Advances In Risk Stratification Research Articles

Current approaches and future perspectives on hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disorder characterized by significant myocardial hypertrophy and varying degrees of fibrosis, affecting approximately 0.2% of the general population, with a higher prevalence in those with cardiac conditions. Despite its frequency, HCM remains underdiagnosed due to its broad clinical spectrum. The disease is equally prevalent in men and women, presenting in forms ranging from mild to severe, and it is the leading cause of sudden cardiac death in adolescents and young adults, particularly athletes. Recent advances in genetic engineering and biotechnology have significantly improved the understanding, diagnosis, and treatment of HCM, emphasizing the importance of early diagnosis in preventing severe complications. This review synthesizes findings from a narrative literature review, highlighting advances in risk stratification, gene therapy, biomarker utilization, and the need for further research to make these innovations more widely available in clinical practice. The study also examines the disease's pathophysiology, genetics, diagnostic methods, and treatment strategies, underlining the importance of personalized approaches to managing HCM.

Management of Ventricular Arrhythmias in Heart Failure: Can Less Be More?

Ventricular arrhythmias (VAs) affect many patients with heart failure and underlying structural heart disease and are associated with significant morbidity and mortality. Antiarrhythmic drugs are often the initial treatment, but medication alone often fails to sufficiently suppress VAs. While catheter ablation (CA) remains the gold standard for treatment of VAs, CA is an invasive procedure and can be associated with periprocedural complications including acute clinical decompensation. Thus, there is an important need for alternative therapies. Recent advances in risk stratification and the development of new ablation technologies may reduce some of the periprocedural complications and limitations of CA. In addition, less invasive therapies for VAs may provide an alternative treatment strategy for patients in both the acute and chronic setting. For patients acutely admitted with ventricular tachycardia electrical storm (VT-ES) or recurrent VT and cardiogenic shock, risk stratification tools have been developed to identify patients at high risk of acute hemodynamic decompensation during CA. These patients require a multidisciplinary approach and might need mechanical circulatory support (MCS) if CA is selected as the treatment strategy. Alternatively, less invasive therapies targeting the autonomic nervous system may be reasonable. In the chronic setting, developments in medical therapy have reduced the risk of sudden cardiac death in heart failure patients and stereotactic whole-body radiation (SBRT) has evolved as a potential, non-invasive therapy. Further research is needed to personalize VA therapy for individual patients.

MDB-74. SERINE/GLYCINE METABOLISM REPRESENTS A NOVEL TARGETABLE THERAPEUTIC VULNERABILITY IN MYC-AMPLIFIED MEDULLOBLASTOMA

Abstract BACKGROUND Medulloblastoma is the most frequent malignant brain tumour of childhood. Whilst advances in risk-stratification and upfront multimodal therapy have led to five-year survival rates around 70%, a subset of tumours remain refractory to current therapies. Group 3 medulloblastomas (MBGRP3) are enriched for amplification or overexpression of the proto-oncogene MYC which conveys a dismal prognosis (<10% survival), highlighting the urgent need for novel therapeutic strategies. Recent advances have revealed a role for metabolic reprogramming in MYC-amplified MBGRP3 tumorigenesis, providing novel opportunities for selective therapeutic targeting. METHODS & RESULTS To investigate MYC-dependent metabolic alterations in MBGRP3, we generated three independent isogenic MBGRP3 cell-based models with regulable MYC expression (iMBGRP3-MYC) using a doxycycline-inducible shRNA system. Using 1H high-resolution magic angle spectroscopy and stable isotope-resolved metabolomics, we identified upregulation of the de novo serine/glycine biosynthesis pathway (SGP), attributable to elevated expression of the rate-limiting enzyme PHGDH, as a novel therapeutic target. Genetic and pharmacological (NCT-503) inhibition of PHGDH induced greater cell death in MYC-expressing cells compared to MYC knockdown cells and increased survival across two independent MYC-amplified MBGRP3 mouse models. The decrease in tumour growth observed was moderate; we therefore hypothesised that a compensatory reliance on exogenous serine/glycine may play a role in sustaining tumour progression under therapy. To explore this, we investigated the impact of exogenous serine/glycine starvation on MBGRP3-MYC tumour development. Starvation resulted in a marked MYC-dependent reduction in cell viability in vitro across independent iMBGRP3-MYC models. Notably, dietary serine/glycine starvation was well-tolerated, delayed tumour progression, and increased survival (by 50%) in an MBGRP3-MYC mouse model (p=0.005), highlighting the metabolic plasticity of MYC-amplified tumours to utilise both de novo and exogenous serine/glycine sources to survive and proliferate. CONCLUSIONS These findings identify serine/glycine metabolism as a targetable therapeutic vulnerability within MYC-amplified MBGroup3 and a novel therapeutic strategy to treat this poor-prognosis disease group.

