction: a prespecified twilight substudy

Abstract Aims Patients with history of myocardial infarction (MI) undergoing percutaneous coronary intervention (PCI) remain at risk of recurrent ischaemic events. The optimal antithrombotic strategy for this cohort remains debated. Methods and results In this prespecified analysis of the TWILIGHT trial, we evaluated the impact of prior MI on treatment effect of ticagrelor monotherapy vs. ticagrelor plus aspirin in patients undergoing PCI with at least one clinical and one angiographic high-risk feature and free from adverse events at 3 months after the index PCI. The primary endpoint was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5, the key secondary endpoint was the composite of all-cause death, MI, or stroke, both at 12 months after randomization. 1937 (29.7%) patients with and 4595 (70.3%) without prior MI were randomized to ticagrelor and placebo or ticagrelor and aspirin. Patients with prior MI had increased rates of death, MI or stroke (5.7 vs. 3.2%, P &amp;lt; 0.001) but similar BARC 2–5 bleeding (5.0 vs. 5.5%, P = 0.677). Ticagrelor monotherapy reduced the risk of BARC 2–5 bleeding in patients with [3.4% vs. 6.7%; hazard ratio (HR): 0.50; 95% confidence interval (CI): 0.33–0.76] and without prior MI [4.2% vs. 7.0%; HR: 0.58; 95% CI: 0.45–0.76; pinteraction = 0.54). Rates of the key secondary ischaemic outcome were similar between treatment groups irrespective of history of MI (prior MI: 6.0% vs. 5.5%; HR: 1.09; 95% CI: 0.75–1.58; no prior MI: 3.1% vs. 3.3%; HR: 0.92; 95% CI: 0.67–1.28; pinteraction = 0.52). Conclusions Ticagrelor monotherapy is associated with significantly lower risk of bleeding events as compared to ticagrelor plus aspirin without any compromise in ischaemic prevention among high-risk patients with history of MI undergoing PCI.

940. The use of a commercially available CMV T Cell Immunity Panel to Assess the Risk of CMV Infections in Hematopoietic Cell Transplant Recipients with Low Level CMV Viremia

BackgroundCytomegalovirus (CMV) infections continue to be associated with increased morbidity and mortality in Hematopoietic Cell Transplant (HCT) recipients. Treatment of high risk patients with low level viremia may reduce overall duration of therapy and reduce complications. CMV T Cell Immunity Panel (TCIP) may help identify patients at high risk of CMV reactivation prior to developing clinically significant CMV infection (CS-CMVi). Our study aims to identify HCT recipients with low level CMV viremia who are at high risk of CMV reactivation with the use of CMV-TCIP while on or off letermovir for prophylaxis. MethodsWe enrolled in a prospective cohort study allogeneic HCT recipients (excluding cord blood transplantation) with low level of CMV viremia (viral load of < 1000 IU/ml) on no therapy, starting October 2019. CMV TCIP assay was performed at enrollment, weeks 1, 2, 3, 4, 6 and 8. CMV TCIP results were interpreted as negative or positive based on percentage of interferon gamma producing CD4+ or CD8+ CMV specific T cells. The primary endpoint was progression to a CS-CMVi. We are presenting the results of the first 30 patients with data up to 4 weeks from enrollment.ResultsAmong the 30 patients, 73% were on letermovir for CMV prophylaxis. Majority of the patients were ≥ 40 years old (77%), male (63%), received transplant for AML (40%), were in complete remission at time of transplant (23%) and received cyclophosphamide (90%). The median time from transplant to enrollment was 77 days (IQR 37-172) (table 1). At enrollment, 10 (33%) patients had a positive CMV TCIP, 10 (33%) had a negative CMV TCIP, and 10 (33%) had an uninterpretable CMV TCIP result due to inability to quantify T cells (table 1). Four (13%) patients developed CS-CMVi; 3 of these patients had a negative TCIP and 1 had unquantifiable CMV TCIP (Figure 1). The mean percentage of CMV specific CD4+ and CD8+ interferon producing cells was 1.76% (SD 2.24) and 9.37% (SD 11.35) for those on letermovir and 2.09% (SD 2.05) and 3.97% (SD 5.24) off letermovir respectively (P >0.05) (Figure 2).Figure 1. Breakdown of the 30 patients during the 4 week follow up period Abbreviations: HCT: Hematopoietic cell transplantation; CMV: Cytomegalovirus; TCIP: T cell immunity panelFigure 2. Box-plot of percentage of CD4+ CMV specific interferon producing cells over time. Threshold for positive result (0.2%) marked. Abbreviations: CMV: CytomegalovirusTable 1. Baseline characteristics of patients enrolled Abbreviations: CMV: Cytomegalovirus; TCIP: T cell immunity panel; IQR: Interquartile rangeConclusionOur results demonstrate the value of the CMV TCIP in identifying high risk HCT recipients prior to developing CS-CMV infection. Disclosures Fareed Khawaja, MBBS, Eurofins Viracor (Research Grant or Support) Ella Ariza Heredia, MD, Merck (Grant/Research Support) Michelle Altrich, PhD, HCLD, Eurofins Viracor (Employee) Roy F. Chemaly, MD, MPH, FACP, FIDSA, AiCuris (Grant/Research Support)Ansun Biopharma (Consultant, Grant/Research Support)Chimerix (Consultant, Grant/Research Support)Clinigen (Consultant)Genentech (Consultant, Grant/Research Support)Janssen (Consultant, Grant/Research Support)Karius (Grant/Research Support)Merck (Consultant, Grant/Research Support)Molecular Partners (Consultant, Advisor or Review Panel member)Novartis (Grant/Research Support)Oxford Immunotec (Consultant, Grant/Research Support)Partner Therapeutics (Consultant)Pulmotec (Consultant, Grant/Research Support)Shire/Takeda (Consultant, Grant/Research Support)Viracor (Grant/Research Support)Xenex (Grant/Research Support)

