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The authors offer a response to criticisms raised about their study on the role of the endothelin-1 (EDN1) axis as a therapeutic target in multiple myeloma (MM). Topics include recognition of aberrant activation of the EDN1 axis as a common mechanism underlying the progression of several solid and blood malignancies, molecular basis of the aberrant expression of EDN receptor B (EDNRB), and effects of EDNRs blockade.

A letter to the editor is presented related to aleukemic granulocytic sarcoma with associated T-cell lymphoblastic lymphoma in the same lymph node: Morphologic features and molecular signatures.

The simultaneous appearance of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) has been rarely reported, with AML occurring more frequently as a secondary event in patients receiving cytotoxic drugs for a primary lymphoproliferative disorder. We describe a case of simultaneous CLL and AML documented by morphological and cytometric analysis in a previously untreated patient. In particular, on the basis of morphological and immunological features, the patient was diagnosed as being affected by CD34 + /CD13 + /CD33 + /HLA-DR + /CD7 + FAB-M2 AML, along with a B-CLL characterized by neoplastic cells expressing a V H 3-53/D3-22/J H 4 Ig, bearing, on average, 3.9% IgV H mutations without evidence of antigen-driven selection. To establish whether the two neoplastic cell populations shared some common molecular signature, we performed IgH gene rearrangement studies on CD34 + /CD19- and CD34-/CD19 + immunomagnetically sorted cell populations: only genomic DNA from the CD19 + /CD34- cell fraction revealed the presence of the IgH gene rearrangement. These results provide evidence that the rare concomitant association of CLL and AML likely arises from simultaneous expansion of two independent clones. [ABSTRACT FROM AUTHOR]

This paper reviews the possible role of catecholamine o-quinones (OQs) in the genesis of Parkinson's disease (PD). This disease is characterized by damage caused to the pigmented catecholaminergic cells in various areas of the brain. The pigment involved is neuromelanin that is the end product of catecholamine oxidation by the o-quinone route. Evidence is presented regarding the overproduction in PD of these catecholamine OQs that damage the electron chain in the mitochondria leading to cell death. The roles of glutathione S-transferase and reactive oxygen species in this are also surveyed. A review of all known biochemical properties of these o-quinones is included. The hypothesis is put forward that an important factor in the genesis of PD may be the overload by environmental toxins of enzymes such as glutathione S-transferase that also detoxify catecholamine OQs. [ABSTRACT FROM AUTHOR]

Objective: To report the exceptional occurrence of ossifying fibromyxoid tumour (OFMT) as a primary bone lesion. OFMT is a rare soft tissue tumour of uncertain differentiation and variable malignant potential, that occurs in adults with a slight male predominance. It is typically located in the subcutis or in the skeletal muscles of the extremities, followed by trunk or head and neck., Methods: Two cases of OFMT proven to arise from bone are presented. The first is a 65-year old female with a history of rib "osteosarcoma", presenting with an inferior lobe left lung mass. The second is a man with a lytic lesion of the 5th cervical vertebra that recurred shortly after resection. Following H&E and immunohistochemical examination, tumour samples were analysed by NGS and by break-apart FISH to detect rearrangement of the PHF1 and TFE3 genes., Results: PHF1 gene-rearrangement was identified by FISH on both the primary and the metastatic lesion of first patient. NGS identified a PHF1 (intron1) and EPC1 (exon 10) fusion transcript later confirmed by positive PHF1 rearrangement on FISH in the second case., Conclusions: The demonstration of PHF1 gene rearrangements represents a fundamental ancillary diagnostic test when presented with challenging examples of OFMT., (Copyright © 2020 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Monosomy of chromosome 17 may affect the assessment of HER2 amplification. Notably, the prevalence ranges from 1% up to 49% due to lack of consensus in recognition. We sought to investigate the impact of monosomy of chromosome 17 to interpretation of HER2 gene status. 201 breast carcinoma were reviewed for HER2 gene amplification and chromosome 17 status. FISH analysis was performed by using double probes (LSI/CEP). Absolute gene copy number was also scored per each probe. HER2 FISH test was repeated on serial tissue sections, ranging in thickness from 3 to 20 µm. Ratio was scored and subsequently corrected by monosomy after gold control test using the aCGH method to overcome false interpretation due to artefactual nuclear truncation. HER2 immunotests was performed on all cases. 26/201 cases were amplified (13%). Single signals per CEP17 were revealed in 7/201 (3.5%) cases. Five out of 7 cases appeared monosomic with aCGH (overall, 5/201, 2.5%) and evidenced single signals in >60% of nuclei after second-look on FISH when matching both techniques. Among 5, one case showed amplification with a pattern 7/1 (HER2/CEP17>2) of copies (3+ at immunotest); three cases revealed single signals per both probes (LSI/CEP=1) and one case revealed a 3:1 ratio; all last 4 cases showed 0/1+ immunoscore. We concluded that: 1) monosomy of chromosome 17 may be observed in 2.5% of breast carcinoma; 2) monosomy of chromosome 17 due to biological reasons rather than nuclear truncation was observed when using the cut-off of 60% of nuclei harboring single signals; 3) the skewing of the ratio due to single centromeric 17 probe may lead to false positive evaluation; 4) breast carcinomas showing a 3:1 ratio (HER2/CEP17) usually show negative 0/1+ immunoscore and <6 gene copy number at FISH.

Purpose: Angiomatoid fibrous histiocytoma (AFH) is a low-grade mesenchymal neoplasm which usually occurs in children and adolescents. Either FUS-ATF1 or EWSR1-ATF1 have been detected in the few cases published, pointing to the interchangeable role of FUS and EWSR1 in this entity. EWSR1-ATF1 also represents the most frequent genetic alteration in clear cell sarcoma, suggesting the existence of a molecular homology between these two histotypes. We investigated the presence of EWSR1-CREB1, recently found in gastrointestinal clear cell sarcoma, and FUS-CREB1, as well as the already reported FUS-ATF1 and EWSR1-ATF1 in a series of AFH., Experimental Design: Fourteen cases were analyzed by fluorescence in situ hybridization (FISH) on paraffin-embedded tissue sections, using a commercial EWSR1 probe and custom-designed probes for FUS, ATF1, and CREB1. In two cases, four-color FISH was also done. Reverse transcription-PCR for the four hypothetical fusion genes was done in one case, for which frozen material was available., Results: Thirteen cases showed rearrangements of both EWSR1 and CREB1, whereas one case showed the rearrangement of both EWSR1 and ATF1. Four-color FISH confirmed the results in two selected cases. Reverse transcription-PCR showed EWSR1-CREB1 transcript in the case analyzed., Conclusion: We identified the presence of either EWSR1-CREB1 or EWSR1-ATF1 in all the cases, strengthening the concept of chromosomal promiscuity between AFH and clear cell sarcoma. Either the occurrence of a second unknown tumor-specific molecular event or, perhaps more likely, divergent differentiation programs of the putatively distinct precursor cells of AFH and clear cell sarcoma might be invoked in order to explain the two different phenotypes.