Advances in Risk Stratification of Patients with Acute Pulmonary Embolism

Advances in Risk Stratification of Patients with Acute Pulmonary Embolism

Prognostic value of extended cardiac risk assessment before elective open abdominal aortic surgery.

Major vascular surgery is associated with ahigh perioperative risk and significant mortality. Despite advances in risk stratification, monitoring, and management of perioperative complications, cardiac complications are still common. Stress echocardiography is well established in coronary artery disease diagnostics; however, its prognostic value before high-risk aortic surgery is unknown. This prospective, single-center study compared the outcome of patients undergoing extended cardiac risk assessment before open abdominal aortic surgery with the outcome of patients who had received standard preoperative assessment. The study included patients undergoing elective open abdominal aortic surgery. Patients who underwent standard preoperative assessment before the start of adedicated protocol were compared with patients who had extended cardiac risk assessment, including dobutamine stress echocardiography, as part of astepwise interdisciplinary cardiovascular team approach. The combined primary endpoint was cardiovascular death, myocardial infarction, emergency coronary revascularization, and life-threatening arrhythmia within 30days. The secondary endpoint was acute renal failure and severe bleeding. In total, 77patients (mean age 68.1 ± 8.1years, 70% male) were included: 39underwent standard and 38underwent cardiac risk assessment. The combined primary endpoint was reached significantly more often in patients before than after implementation of the extended cardiac stratification procedure (15% vs. 0%, p = 0.025). The combined secondary endpoint did not differ between the groups. Patients with extended cardiac risk assessment undergoing elective open abdominal aortic surgery had better 30-day outcomes than did those who had standard preoperative assessment.

PO-05-192 LOCAL HETEROGENEITY OF LATE GADOLINIUM ENHANCEMENT PREDICTS VENTRICULAR ARRHYTHMIA IN HYPERTROPHIC CARDIOMYOPATHY

Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden cardiac death in young people. Despite recent advances in risk stratification using cardiac magnetic resonance (CMR) imaging, risk prediction remains suboptimal. Improved risk stratification is therefore warranted. Whether local heterogeneity of Late Gadolinium Enhancement (LGE) signal is associated with ventricular arrhythmia remains unknown. To determine whether local heterogeneity of LGE signal on CMR predicts ventricular arrhythmia and appropriate shocks after implantable cardioverter defibrillator (ICD) implantation in patients with HCM. Local heterogeneity was quantified by LGE-CMR signal dispersion score and compared with cardiovascular outcomes in 179 HCM patients who underwent ICD implantation. The primary outcome was appropriate ICD shocks. During a median follow-up time of 7.3 years the event rate was 0.015 per person year. History of ventricular arrhythmia (HR 9.413, p<0.001) and sudden cardiac death (HR 13.82, p<0.001) were associated with receiving an appropriate ICD shock in both univariable and multivariable analyses. History of syncope, family history of sudden cardiac death, non-sustained ventricular tachycardia, left ventricular wall thickness and presence of LGE were not associated with the primary outcome. When compared to patients without ICD shock, patients who received ICD shocks had higher burden of LGE gray zone (16.8±7.5% vs 25.8±3.5% p<0.001) and scar (10.5±6.7% vs 18.7±4.3% p<0.001) on CMR. Importantly, patients with ICD shocks had a higher dispersion score (1.20 vs 0.97, respectively), signifying higher degree of LGE signal heterogeneity (p=0.047). Dispersion score, a marker of local LGE signal heterogeneity of scar and gray zone was associated with a higher burden of ICD shocks in HCM patients who received ICDs. Mechanistically, local LGE signal heterogeneity could represent complex scar. These results may contribute to improved risk stratification for ventricular arrhythmia in HCM patients.

Targeting Leukemia-Initiating Cells and Leukemic Niches: The Next Therapy Station for T-Cell Acute Lymphoblastic Leukemia?

