Pediatric Erythroid Sarcoma Diagnostically Confirmed by Identification of a Recurrent NFIA::CBFA2T3 Fusion.

Erythroid sarcoma (ES) is exceedingly rare in the pediatric population with only a handful of reports of de novo cases, mostly occurring in the central nervous system (CNS) or orbit. It is clinically and pathologically challenging and can masquerade as a nonhematopoietic small round blue cell tumor. Clinical presentation of ES without bone marrow involvement makes diagnosis particularly difficult. We describe a 22-month-old female with ES who presented with a 2-cm mass involving the left parotid region and CNS. The presence of crush/fixation artifact from the initial biopsy made definitive classification of this highly proliferative and malignant neoplasm challenging despite an extensive immunohistochemical workup. Molecular studies including RNA-sequencing revealed a NFIA::CBFA2T3 fusion. This fusion has been identified in several cases of de novo acute erythroid leukemia (AEL) and gene expression analysis comparing this case to other AELs revealed a similar transcriptional profile. Given the diagnostically challenging nature of this tumor, clinical RNA-sequencing was essential for establishing a diagnosis.

Clinical and genomic characterization of an ATRA-insensitive acute promyelocytic leukemia variant with a FNDC3B::RARB fusion.

The promyelocytic leukemia-retinoic acid receptor-α (PML::RARA) fusion is the hallmark of acute promyelocytic leukemia (APL) and is observed in over 95% of APL cases. RARA and homologous receptors RARB and RARG are occasionally fused to other gene partners, which differentially affect sensitivity to targeted therapies. Most APLs without RARA fusions have rearrangements involving RARG or RARB, both of which frequently show resistance to all-trans-retinoic acid (ATRA) and/or multiagent chemotherapy for acute myeloid leukemia (AML). We present a 13-year-old male diagnosed with variant APL with a novel FNDC3B::RARB in-frame fusion that showed no response to ATRA but responded well to conventional AML therapy. While FNDC3B has been identified as a rare RARA translocation partner in ATRA-sensitive variant APL, it has never been reported as a fusion partner with RARB and it is only the second known fusion partner with RARB in variant APL. We also show that this novel fusion confers an RNA expression signature that is similar to APL, despite clinical resistance to ATRA monotherapy.

Decision of Anticoagulation in Nonvalvular Atrial Fibrillation in the Real World in the Non-Antivitamin K Anticoagulants Era.

Background. Patients with nonvalvular atrial fibrillation (NVAF) have five times higher risk of stroke than the general population. Anticoagulation (ACO) in NVAF is a class I indication after assessing the CHA2DS2-VASc and HAS-BLED scores. However, in the real world, NVAF patients receive less ACO than needed due to patients' comorbidities that can be assessed by the Charlson comorbidity index (CCI). The use of non-antivitamin K anticoagulants (NOAC) has improved the decision to anticoagulate. Objective. We analyzed the factors influencing the ACO prescribing decision in NVAF patients in the real world and the changes induced by the introduction of NOAC. Method. We carried out an observational retrospective cross-sectional study that included consecutive patients with permanent NVAF and CHA2DS2-VASc ≥ 2, admitted to a community hospital between 2010-2011 (group 1, 286 patients), when only vitamin K antagonists (VKA) were used, and 2018-2019 (group 2, 433 patients), respectively. We calculated CHA2DS2-VASc, HAS-BLED, and CCI and recorded the ACO decision and the use of VKA or NOAC in group 2. We compared the calculated scores between ACO and non-anticoagulated (nonACO) patients in both groups and between groups. Results. A 31.5% share of patients in group 1 and 12.9% in group 2 did not receive ACO despite a CHA2DS2-VASc score ≥ 2. In group 1, nonACO patients had higher HAS-BLED and CCI scores than the ACO patients, but their CHA2DS2-VASc scores were not significantly different. Old age, dementia, severe chronic kidney disease, neoplasia, and anemia were the most frequent reasons not to prescribe anticoagulants. In group 2, more nonACO patients had dementia, diabetes mellitus, and higher HAS-BLED than ACO patients. Moderate-severe CKD, neoplasia with metastasis, liver disease, anemia, and diabetes mellitus were statistically significantly more frequent in nonACO patients from group 1 than those from group 2. In group 2, 55.7% of ACO patients received NOAC. Conclusions. In real-world clinical practice, the decision for anticoagulation in NVAF is influenced by patient age, comorbidities, and risk of bleeding, and many patients do not receive anticoagulants despite a high CHA2DS2-VASc score. The use of NOAC in the past few years has improved treatment decisions. At the same time, the correct diagnosis, treatment, and surveillance of comorbidities have cut down the risk of bleeding and allowed anticoagulant use according to guidelines.

