Differential diagnosis of spontaneous intracranial hemorrhage in young

In recent years, cerebral vascular diseases have been increasingly detected in young patients. It is due not only to better physicians’ knowledge about this pathology, but also to the improvement of its diagnosis methods. Modern neuroimaging techniques allow us to clarify the nature of hemorrhage, to determine the volume and location of intracerebral hematoma, and to establish the degree of concomitant edema and dislocation of the brain. However, despite the high accuracy of the research, it is not always possible to establish the cause that led to a brain accident, which greatly affects the tactics of management and outcomes in this category of patients. A special feature of the structure of cerebrovascular diseases of young people is the high proportion of hemorrhagic stroke, the causes of which are most often arterio-venous malformations. Meanwhile, there are a number of other causes that can lead to hemorrhage into the brain substance. These include disorders of blood clotting, and various vasculitis, and exposure to toxic substances and drugs, and tumor formations (primary and secondary). All these pathological factors outline the range of diagnostic search in young patients who underwent hemorrhagic stroke. Diagnosis of these pathological conditions with the help of modern visualization techniques is considered to be easy, but this is not always the case. In this article, the authors give their own clinical observation of a hemorrhagic stroke in a young patient, which demonstrates the complexity of the diagnostic search in patients with this pathology.

Abstract 13829: Index Event, Clinical Outcomes and Response to Vericiguat in the Victoria Trial

Introduction: The VICTORIA (Vericiguat Global Study in Subjects with HF with Reduced EF) trial included 5050 patients in 3 discrete subgroups reflecting their index worsening heart failure (HF) event: <3 months after HF hospitalization (HFH) (n=3366), 3-6 months after HFH (n=871), and those requiring IV diuretic therapy without HFH within the prior 3 months (n=813). We evaluated clinical characteristics, outcomes and treatment response to vericiguat across these index event subgroups in VICTORIA. Methods: We compared primary composite (CV death and HFH) and secondary (all-cause death and HFH) outcomes across index event subgroups, both before and after adjusting for clinical covariates (HF duration, NYHA class, medical history, heart rate, HF medications and laboratory values including baseline NT-proBNP), as well as their response to vericiguat. Results: Baseline characteristics were balanced between treatment arms within each subgroup. Over a median follow up of 10.8 months, the absolute primary event rates were high in all subgroups (20.5 - 42.5 per 100 patient-years, Figure). Compared to the IV diuretic group highest relative risk was in HFH <3 months (HR 1.69, 95% CI 1.46-1.95), followed by HFH 3-6 months (HR 1.26, 95% CI 1.06-1.50). After multivariable adjustment, this difference remained significant only in HFH <3 months (adjusted HR [vs IV diuretic] 1.47, 95% CI 1.26-1.72). Vericiguat was associated with reduced risk of the primary outcome overall (HR 0.90, 95% CI 0.82-0.98) and in all 3 subgroups, with no evidence of treatment heterogeneity. Similar results were evident for the secondary composite outcome. Conclusions: Among patients with worsening chronic HF, those within a 3 month window of HFH had almost a 1.5 times risk of CV death or HFH compared to those requiring IV diuretics but not HFH , irrespective of age or clinical risk factors. Vericiguat added to standard therapy was associated with similar benefit across the spectrum of risk in worsening HF.

Selected intriguing forms of treatment for chronic heart failure – data from international observational registries

The presented paper gathers the results of three publications based on prospective, international, observation registries of patients with heart failure (HF) – HF Pilot, HF Long-Term and QUALIFY (The quality of adherence to guideline recommendations for life-saving treatment in heart failure). The aim of the analysis was to assess the effect of beta-blockers on prognosis in HF with associated atrial fibrillation; to compare the effectiveness of furosemide and torasemide in HF; and to assess the adherence of physicians in Poland to European recommendations. 797 patients were included in the analysis assessing the effects of beta-blockers. Patients with a beta blocker compared to those without were less likely to achieve primary (all-cause death; 10.9% vs 25.6%, p = 0.001) and secondary (all-cause death or HF hospitalization; 30.6% vs 44.2%, p = 0.02) endpoints. Beta-blocker was an independent predictor of only the primary endpoint (HR 0.52; 95% CI, 0.31–0.89; p = 0.02). Both endpoints were least frequently observed in the group with a heart rate of 80–109/min. In the group of 1440 patients with HF, it was shown that patients treated with torasemide compared to furosemide were less likely to experience secondary (death from any cause or HF hospitalization; 26.4% vs 34.7%; p = 0.04), but not primary (death from any cause; 9.8% vs 14.1%; p = 0.13) endpoint. Patients treated with furosemide also had a greater severity of HF symptoms in NYHA class (p = 0.04). Adherence of physicians in Poland to HF treatment guidelines was also analyzed. An analysis of 209 HF outpatients with reduced left ventricular ejection fraction showed a satisfactory adherence to the recommended HF therapy in 72% of cases.