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive subtype of hematological malignancy characterized by its high heterogeneity and potentially life-threatening clinical features. Despite the advances in risk stratification and therapeutic management of T-ALL, patients often suffer from treatment failure and chemotherapy-induced toxicity, calling for greater efforts to improve therapeutic efficacy and safety in the treatment of T-ALL. During the past decades, increasing evidence has shown the indispensable effects of leukemia-initiating cells (LICs) and leukemic niches on T-ALL initiation and progression. These milestones greatly facilitate precision medicine by interfering with the pathways that are associated with LICs and leukemic niches or by targeting themselves directly. Most of these novel agents, either alone or in combination with conventional chemotherapy, have shown promising preclinical results, facilitating them to be further evaluated under clinical trials. In this review, we summarize the latest discoveries in LICs and leukemic niches in terms of T-ALL, with a particular highlight on the current precision medicine. The challenges and future prospects are also discussed.

27. Cellular aging for risk stratification in adult deformity surgery: utilization of seven epigenetic clocks and two telomere length measurements in the analysis of comorbidity burden, frailty, disability and complications in adult deformity surgery

<h3>BACKGROUND CONTEXT</h3> Recent advances in risk stratification have led to improvements in our ability to predict complications, cost and outcomes. Chronological age is important in almost all risk calculators; however, genetic or biological age may be more informative. Several techniques exist to assess genetic age including DNA methylation patterns with epigenetic clocks, telomere length and analysis of both mitochondrial DNA and single nucleotide polymorphisms. Our lab recently demonstrated a novel association between telomere length and 90-day complications in adult deformity surgery. There are no current risk stratification tools that integrate markers of cellular aging or biophysiologic reserve. Determining the optimal aging biomarkers to include in risk assessment models will be critical to future work in preoperative risk assessment. <h3>PURPOSE</h3> To assess the utility of epigenetic clocks and telomere length in evaluating comorbidity burden, frailty, disability and postoperative complications. <h3>STUDY DESIGN/SETTING</h3> Prospective cohort of adult deformity patients performed at a single academic center. <h3>PATIENT SAMPLE</h3> Adult patients with spinal deformity undergoing elective surgery. <h3>OUTCOME MEASURES</h3> Any medical or surgical complication within 90 days from surgery. <h3>METHODS</h3> Adult spinal deformity patients were prospectively enrolled. Demographics, frailty index (ASD-FI), Charlson comorbidity index (CCI), Oswestry Disability Index (ODI), and whole blood were collected along with presence of any medical or surgical complications at 90 days. CpG methylation was quantified using the Illumina EPIC array platform. Raw methylation data were processed using a custom pipeline in R to extract 7 epigenetic metrics: Horvath Age, Hannum Age, instantaneous pace of aging (DunedinPACE), and 4 principal component (PC) corrected epigenetic age metrics (PC Horvath, PC Hannum, PC PhenoAge, and PC GrimAge). Telomere length was measured directly by qPCR (TSR) or indirectly by methylation-based estimation (PC DNAmTL), which estimates telomere length using specific methylation sequences and correlation to leukocyte telomere length. Linear regression with biweight midcorrelation (bicor) was used to compare continuous variables. Logistic regression with odds radio (OR) was used for complications. Gender and BMI were treated as fixed-effects and added to each model. <h3>RESULTS</h3> A total of 43 patients were included with mean age of 65 years and 21 women (49%). A mean of 11 levels were fused posteriorly with 21 combined anterior-posterior approaches (43%) and 18 three-column osteotomies (42%). There were no significant differences in age, gender, BMI, preoperative ASA classification, CCI score, ODI, or surgical variables between patients who had complications compared to those without. CCI correlated with epigenetic age using 6 epigenetic clocks (Hannum Age, Horvath Age, PC Hannum, PC Horvath, PC PhenoAge, PC GrimAge) and estimated telomere length (PC DNAmTL). ASD-FI correlated with epigenetic age using the DunedinPACE epigenetic clock (bicor=0.439, p=0.003). ODI showed a trend toward correlation with epigenetic age using DunedinPACE, but did not meet statistical significance (bicor=0.262, p=0.098). Both direct and indirect telomere measures were associated with 90-day complications (TSR, OR=1,466, p=0.014 and PC DNAmTL, OR=279, p=0.010), while epigenetic age using the PC GrimAge clock showed only a trend (OR=1.09, p=0.067). <h3>CONCLUSIONS</h3> Epigenetic clocks seem to correlate with comorbidity (CCI) and disease-specific frailty (ASD-FI), while telomere length is significantly associated with complications. Perhaps most importantly, both direct and indirect measures of telomere length showed significant associations with complications, validating both approaches for this application. Integration of biomarkers into current risk calculators has significant potential for improved prediction accuracy, preoperative optimization and tailored surgical planning. <h3>FDA DEVICE/DRUG STATUS</h3> This abstract does not discuss or include any applicable devices or drugs.