VpreB surrogate light chain expression in B-lineage ALL: a report from the Children's Oncology Group.

Immunotherapies directed against B-cell surface markers have been a common developmental strategy to treat B-cell malignancies. The immunoglobulin heavy chain surrogate light chain (SLC), comprising the VpreB1 (CD179a) and Lamda5 (CD179b) subunits, is expressed on pro- and pre-B cells, where it governs pre-B-cell receptor (BCR)-mediated autonomous survival signaling. We hypothesized that the pre-BCR might merit the development of targeted immunotherapies to decouple "autonomous" signaling in B-lineage acute lymphoblastic leukemia (B-ALL). We used the Children's Oncology Group (COG) minimal residual disease (MRD) flow panel to assess pre-BCR expression in 36 primary patient samples accrued to COG standard- and high-risk B-ALL studies through AALL03B1. We also assessed CD179a expression in 16 cases with day 29 end-induction samples, preselected to have ≥1% MRD. All analyses were performed on a 6-color Becton-Dickinson flow cytometer in a Clinical Laboratory Improvement Amendment/College of American Pathologist-certified laboratory. Among 36 cases tested, 32 cases were at the pre-B and 4 cases were at the pro-B stages of developmental arrest. One or both monoclonal antibodies (mAbs) showed that CD179a was present in ≥20% of the B-lymphoblast population. All cases expressed CD179a in the end-induction B-lymphoblast population. The CD179a component of the SLC is commonly expressed in B-ALL, regardless of genotype, stage of developmental arrest, or National Cancer Institute risk status.

Androgen Deprivation Therapy, Hypogonadism and Cardiovascular Toxicity in Men with Advanced Prostate Cancer.

Androgen deprivation therapy (ADT) is successfully used in patients with advanced prostatic cancer, but there are many concerns about its systemic side effects, especially due to advanced age and frequent comorbidities in most patients. In patients treated with ADT there are metabolic changes involving the glycaemic control and lipid metabolism, increased thrombotic risk, an increased risk of myocardial infarction, severe arrhythmia and sudden cardiac death. Still, these adverse effects can be also due to the subsequent hypogonadism. Men with heart failure or coronary artery disease have a lower level of serum testosterone than normal men of the same age, and hypogonadism is related to higher cardiovascular mortality. Many clinical studies compared the cardiovascular effects of hypogonadism post orchiectomy or radiotherapy with those of ADT but their results are controversial. However, current data suggest that more intensive treatment of cardiovascular risk factors and closer cardiological follow-up of older patients under ADT might be beneficial. Our paper is a narrative review of the literature data in this field.

Subclinical left ventricular dysfunction in men under androgen deprivation therapy for prostate cancer, revealed by speckle-tracking-derived parameters, repolarization, and myocardial injury markers.

