Immune pathway upregulation and lower genomic instability distinguish EBV-positive nodal T/NK-cell lymphoma from ENKTL and PTCL-NOS

Primary EBV+ nodal T/NK-cell lymphoma (PTCL-EBV) is a poorly understood disease which shows features resembling extranodal NK/T-cell lymphoma (ENKTL) and is currently not recognized as a distinct entity but categorized as a variant of PTCL-NOS. Herein, we analyzed copy-number aberrations (n=77) with focus on global measures of genomic instability (GI) and homologous recombination deficiency (HRD) and performed gene expression (n=84) and EBV miRNA expression profiling (n=24) and targeted mutational analysis (n=16) to further characterize PTCL-EBV in relation to ENKTL and PTCL-NOS. Multivariate analysis revealed a significantly worse outcome of PTCL-EBV compared to PTCL-NOS (P=0.002) but not ENKTL. Remarkably, PTCL-EBV exhibited significantly lower GI and HRD scores compared to ENKTL and PTCL-NOS. Gene Set Enrichment Analysis revealed many immune-related pathways, interferon alpha/gamma response, and IL6_JAK_STAT3 signaling to be significantly upregulated in PTCL-EBV and correlated with lower GI-scores. We also identified NFκB-associated genes, BIRC3, NFκB1 (p50) and CD27, and their proteins to be upregulated in PTCLEBV. PTCL-EBV demonstrated mostly type 2 EBV latency pattern and, strikingly, exhibited downregulated expression of most EBV miRNAs compared to ENKTL and their target genes were also enriched in immune-related pathways. PTCL-EBV also showed frequent mutations of TET2, PIK3CD and STAT3, and are microsatellite stable. Overall, the poor outcome, low genomic instability, upregulation of immune pathways and downregulation of EBV miRNAs are distinctive features of PTCL-EBV. Our data support the consideration of PTCL-EBV as a distinct entity, provide novel insights into the disease pathogenesis and offer potential new therapeutic targets for this tumor.

Orbitofrontal Extradural Hematoma: Unusual Cause of Proptosis

Traumatic orbital subperiosteal hematoma are a distinct entity and should not be confused with orbital extradural hematoma. Most of the orbital subperiosteal hematoma are small in volume and resolve spontaneously. Management should be based on the clinico-radiological condition. A delayed proptosis may be simply due to orbital venous congestion due to a substantial hematoma or due to a carotid-cavernous fistula. Differentiation between the two is paramount to decide management strategy.

Gyermekkori indolens lymphomák differenciáldiagnosztikája

Összefoglaló. Bevezetés: A gyermekkorban előforduló hematológiai megbetegedések közül az indolens non-Hodgkin-lymphomák igen ritka entitásnak számítanak. A betegség általában körülírt nyirokcsomó-megnagyobbodással jelentkezik, mely jellemzően lokalizált marad, szisztémás tünetek megjelenése nélkül, a prognózis kifejezetten kedvező. Morfológiai képük igen változatos, ami miatt gyakran differenciáldiagnosztikai kihívást jelentenek. Sajátos klinikopatológiai megjelenésük és rendkívül kedvező gyógyhajlamuk miatt a 2016-os WHO klasszifikációban önálló entitásként szerepelnek, mint gyermekkori-típusú follikuláris lymphoma és gyermekkori nodális marginális zóna lymphoma. Jelen tanulmányunk célja volt átfogó képet adni a gyermekkori indolens lymphomákról, különös hangsúlyt fektetve a differenciáldiagnosztikai problematikára. Közleményünkben részletes ismertetésre kerülnek az egyes szövettani típusok, morfológiai, immunhisztokémiai, klinikai és genetikai jellemzők szerint. Summary. Introduction: Indolent non-Hodgkin lymphomas in the pediatric and young adult population are very rare. The disease usually presents as isolated, localized lymphadenopathy most often in the head and neck regions, without generalized symptoms. The histology mainly shows mature B-cell lymphoma phenotypes, distinction from reactive lymphoid hyperplasias can be often difficult. Pediatric indolent lymphomas show characteristic clinicopathological features with excellent prognosis that differ from the adult counterpart; these lymphomas can be found as a distinct entity in the 2016 WHO classification as the pediatric-type follicular lymphoma and the pediatric-type nodal marginal zone lymphoma. In this study we present the pathologic characteristics: morphology, immunophenotype and genetical features and the important differential diagnostics of these entities.