Advances in Risk Stratification and Treatment of Polycythemia Vera and Essential Thrombocythemia.

Estimating and modifying thrombotic risk is currently the mainstay of care for patients with polycythemia vera (PV) and essential thrombocythemia (ET). In recent years, however, increased attention has shifted towards quality of life and disease modification. In this review, we discuss recent advances in risk stratification, present updated results for ruxolitinib and interferon randomized clinical trials, discuss new approaches in antiplatelet and anticoagulant treatment, and summarize early phase trials of novel agents and emerging therapeutic concepts for the treatment of PV and ET. International collaborations and novel technologies, i.e., next-generation sequencing and machine learning techniques, have demonstrated excellent abilities to improve thrombotic risk stratification in PV and ET. Updated results from ruxolitinib and interferon randomized clinical trials have confirmed excellent efficacy and safety of these agents, both as first- and second-line treatments. Early trials of novel agents (histone deacetylase inhibitors, telomerase inhibitors, lysine-specific demethylase-1 inhibitors, human double-minute 2 inhibitors, and hepcidin mimetics) have shown encouraging efficacy and safety in blood count control, reduction of splenomegaly, and alleviation of disease-related symptoms. Finally, accumulating evidence suggested that direct oral anticoagulants may be a valid therapeutic alternative to warfarin for prolonged thromboprophylaxis. International collaborations ("big data") with the help of new technologies represent an exciting new approach to analyze rare outcomes in rare diseases, especially for identifying novel prognostic biomarkers in PV and ET. Randomized clinical trials are also needed to fully elucidate whether novel agents may establish new standards of care.

Abstract P2118: Modeling Arrhythmia Risk In Human Stem Cell Derived Cardiomyocytes

In older (45+ years) populations, sudden cardiac death (SCD) is primarily caused by ischemic heart disease while in younger populations, SCD is often due to genetic causes. Despite recent advances in risk stratification based on clinical evaluation and genetic testing, our ability to predict SCD risk in the younger population remains inadequate. Implantable cardioverter defibrillators (ICDs) have been an essential intervention to reduce the number of out-of-hospital cardiac arrests in patients determined to be at risk of SCD. Nevertheless, one third of patients with an ICD receive inappropriate shocks and are exposed to infection without clear benefit. In addition, some children and young adults receive an ICD that will never deliver a shock even after decades of follow-up. No clear guidelines have been established to detect SCD-predisposing conditions due to cost, sensitivity, and specificity of testing modalities. Human iPSC-derived cardiomyocytes (hiPSC-CMs) are a widely recognized and reliable in vitro platform to study clinical phenotypes but have never been used in the context of SCD risk prediction. We hypothesize that we can establish an hiPSC-CMs cellular model to predict SCD risk. Sixty individuals were recruited and classified in one of five categories, ranging from healthy controls with no known cardiac disease (category 1) to individuals that show the highest SCD risk (category 5). These 5 categories are defined by 3 main parameters: 1) absence or presence of ICD, 2) whether the ICD was placed as primary or secondary prevention and 3) the number of shocks received after ICD implantation. hiPSCs were reprogrammed using blood samples and then differentiated into cardiomyocytes. Molecular and electrophysiology measurements were performed for the different risk categories using high-throughput systems. hiPSC-CMs were assayed by single-cell calcium imaging, microelectrode array and automated action potential and current recordings. In vitro measurements revealed that specific parameters such as field potential duration correlate with the SCD risk and outcome. In conclusion, this study will provide a cellular-based tool to determine patient-specific SCD risk in order to advance medical care for at-risk patients and their family members.

Meeting abstracts from the 15th international conference on neonatal and childhood pulmonary vascular disease

Meeting abstracts from the 15th international conference on neonatal and childhood pulmonary vascular disease

Allogeneic Hematopoietic Stem Cell Transplantation for Children With Acute Lymphoblastic Leukemia: Shifting Indications in the Era of Immunotherapy.