OBJECTIVE: To analyze global left ventricular longitudinal strain (GLS), mechanical dispersion (MD), electrocardiographic repolarization, and myocardial injury markers changes during androgen deprivation therapy (ADT) and subsequent hypogonadism in men with advanced prostate cancer. METHODS: We included 31 patients 69.7 ± 7.3 years old, in sinus rhythm, with stable cardiac conditions and evaluated them by echocardiography, electrocardiography, and blood sampling for high sensitivity cardiac troponin I (hs-cTnI), and N-terminal pro-brain natriuretic peptide (NTproBNP), at ADT initiation (M0) and after 6 months of treatment (M1). Peak longitudinal strain by speckle-tracking echocardiography was assessed in 17 left ventricular segments and averaged to GLS. Standard deviation of time intervals from the start of Q/R on electrocardiogram to peak longitudinal strain in the 17 segments (MDSD ), and the difference between the longest and shortest time-to-peak strain intervals (MDdelta ) were calculated as indices of MD. Fridericia corrected electrocardiographic repolarization parameters were analyzed as follows: QT interval (QTc), mean and maximum values of Tpeak-Tend interval (Tpe), and Tpe/QT ratio, Tpe dispersion (Tped). RESULTS: Significant impairments of the following parameters were registered between M0 and M1: GLS (%) (-16.93 ± 3.89; -14.43 ± 3.57, P < .001), MDSD (ms) (77.4 ± 21.4; 89 ± 27, P = .004), MDdelta (ms) (225.3 ± 78.3; 259.9 ± 108.4, P = .02), QTc (ms) (458.8 ± 43.4; 485.6 ± 45.1, P = .01), maxTpe/QT (0.246 ± 0.04; 0.268 ± 0.04, P = .01), maxTpe (ms) (105.4 ± 23.2; 119.5 ± 26.4 P = .01), meanTpe (ms) (83.3 ± 16.8; 90.7 ± 19.3, P = .02), and hs-cTnI (ng/mL) (4.6 ± 5.4; 5.4 ± 6.4, P = .01). Mean serum testosterone level at M1 was 0.1 ± 0.13 ng/mL. The patients' clinical cardiological status remained stable during follow-up. CONCLUSIONS: ADT and subsequent hypogonadism induce subclinical alterations in GLS, MD, electrocardiographic repolarization parameters, and hs-cTnI during the first 6 months of treatment.

Mutual Information Reveals Non-linear Relationships between Electrocardiographic Conduction or Repolarization Indices and Mechanical Dispersion by Speckle-Tracking Echocardiography in the General Population.

Electrical inhomogeneities can lead to regional heterogeneity in left ventricular contraction. We investigated the correlation between electrocardiographic parameters of conduction and/or repolarization and myocardial longitudinal strain-derived parameters in a general population. Mean and dispersion (maximum-minimum) values were calculated for the electrocardiographic indices: QT interval, Tpeak-Tend interval (Tpe), JTpeak interval (JTp), JTend interval (JTe), QTpeak interval (QTp). Mechanical dispersion was assessed using the standard deviation (SD) of time-to-peak longitudinal strains (MDSD) and the difference between the longest time and shortest time to peak strain (MDdelta) by speckle-tracking echocardiography. A total of 59 patients, 60 ± 12 y, were included. Tpe, Tpe/QT, Tpe/JTp and Tpe/JTe correlated well with MDSD and MDdelta (r ≥ 0.43, p < 0.001). Mutual information revealed significant non-linear relationships between most of the electrocardiographic indices measured and mechanical dispersion. In conclusion, there is a moderate linear correlation between electrocardiographic indices reflecting repolarization heterogeneities and speckle tracking-assessed mechanical dispersion.

Evolution of Electrocardiographic Repolarization Parameters During Antiandrogen Therapy in Patients with Prostate Cancer and Hypogonadism.

We assessed the effects of antiandrogen therapy on ECG parameters of ventricular repolarization related to arrhythmic risk in 35 patients aged 70.3 ± 7 years with advanced prostate cancer treated with degarelix associated with enzalutamide (group A, 26 patients) or degarelix monotherapy (group B, 9 patients). We analyzed Fridericia corrected Q-T interval (QTc), Q-T dispersion (QTd), J-Tpeak interval (JTp), mean and maximum Tpeak-Tend interval (Tpe) and Tpe/QT ratio, Tpeak-Tend dispersion (Tped), index of cardio-electrophysiological balance (iCEB) from ECG tracings, and occurrence of ventricular premature beats (VPB) recorded by Holter ECG, before initiation of medication (M0) and after 6 months of treatment (M1). The groups had similar demographics except for a higher prevalence of prior myocardial infarction in group B (p = 0.01). All patients had low serum testosterone at M1. Baseline QTc, QTd, maxTpe/QT, meanTpe, maxTpe, Tped values were higher in B compared to A. They had a significant prolongation at M1 only in A. 20 patients in A and 6 in B had a 10% prolongation or decrease of iCEB (p = 0.66). In 5 patients, VPB severity increased from non-complex to complex: 3 in A and 2 in B (p = 0.31), but no sustained ventricular arrhythmia was registered. In conclusion, after 6 months of treatment, patients with hypogonadism on degarelix associated with enzalutamide had significant prolongation of QTc, QTd, maxTpe, meanTpe/QT, maxTpe/QT, Tped compared to patients on degarelix alone. The proportion of patients with 10% iCEB variation was similar between groups. There was no record of severe arrhythmias during the first 6 months of treatment.