A pragmatic diagnostic approach to primary intracranial germ cell tumors and their treatment outcomes

Background: Primary intracranial germ cell tumors (ICGCT) are often diagnosed with tumor markers and imaging, which may avoid the need for a biopsy. An intracranial germ cell tumor with mild elevation of markers is seldom stratified as a distinct entity. Methods: Fifty-nine patients were stratified into three groups: pure germinoma (PG), secreting germinoma (SG) and non-germinomatous germ cell tumors (NGGCTs). Results: At 5 years, progression-free survival and overall survival of the three groups (PG vs SG vs NGGCT) were 91% versus 81% versus 59%, and 100% versus 82% versus 68%, respectively. There was no statistically significant difference in outcome among histologically and clinically diagnosed germinomas. Conclusion: A criterion for clinical diagnosis when a biopsy is not feasible is elucidated, and comparable outcomes were demonstrated with histologically diagnosed germinomas.

Differential impact of IDH1/2 mutational subclasses on outcome in adult AML: Results from a large multicenter study

Mutations of the isocitrate dehydrogenase-1 (IDH1) and IDH2 genes are amongst the most frequent alterations in acute myeloid leukemia (AML) and can be found in ~20% of patients at diagnosis. Among 4930 patients (median age 56 years, interquartile range 45-66) with newly diagnosed, intensively treated AML, we have identified IDH1 mutations (mIDH1) in 423 (8.6%) and IDH2 mutations (mIDH2) in 575 (11.7%) patients. Overall, there were no differences in response rates or survival for patients with mIDH1 or mIDH2 compared to patients without mutated IDH1/2. However, distinct clinical and co-mutational phenotypes of the most common subtypes of IDH1/2 mutations could be associated with differences in outcome. IDH1-R132C was associated with significantly increased age, lower white blood cell count (WBC), less frequent co-mutation of NPM1 and FLT3-ITD as well as lower rate of complete remissions and a trend for reduced overall survival (OS) compared to other mIDH1 variants and wtIDH1/2. In our analysis, IDH2-R172K was associated with significantly lower WBC, more karyotype abnormalities, and less frequent co-mutations of NPM1 and/or FLT3-ITD. Among patients within the ELN2017 intermediate- and adverse-risk groups, RFS and OS were significantly better for patients with IDH2-R172K compared to wtIDH, providing evidence that AML with IDH2-R172K could be a distinct entity with a specific co-mutation pattern and favorable outcome. In summary, the presented data from a large cohort of IDH1/2 mutant AML patients indicate novel and clinically relevant findings for the most common IDH-mutation subtypes.

Eosinophilic Chronic Obstructive Pulmonary Disease

Recent therapeutic advances in the management of asthma have underscored the importance of eosinophilia and the role of pro-eosinophilic mediators such as IL-5 in asthma. Given that a subset of patients with COPD may display peripheral eosinophilia similar to what is observed in asthma, a number of recent studies have implied that eosinophilic COPD is a distinct entity. This review will seek to contrast the mechanisms of eosinophilia in asthma and COPD, the implications of eosinophilia for disease outcome, and review current data regarding the utility of peripheral blood eosinophilia in the management of COPD patients.

OF ALCOHOL, APES, AND TAXES: GÜNTER SCHMÖLDERS AND THE REINVENTION OF ECONOMICS IN BEHAVIORAL TERMS

The article examines an early and idiosyncratic version of behavioral economics or “empirical socio-economics,” which the German economist and taxation expert Günter Schmölders developed in the postwar decades. Relying on both his published papers and his lecture notes and correspondence, it scrutinizes Schmölders’s intellectual upbringing in the tradition of the Historical School of Economics (Historische Schule der Nationalökonomie) and his relation to the emerging ordoliberalism, demonstrating that the roads that led to dissatisfaction with the emerging neoclassical mainstream and the unrealistic behavioral assumptions of macroeconomic models were manifold. Accordingly, it shows that behavioral economics is compatible with various intellectual and political backgrounds and convictions. Yet, it still forms a distinct entity: comparing Schmölders with contemporary and later behavioral economists, I will show that they shared essential methodological assumptions as well as an understanding of human beings as decision-making organisms.