Pediatric acute lymphoblastic leukemia generally carries a good prognosis, and most children will be cured and become long-term survivors. However, a portion of children will harbor high-risk features at the time of diagnosis, have a poor response to upfront therapy, or suffer relapse necessitating more intensive therapy, which may include allogeneic hematopoietic stem cell transplant (HSCT). Recent advances in risk stratification, improved detection and incorporation of minimal residual disease (MRD), and intensification of upfront treatment have changed the indications for HSCT over time. For children in first complete remission, HSCT is generally reserved for those with the highest risk of relapse. These include patients with unfavorable features/cytogenetics who also have a poor response to induction and consolidation chemotherapy, usually reflected by residual blasts after prednisone or by detectable MRD at pre-defined time points. In the relapsed setting, children with first relapse of B-cell ALL are further stratified for HSCT depending on the time and site of relapse, while all patients with T-cell ALL are generally consolidated with HSCT. Alternatives to HSCT have also emerged over the last decade including immunotherapy and chimeric antigen receptor (CAR) T-cell therapy. These novel agents may spare toxicity while attempting to achieve MRD-negative remission in the most refractory cases and serve as a bridge to HSCT. In some situations, these emerging therapies can indeed be curative for some children with relapsed or resistant disease, thus, obviating the need for HSCT. In this review, we seek to summarize the role of HSCT in the current era of immunotherapy.

Clinical Outcomes of Malignancy-Related Neutropenic Fever Admissions in the United States: A 10-Year National Study

Background: Neutropenia and neutropenic fever are a major cause of in-hospital morbidity and mortality in cancer patients. In this study, we aim to analyze trends in hospital outcomes of cancer-related neutropenic fever admissions and investigate clinical predictors associated with outcomes. Methods: We queried the National Inpatient Sample (NIS) database (2008-2017), using ICD-9 and ICD-10 codes accordingly, to identify cancer-related neutropenic fever admissions in the US hospitals. Cases younger than 18 years of age and cases that did not have malignancy as a primary or secondary diagnosis were excluded. Baseline characteristics of survivors were compared with non-survivors. Statistical analysis was performed using SPSS v26 (IBM Corp, Armonk, NY, USA). The adjusted odds ratio (aOR) and 95% confidence interval (CI) were calculated using the Cochran-Mantel-Haenszel test. A multivariate regression model was deployed to assess predictors of inpatient mortality. Complex weights were used throughout all calculations, enabling appropriate national projections. Results: A total of 159,065 records were identified using our inclusion and exclusion criteria, corresponding to 778,427 admissions nationally. The in-hospital mortality rate for all patients was 5.9%. Most common documented sources of infections were respiratory (24.3%), followed by urinary tract infections (13.2%), intraabdominal infections (7.6%), and skin and soft tissue infections (7.1%). Overall, sepsis was present in about quarter of the admissions, while acute kidney injury and respiratory failure were also prevalent (13.2% and 6.9%, respectively). On regression analysis, older age (OR 1.026; 95% CI, 1.025 - 1.027; P &amp;lt;0.001), heart failure (OR 1.90; 95% CI, 1.84 - 1.96; P &amp;lt;0.001), liver disease (OR 1.64; 95% CI, 1.56 - 1.72; P &amp;lt;0.001), chronic kidney disease (OR 1.325 95% CI, 1.30 - 1.39; P &amp;lt;0.001), coagulopathy (OR 1.67; 95% CI, 1.64-1.71; P &amp;lt;0.001), and metastatic disease (OR 1.70; 95% CI, 1.65- 1.74; P &amp;lt;0.001), were independent predictors of increased in-hospital mortality among patients admitted with febrile neutropenia, whereas female sex was associated with relatively favorable outcome (OR 0.93; 0.92-0.95; P &amp;lt;0.001). Based on the source of infection that was documented during admission, we found respiratory infections (OR 1.27; 95% CI, 1.24-1.30; P &amp;lt;0.001), meningoencephalitis (OR 1.23; 95% CI, 1.12-1.36; P &amp;lt;0.001), and systemic mycosis (OR 1.28; 95% CI, 1.24-1.32; P &amp;lt;0.001) were associated with worse outcome, while patients who had urinary (OR 0.75; 95% CI, 0.72-0.78; P &amp;lt;0.001) or soft tissue source of infection (OR 0.75; 95% CI, 0.71-0.79; P &amp;lt;0.001), or neutropenic enterocolitis (OR 0.91; 95% CI, 0.84-0.98; P &amp;lt;0.001) had a relatively better outcome. In terms of complications during admission, we found the occurrence of acute kidney injury (OR 2.13; 95% CI, 2.07-2.18; P &amp;lt;0.001), sepsis (OR 2.39; 95% CI, 2.32-2.45; P &amp;lt;0.001), septic shock (OR 3.25; 95% CI, 3.14-3.35; P &amp;lt;0.001), acute encephalopathy (OR 1.71 95% CI, 1.63-1.79; P &amp;lt;0.001), and acute respiratory failure (OR 9.98; 95% CI, 9.71-10.24; P &amp;lt;0.001) were associated with higher mortality. Conclusion: Despite the advances in risk stratification and frequent use of unified protocols that incorporate prophylactic growth factors in the therapeutic regimens, incidence of in-hospital mortality of febrile neutropenia appears to be unchanged over the decade between 2008 and 2017. We identified older age, metastatic disease, presence of chronic heart failure, liver disease, chronic kidney disease, coagulopathy, presence of acute kidney injury, sepsis, acute respiratory failure, encephalopathy, and septic shock as independent predictors of increased in-hospital mortality among patients admitted with febrile neutropenia. Further studies are needed to further explore predictors of poor outcomes in those patients. Figure Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