Efficacy and Safety of Different Dosages of Decitabine in the Treatment of High-Risk Patients with Myelodysplastic Syndrome

To investigate the efficacy of high-risk myelodysplastic syndrome (MDS) patients treated by different doses of decitabine (DAC) and its safety. Thirty patients with high-risk MDS were all treated by demethylation drug DAC. According to the doses of DAC, 30 patients were divided into 10-day regimen [6 mg/(m2·d)×10 d, 15 patients] group and 5-day regimen [15 mg/(m2·d)×5 d, 15 patients] group. The efficacy and adverse events of the patients in the two groups were observed. The patients were followed up to May 2020, in the 10-day regimen group, 10 cases achieved complete remission (CR), 3 cases achieved partial remission (PR), and 2 cases were progressive disease (PD). Four cases died, including 1 case for heart failure, 2 cases for respiratory failure and 1 case for serious infection. In the 5-day regimen group, 11 cases achieved CR, 1 case achieved PR, 3 cases were PD. Five cases died, including 2 cases for heart failure and 3 for serious infection. The CR rate and ORR of the patients in the two groups were 66.67% vs 73.33%, 86.67% vs 80.00%, respectively, which showed no significant differences, and the efficacy also showed no significant difference. After treatment, the levels of WBC, NE, Hb and PLT of the patients in 10-day regimen group were higher than those in 5-day regimen. In the 10-day regimen group, there were 11 cases of pneumonia, 2 cases of bacteremia, 1 case of skin infection and 1 case of urinary tract infection. While in the 5-day regimen group, 13 cases of pneumonia, 5 cases bacteremia, 1 case of skin infection and 3 cases of urinary tract infection. There were 2 cases with mild gastrointestinal response in the 10-day regimen group, and 7 cases with obvious nausea and anorexia in the 5-day regimen group. The symptoms were relieved after the treatment of acid suppression, stomach protection and antiemetic. The liver, kidney and heart function were monitored. One case liver function damage and 2 cases cardiac insufficiency were observed in the 10-day regimen group. Seven cases regimen cardiac insufficiency and 4 cases regimen liver function damage were observed in the 5-day regimen group. 10-day regimen and 5-day regimen are equally effective, but 10-day regimen is less myelosuppressive and more safer, which can be applied in clinical.

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.