AMARTYA SEN’S CRITIQUE OF THE RAWLSIAN THEORY OF JUSTICE: AN ANALYSIS

Purpose: The present paper tries to cross-examine Sen’s notion of justice and to find a midway between the ideal and non-ideal theorizing of justice. Besides, searching for reconciliation between Rawls and Sen, the present paper also attempts to go beyond Sen, while critically engaging with his idea of justice. Methodology: This study has applied qualitative method; however, both the historical and analytical methods are employed for reaching out the conclusive findings of the study. As the sources of this paper are basically secondary, all necessary and relevant materials are collected from a range of related books, articles, journals, newspapers, and reports of various seminars and conferences that fall within the domain of the study area. Main Findings: While analyzing Sen’s critique of Rawlsian theory, the study finds that the Rawlsian theory cannot be discarded only as a theory that formulates ideal justice and is not redundant. The study while revisiting Sen’s notion finds that there is also a possibility of reconciliation between ideal and non-ideal theorizing of justice. Application: This study will be useful in understanding the debate between ideal versus non-ideal theories of justice that has lately been haunting the political philosophy. Besides, it will also be useful in searching for reconciliation between Rawls’ and Sen’s paradigms of justice and thereby offering a conception of justice that is reasonable and true in assessing issues of justice in the present scenario. Novelty/ Originality: Revisiting Sen’s notion of justice and analyzing such dimensions of politics, the study will benefit the reader to evaluate the debate between ideal versus non-ideal theorizing of justice. Moreover, by searching for a possibility between Rawls and Sen, the study will contribute towards developing an alternative approach and understanding of justice.

Clinical Outcome of De Novo Adult Acute Lymphoblastic Leukemia (ALL) with 11q23/Mixed Lineage Leukemia (MLL) Gene Rearrangements

Introduction: The MLL gene on located on 11q23 plays an essential role in positive regulation of gene expression in early embryonic development and hematopoiesis. Fusion genes, such as MLL-AF4 resulting from t(4:11)(q21;q23), alter normal cellular proliferation and differentiation, favoring leukemogenesis. The DOT1L histone methyltransferase associated with MLL appears to be required for maintenance of ALL. MLL-AF4 is detected in about 10% of de novo B-lymphoblastic leukemia or 30=40% of pro-B ALL subtypes. The 11q23/MLL subtype of ALL has been associated with extremely poor outcomes. We conducted a retrospective analysis of de novo adult ALL with 11q23/MLL gene rearrangements. Methods: Overall the database included 74 pts with 11q23/MLL gene rearrangements referred to our institution between 1980 and 2014. Of these, 20 (27%) pts were relapsed/refractory, 4 (5%) were minimally pretreated, 5 (7%) were inevaluable for response, 3 (4%) had concomitant Philadelphia chromosome, 2 (3%) were T-lineage, 2 (3%) were mature B-ALL. The remaining 38 cases comprised the study cohort evaluated with respect to pretreatment characteristics and outcome measures such as response to therapy, remission duration (CRD), and survival (OS). Results: Baseline characteristics of the cohort included median age 44 yrs (range, 20-75); 26% were older than 60 yrs. Ten (26%) pts had a prior malignancy and were designated secondary ALL. Five (13%) pts had CNS disease at presentation. Median WBC count was 69.8 K/uL (range, 0.5-612); 24 (63%) pts had WBC > 30 K/uL. Nineteen (50%) pts had serum LDH > 1400 U/L. Co-expression of myeloid markers (CD13, CD33 +/- CD117) was noted in 6 (16%) pts. Distribution of the 11q23/MLL gene aberrancies were: t(4;11) (q21; q23) in 25 (66%) pts, 11q23 without translocation partner in 10 (26%) pts, and t(11;19)(q23;p13.1) in 3 (8%) pts. Thirty two (84%) pts were treated per the hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high dose methotrexate and cytarabine) regimen (3 [10%] received concurrent rituximab) and 6 (16%) pts were treated per the augmented BFM regimen. Overall response rate was 95%; complete remission (CR) in 92% and CR without platelet recovery (CRp) in 3%. Overall median CRD was 26.3 mos (range 0.2-93+ mos); median OS was 24.2 mos. Overall, the 5-yr CRD and OS rates were 19% and 26%, respectively, with a median follow-up of 60 mos (range, 4.8-173+ mos). Median OS in pts with 11q23 without chromosomal translocation was 48.5 mos, compared with 24 mos for t(11; 19) and 13.3 mos for t(4; 11) (p= 0.07) (Fig. 1). There were no differences in outcomes by older age or designation as secondary ALL. Conclusion: The 11q23/MLL positive B-lymphoblastic subsets are associated with differentially inferior outcomes, although MLL-AF4 remains the ALL subset associated with highest risk of disease recurrence particularly in the absence of allogeneic stem cell transplantation; the relatively rarity of these subsets poses challenges in establishing the optimal treatment strategies. Therapeutic approaches incorporating hypomethylating agents, histone deacetylase inhibitors, and CAR-T cells could improve these dismal outcomes; targeted agents such as DOT1L inhibitors are under investigation in clinical trials. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Secondary ALL May be Independent of Prior Cytotoxic Therapy