A Focused Review on Advances in Risk Stratification of Malignant Polyps.

Colorectal cancer is the third most common cancer in both men and women in the United States, with most cases arising from precursor adenomatous polyps. Colorectal malignant polyps are defined as cancerous polyps that consist of tumor cells invading through the muscularis mucosae into the underlying submucosa (pT1 tumor). It has been reported that approximately 0.5-8.3% of colorectal polyps are malignant polyps, and the potential for lymph node metastasis in these polyps ranges from 8.5% to 16.1%. Due to their clinical significance, recognition of malignant polyps is critical for clinical teams to make treatment decisions and establish appropriate surveillance schedules after local excision of the polyps. There is a rapidly developing interest in malignant polyps within the literature as a result of an increasing number of identifiable adverse histologic features and recent advancements in endoscopic treatment techniques. The purpose of this paper is to have a focused review of the recent histopathologic literature of malignant polyps.

Immunotherapy in pediatric acute lymphoblastic leukemia.

The 5-year survival rate for children and adolescents with acute lymphoblastic leukemia (ALL) has improved to more than 90% in high-income countries. However, further increases in the intensity of conventional chemotherapy would be associated with significant adverse effects; therefore, novel approaches are necessary. The last decade has seen significant advances in targeted therapy with immunotherapy and molecular therapeutics, as well as advances in risk stratification for therapy based on somatic and germline genetic analysis and monitoring of minimal residual disease. For immunotherapy, the approval of antibody-based therapy (with blinatumomab in 2014 and inotuzumab ozogamicin in 2017) and T cell-based therapy (with tisagenlecleucel in 2017) by the US Food and Drug Administration has significantly improved the response rate and outcomes in patients with relapsed/refractory B-ALL. These strategies have also been tested in the frontline setting, and immunotherapy against a new ALL-associated antigen has been developed. Incorporating effective immunotherapy into ALL therapy would enable the intensity of conventional chemotherapy to be decreased and thereby reduce associated toxicity, leading to further improvement in survival and quality of life for patients with ALL.

Advances in risk stratification of bladder cancer to guide personalized medicine.

Bladder cancer is a heterogeneous disease that poses unique challenges to the treating clinician. It can be limited to a relatively indolent papillary tumor with low potential for progression beyond this stage to muscle-invasive disease prone to distant metastasis. The former is best treated as conservatively as possible, whereas the latter requires aggressive surgical intervention with adjuvant therapies in order to provide the best clinical outcomes. Risk stratification traditionally uses clinicopathologic features of the disease to provide prognostic information that assists in choosing the best therapy for each individual patient. For bladder cancer, this informs decisions regarding the type of intravesical therapy that is most appropriate for non-muscle-invasive disease or whether or not to administer neoadjuvant chemotherapy prior to radical cystectomy. More recently, tumor genetic sequencing data have been married to clinical outcomes data to add further sophistication and personalization. In the next generation of risk classification, we are likely to see the inclusion of molecular subtyping with specific treatment considerations based on a tumor’s mutational profile.