Particular etiology in a case of peripheral tetraparesis.

Lead intoxication is a rare but potentially fatal disease without appropriate intervention. The diagnosis is often difficult because of various organs involvement. We report the case of nonprofessional lead intoxication manifested by tetraparesis, severe anemia, and hemolysis in a patient having also unknown beta thalassemia minor.

Diagnostic Pitfalls in a Man with Systemic Lupus Erythematous.

Systemic lupus erythematosus (SLE) is a chronic multi-systemic immune-mediated disease with confusing symptoms and delayed diagnosis. We report the case of a 32-year-old man with a persistent Venereal Disease Research Laboratory (VDRL)-positive reaction treated for syphilis 5 years previously, who was admitted for rash, weight loss, pancytopenia, inflammatory syndrome, and an important spontaneous prolongation of activated partial thromboplastin time (aPTT). Antiphospholipid antibodies were identified in the patient and he was diagnosed with SLE. The unrecognized false positive VDRL reaction and the delayed diagnosis of SLE were harmful as the patient had developed renal and cardiac complications by the time of diagnosis. LEARNING POINTS: VDRL positive reaction as a diagnostic tool for syphilis must be confirmed by other tests like TPHA and Western Blot reaction, especially in the absence of a clinical context, taking into account the possibility of false positive results.Spontaneous prolongation of aPTT can be related to the presence of antiphospholipid antibodies.In medical practice, the clinician must always consider the uniqueness of a diagnosis that integrates all the clinical and laboratory data, even if the associations might seem confusing.

Proteinaceous Lymphadenopathy in a Young Patient With History of Classical Hodgkin Lymphoma: A Case Report With Literature Review.

Proteinaceous lymphadenopathy (PLD) is a poorly defined, underreported pathological entity of uncertain etiology characterized by massive deposition of amorphous, eosinophilic, and periodic acid-Schiff-positive material involving lymph nodes, which is distinct from amyloid and clonal immunoglobulin deposition. PLD can resemble collagen sclerosis and needs to be differentiated from lymphomas with sclerosis, particularly classical Hodgkin lymphoma, nodular sclerosis type, and therefore is an important pitfall in the diagnosis of lymphoma with sclerosis. We are reporting a young patient with history of classical Hodgkin lymphoma who eventually developed PLD and review the literature on this subject.

Expanding the Phenotype of ALK-positive Histiocytosis: A Report of 2 Cases.

ALK-positive histiocytosis is a recently described rare histiocytic proliferative disorder of early infancy. When infants present with anemia, thrombocytopenia, and hepatosplenomegaly, this entity should be included in the differential diagnosis along with hemophagocytic lymphohistiocytosis, metabolic/storage diseases, hematopoietic malignancies, and autoimmune thrombocytopenia. We report 2 new cases of ALK-positive histiocytosis, one with kidney involvement and the other with extensive bone marrow involvement in addition to an overt liver disease. Renal involvement by ALK-positive histiocytosis has not been reported. The infiltrating histiocytes in this case showed Rosai-Dorfman disease-like morphology including emperipolesis. The histiocytes in the second case with extensive bone marrow involvement had foamy cytoplasm initially suggesting storage disease. Our 2 cases highlight previously unrecognized diversity of ALK-positive histiocytosis in clinical manifestation, organ involvement, and cytomorphologic features and further elucidate the diagnostic challenges of this rare entity.

Electrocardiographic measures of repolarization dispersion and their relationships with echocardiographic indices of ventricular remodeling and premature ventricular beats in hypertension.