Background: Little is known about secondary acute lymphoblastic leukemia (ALL). The entity 'secondary ALL', refers to a diagnosis of ALL following a previous malignancy and includes 2 types of patients: those who received chemo-/radio-therapy for their prior malignancy (therapy-associated ALL, t-ALL) and those who did not (antecedent-malignancy ALL, am-ALL). This retrospective single center study describes a cohort of secondary ALL patients and assesses the features of t-ALL and am-ALL. Methods: Patients included in this study were treated for ALL at Memorial Sloan Kettering Cancer Center (MSKCC), in the years 1993-2013. Inclusion criteria were a diagnosis of ALL and a history of any previous malignancy, irrespective of whether therapy was given for the prior malignancy. Patients with Burkitt leukemia or non-melanoma skin cancer were excluded. Fisher's exact test, Wilcoxon rank-sum test and Kaplan-Meier methodology were used. Results: Thirty two patients with secondary ALL were identified representing 3.8% of all ALL patients treated at MSKCC during these 20 years. Among 328 adults (age>21 yrs) the incidence was 8.8%. Of the 32 patients 25% had a history of breast cancer (n=8), 19% lymphoma or myeloma (n=6) and 16% colorectal cancer (n=5). Thirty one of B ALLs (91%) were CALLA positive (CD10+). Thirteen patients (56%) received both chemotherapy and radiotherapy, 6 (26%) only chemotherapy, 2 (9%) - radiotherapy only and another 2 (9%) received radioactive iodine for thyroid carcinoma. In the t-ALL group, 89% of chemotherapy recipients received alkylating agents for their first malignancy and 47% received topoisomerase II inhibitors. The table summarizes the characteristics, complete response (CR) rate and overall survival (OS) of the whole cohort as well as a comparison between t-ALL and am-ALL. No significant difference between groups was found regarding the incidence of B/T ALL, extramedullary disease (EMD), WBC counts, LDH level, incidence of Ph+ ALL, CR rate and OS. The estimated 3- year OS for the entire cohort was 20%. Conclusion: Although as far as we knowthis is the largest reported study of secondary ALL, the overall number is small and should be interpreted with caution. The overall incidence of secondary ALL is not low among adults (8.8%) while secondary T-cell ALL is very rare. In contrast to previous reports, most of the secondary ALLs are CALLA-positive and do not have MLL abnormalities. Radioactive iodine may be associated with development of secondary ALL. The similar characteristics and behavior of t- and am-ALL patients, together with high incidence of family-malignancy in both groups raise the possibility that secondary ALL patients may have an inherent predisposition to develop more than one malignancy and a history of previous therapy may be of lesser importance in the pathogenesis of secondary ALL. Molecular genetic profiling of secondary ALL patients, in the future, may provide insights into this issue. The long-term survival of secondary ALL patients appears similar to other ALL patients of the same age, thus the diagnosis of secondary ALL should not impact on the therapeutic strategy. Abstract 3648 Characteristics of secondary ALL, t-ALL and am-ALL Combined t-ALL am-ALL P N=32 N=23 N=9 Age at 1st malignancy Dx, yrs med. (range) 46 (2.4-83) 44 (2.4-75) 73 (18-83) .01 Age at ALL Dx, yrs med. (range) 55.5 (3.3-83) 52 (3.3-76) 75 (23-83) .01 Male, n (%) 17 (53) 10 (43) 7 (78) .12 Malignancy in 1st degree relative 15/26 (58) 11/19 (58) 4/7 (57) .99 1st malignancy, n (%) .39 Carcinoma 20 (63) 13 (57) 7 (78) Hematologic 5 (16) 5 (22) 0 Other 7 (22) 5 (22) 2 (22) Interdiagnoses interval, yrs med. (range) 5.33 (0.1-28) 7 (0.75-28) 4 (0.1-16) .06 B-ALL, n (%) 28/31 (90) 20/23 (87) 8/8 (100) .55 EMD, n (%) 9 (28) 7 (30) 2 (22) .99 Blood tests at diagnosis WBC, med. (range) 5.2 (0.4-90.6) 6.9 (0.7-68.4) 5.1 (0.4-90.6) .60 ANC, med. (range) 1.2 (0.1-13) 0.95 (0.1-13) 2.1 (0.2-12.1) .76 HgB, med. (range) 10.1 (5.9-14.9) 10.4 (8.1-14.9) 8.6 (5.9-12.8) .23 PLT, med. (range) 48 (11-251) 43 (20-212) 106 (11-251) .49 LDH, med. (range) [N 60-200] 360 (61-866) 371 (61-858) 273 (181-866) .87 Cytogenetics t(9,22) 12 (38) 8 (35) 4 (44) .68 Hyperdiploid 5 (16) 4 (17) 1 (11) - del 7/7p 6 (19) 4 (17) 2 (22) - del11q23 (MLL) 2 (06) 2 (09) 0 - t(4,11) 2 (06) 2 (09) 0 - CR, n (%) 25/26 (96) 18/19 (95) 7/7 (100) .99 OS .97 12 months, (95% CI) 0.49 (0.33-0.72) 0.41 (0.24-0.69) 0.71 (0.45-0.99) 24 months, (95% CI) 0.25 (0.12-0.49) 0.29 (0.14-0.59) 0.14 (0.02-0.88) Disclosures Stein: Seattle Genetics, Inc.: Research Funding; Janssen Pharmaceuticals: Consultancy.