Intensified induction therapy with reduced total anthracycline exposure in pediatric low-risk acute myeloid leukemia.

10533 Background: Despite advances in risk stratification and therapy, the post-induction disease free survival (DFS) and overall survival (OS) for children with low-risk acute myeloid leukemia (LR-AML) remain low with DFS and OS of 50% and 68%, respectively, on the standard arm of the recent Children’s Oncology Group (COG) trial, AAML1031. Additionally, current therapy for pediatric LR-AML contains anthracycline doses exceeding thresholds known to increase the risk of adverse cardiac effects. In an effort to decrease exposure to cardiotoxic therapy, the Aflac Cancer and Blood Disorders Center adopted an institutional practice to treat LR-AML patients with a regimen of intensified induction therapy with decreased anthracycline exposure (Aflac-AML consisting of ADE10, Mitox/HiDAC, HiDAC/VP, Capizzi II). The aim of this study is to describe the associated toxicities and outcomes of this regimen in pediatric LR-AML. Methods: We retrospectively reviewed medical records of patients diagnosed with de novo LR-AML and treated per the Aflac-AML regimen from 2011-2014. Charts were reviewed for cardiac outcomes, ICU admissions, and the rate of infectious toxicities. DFS and OS were determined using Kaplan-Meier survival analysis. Results: We identified 11 LR-AML patients treated with Aflac-AML therapy. Patients received a planned 317 mg/m2 cumulative anthracycline dose vs 442 mg/m2for those treated on AAML1031. There was no decrease in LVEF with a mean change of +2.17% for Aflac-AML patients from the time of diagnosis to therapy completion (p = 0.23). The primary infectious toxicities observed were febrile neutropenia and bacterial infections with a median of 36.4±6% documented bacterial infections per cycle. Fungal and viral infections were rare as were ICU admissions – median 4.5±4% per cycle – and there were no toxic mortalities. The 3-year DFS and OS from end of induction I for Aflac-AML patients were 72.7% and 90.9%, respectively. Conclusions: The Aflac-AML regimen resulted in short-term toxicities and outcomes comparable to current chemotherapy regimens for pediatric LR-AML but with reduced anthracycline exposure. These data support use of this regimen for pediatric LR-AML patients.

State-of-the-Art Pulmonary CT Angiography for Acute Pulmonary Embolism.

Pulmonary CT angiography (CTA) is the imaging modality of choice in suspected acute pulmonary embolism (PE). Current pulmonary CTA techniques involve ever lower doses of contrast medium and radiation along with advanced postprocessing applications to enhance image quality, diagnostic accuracy, and provide added value in patient management. The objective of this article is to summarize these current developments and discuss the appropriate use of state-of-the-art pulmonary CTA. Pulmonary CTA is well established as a fast and reliable means of excluding or diagnosing PE. Continued developments in CT system hardware and postprocessing techniques will allow incremental reductions in radiation and contrast material requirements while improving image quality. Advances in risk stratification and prognostication from pulmonary CTA examinations should further refine its clinical value while minimizing the potential harm from overutilization and overdiagnosis.

Atrial fibrillation in patients with diabetes: molecular mechanisms and therapeutic perspectives.

Atrial fibrillation (AF) remains the most frequent sustained cardiac arrhythmia worldwide and its incidence increases with ageing, cardiovascular risk factors and comorbidities. Prevalence of diabetes mellitus (DM) is growing fast and is assuming pandemic proportions mostly due to overnutrition and sedentary habits. Experimental and clinical evidences suggest that DM and AF are strongly interconnected. The present review addresses in detail new molecular pathways implicated in the etiology of AF and their relevance for mechanism-based therapeutic strategies in this setting. Advances in risk stratification, drug therapy (i.e., novel anticoagulants) and catheter ablation are also described.

THE TREATMENT FOR RELAPSED AND REFRACTORY FORMS OF ACUTE MYELOID LEUKEMIA

The review focuses on relapse and refractory forms of acute myeloid leukemia, which is a heterogeneous disease and does not have a single universal therapeutic scheme. The paper presents the characteristics of protocols with inclusion of new agents, shows the role of allogenic hematopoietic stem cell transplantation and advances in risk stratification for the treatment for acute myeloid leukemia. The prospects of the therapy personalization based on molecular tests have been determined. The application of more effective induction and post-remission protocols shows a guaranteed reduction in the relapse rate.