OBJECTIVE: To examine the relationship between Tpeak- Tend interval (Tpe) and Tpe/QT ratio with occurrence of ventricular premature beats (VPBs) and left ventricular remodeling in hypertension. METHODS: A total of 52 patients with mild to moderate essential hypertension were included, undergoing echocardiography and 24-hours Holter monitoring. Ventricular remodeling was assessed by left ventricular mass index (LVMI) using the Devereux formula and diastolic function by transmitral E and A wave velocities and E/A ratio. Tpe was measured in the precordial leads. The end of the T wave was set by the method of the tangent to the steepest descending slope of the T wave. RESULTS: Tpe and Tpe/QT in leads V2 (r = 0.33, P = 0.01; r = 0.27, P = 0.04 respectively) and V3 (r = 0.40, P = 0.002; r = 0.40, P = 0.003, respectively) correlated significantly with LVMI. A significant inverse relationship was observed between E/A ratio and QT (r = -0.33, P = 0.01), Tpe in V3 (r = -0.39, P = 0.003) and Tpe/QT in V3 (r = -0.31, P = 0.02). Tpe in V3, V5, mean Tpe and maximum Tpe with cut-off values of 60 ms, 59 ms, 62 ms and 71 ms, respectively, associated with the occurrence of ventricular premature beats. CONCLUSIONS: The repolarization parameters Tpe interval and Tpe/QT ratio correlate with LVMI and indices of left ventricular diastolic function and show better predictive values than traditional parameters such as QT interval and QT dispersion. Lead V3 is the best lead for measuring Tpe and Tpe/QT. These ECG indices can therefore be used in clinical practice to monitor LV remodeling and predict occurrence of VPBs.

Sinusoidal CD30+ diffuse large B-cell lymphoma can masquerade as anaplastic large cell lymphoma in pediatric posttransplant lymphoproliferative disorders.

Posttransplant lymphoproliferative disorder (PTLD) is a known complication of solid organ transplantation. Diffuse large B-cell lymphoma (DLBCL) is frequently seen in this setting. However, CD30+ DLBCL with sinusoidal pattern of involvement has not been reported in pediatric PTLD. We are reporting a 9-year-old female child presented with diffuse lymphadenopathy postheart transplantation. The pattern of involvement was suggestive of anaplastic large cell lymphoma, but the malignant cells were positive for B-cell markers and negative for anaplastic lymphoma kinase. The patient was treated aggressively with multiagent chemotherapy and rituximab. Accurate diagnosis in PTLD is paramount in making management decisions.

Identification of High-risk Cryptic CRLF2 Rearrangements in B-Cell Acute Lymphoblastic Leukemia Utilizing an FGFR3/IGH Dual-Color Dual-Fusion DNA Probe Set.

B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood malignancy with gene rearrangements involving the IGH locus occurring in ∼5% of cases. Fluorescence in situ hybridization (FISH) probes targeting the IGH locus are not included in the standard children's oncology group (COG) fluorescence in situ hybridization panel. At our institute, we incorporated the use of FGFR3/IGH dual-color dual-fusion DNA probes for confirmation of aneuploidy 4 and 14 in diagnostic B-ALL specimens. Subsequently we have identified 4 B-ALL cases with cryptic CRLF2-IGH translocations that would otherwise have gone undetected. Detection of genetic alterations in B-ALL, such as CRLF2 rearrangements, may enhance patient risk stratification and therapy options in pediatric B-ALL.

Central nervous system involvement by myeloid sarcoma: a report of 12 cases and review of the literature.

Myeloid sarcoma (MS) is an extramedullary malignancy of myeloid origin. It can occur in any organ. Common sites are skin, bone, lymph nodes, and soft tissue. Central nervous system (CNS) involvement is very uncommon. We report 12 new pathology-confirmed cases of CNS MS with literature review. Median age was 42.5 years (range: 0 - 84 years). Bone marrow involvement by hematologic neoplasia was co-incidental (n = 8) or occurred 8 - 51 months prior to CNS MS (n = 3). Abnormal radiological findings detected in all patients, included hemorrhagic (n = 5) or enhancing (n = 2) lesions, with multiple ring-enhancing dura-based masses in 1 patient. Seven tumors had abnormal cytogenetics including: t(11; 19) (q23; p13.3), +8, inv (16), t(9; 22), t(8; 21), del(5q), and +21. One had a complex karyotype and 2 were cytogenetically normal. One MS had the JAK2V617F mutation. Treatment modalities included surgery for decompression (n = 2), radiotherapy (n = 2), chemotherapy (n = 6), and stem cell transplant (n = 2). Nine patients died days to 12 months post CNS MS diagnosis (median = 4 months). Two patients were alive without evidence of disease at 16 and 50 months following MS diagnosis and one was lost to follow-up. The clinical and imaging features for CMS MS overlap with those of intracranial hemorrhage and primary CNS tumors. It is therefore important to maintain a high index of suspicion and perform a biopsy whenever clinically appropriate. A meticulous workup is necessary to avoid misdiagnosis of other hematopoietic or nonhematopoietic neoplasms. Since CNS MS is potentially curable, timely recognition is paramount.