Gain-of-Function WASP Mutations in Pediatric and Adult Patients with Myelodysplasia or AML.

X-linked neutropenia (XLN, OMIM #300299)) was first described in 2001 in a three-generation Belgian family with five affected members and with a L270P gain-of-function mutation in the GTPase binding domain (GBD) of the Wiskott-Aldrich-syndrome protein (WASP) (Nat Genet2001,27,313). Although all five L270P cases originally presented with neutropenia, two of them eventually developed a myeloid malignancy while under G-CSF, with monosomy 7 in the malignant cells. One male (II.3) developed a myelodysplastic syndrome (MDS-RAEB) at age 65, achieved stable remission after three courses of decitabine, but died three years later due to an unrelated cause. A second patient (III.6) succumbed to refractory MDS RAEB, rapidly evolving to MDS-RAEBt at age 38. Since our original report, two more cases with XLN have been reported, one with a I294T and one with a S272P WASP mutation. (Ancliff et al. Blood online 2006). The I294T case, 4 years old, had myelodysplastic features at presentation. These observations have prompted us to investigate whether inherited gain-of-function WASP mutations are associated with paediatric MDS or AML. In addition we have explored whether acquired WASP mutations occur in adult myeloid malignancies. 207 cases were examined. Male/female ratio was 1.35. 34 cases were between 2 months and 20 years old and 173 cases were between 21 and 89 years old. There were 48 cases with myelodysplasia, 157 had acute myeloid leukaemia and 2 had myelofibrosis. 29% had monosomy 7. There were two brothers with monosomy 7, one with AML M5 and the other with secondary ALL after MDS. Exons 7-10, encoding the GTPase Binding Domain (residues 230-381), were amplified and screened for mutations using dHPLC. In these 207 samples from patients with MDS or AML, no mutations were found in the exons 7-9 of the WAS gene. One mutation was found in intron 6 in a male patient with AML and monosomy 7. The mutation did not influence splicing of the exon and was thus considered irrelevant. Four patients had a known T1029C (V332A) single nucleotide polymorphism in exon 10. One patient with AML (age 50y) had a C975T (P314S) mutation in exon 10, which has not been reported previously. Since this mutation occurs in less than 1%, it does not qualify as a polymorphism. If relevant for the pathogenesis of AML, the mutation is very rare whatsoever. Although the eventual risk of malignant myeloid transformation appears to be increased in L270P XLN, we could not, with one exception, identify mutations in exons 7-10 of the WAS gene in this series of paediatric and adult MDS/AML. Therefore, inherited or acquired WAS mutations do not seem to be commonly associated with pediatric or adult MDS or AML. Our data therefore do not support screening for exon 7-10 mutations of WAS in the context of paediatric or adult MDS and AML.