Plasmacytoid Dendritic Cells (pDC) are type I interferon (IFN)-producing cells that play a key role in immune responses. Two major types of neoplastic counterparts for pDC are now discriminated: ...Blastic pDC Neoplasm (BPDCN) and Mature pDC Proliferation (MPDCP), associated with myeloid neoplasm. Two types of MPDCP are now better described: Chronic MyeloMonocytic Leukemia with pDC expansion (pDC-CMML) and Acute Myeloid Leukemia with pDC expansion (pDC-AML). Differential diagnosis between pDC-AML and BPDCN is particularly challenging, and genomic features can help for diagnosis. Here, we systematically review the cytogenetic, molecular, and transcriptional characteristics of BPDCN and pDC-AML. BPDCN are characterized by frequent complex karyotypes with recurrent MYB/MYC rearrangements as well as recurrent deletions involving ETV6, IKZF1, RB1, and TP53 loci. Epigenetic and splicing pathways are also particularly mutated, while original processes are dysregulated, such as NF-kB, TCF4, BCL2, and IFN pathways; neutrophil-specific receptors; and cholinergic signaling. In contrast, cytogenetic abnormalities are limited in pDC-AML and are quite similar to other AML. Interestingly, RUNX1 is the most frequently mutated gene (70% of cases). These typical genomic features are of potential interest for diagnosis, and also from a prognostic or therapeutic perspective.
In 2011, the French National Cancer Institute recommended ALK-fluorescence in situ hybridization (FISH) testing in all EGFR/KRAS-negative adenocarcinomas by all the hospital molecular genetics ...platforms of cancers; however, this technique remains time and cost consuming and not suitable for a large-scale screening, in contrast to immunohistochemistry (IHC).
To evaluate IHC as a prescreening tool, 441 specimens, including small biopsies and surgical specimens, were analyzed prospectively on the Grenoble molecular genetics platform. EGFR and KRAS mutation analyses and ALK IHC, using the 5A4 mAb on an automated staining module, were performed on all specimens; 100 were tested by both ALK IHC and FISH (break-apart probe).
Twenty-seven cases out of 441 were strongly positive (3+ intensity in more than 60% of cells) with ALK mAb, two additional cases exhibited a faint staining (1+) in less than 30% of the cells. Among the 100 cases analyzed by IHC and FISH, 19 were not interpretable by FISH, but 21 were positive with both techniques. Sensitivity and specificity of IHC when compared with FISH were 95 and 100%, respectively. Eleven patients were included in crizotinib trials. Among the 352 analyzable specimens for mutations, 7% were EGFR and 29% were KRAS mutated.
Our IHC protocol, using a commercially available antibody and an amplification step on an automated staining module, led to intense cytoplasmic staining in 6.5% of the adenocarcinomas screened. Our results favor ALK IHC prescreening on a daily routine on surgical specimens and on small biopsies before FISH testing.
Acute myeloid leukemia (AML) with inv(16)/t(16;16) is among the most frequent AML subtypes. It is recognized by the detection of the CBFB-MYH11 fusion which confers a favorable prognosis, ...irrespective of the presence of secondary cytogenetic abnormalities. However, the effect of additional genetic anomalies on the behavior of inv(16) AML is debatable. Recent case reports describe an unfavorable prognosis for those patients, characterized by early relapse and death. In this study, we present a series of patients with CBFB-MYH11 fusion and high-risk rearrangements to increase knowledge about this potentially distinct subgroup.
All cases with inv(16)/ t(16;16) and one or more high risk abnormalities were reviewed at two tertiary healthcare centers between years 2006 and 2020 in terms of demographics, biological and clinical data.
Among the total 1447 and 1283 AML cases, the frequency was found to be 0,2% and 0.3%. Clinical data could be retrieved for 5 patients. Detected high-risk abnormalities included TP53 and 5q deletion, complex and monosomal karyotype. The median age was 67 years, with a majority of females (M:F = 1:1.5). Two out of 5 patients presented with therapy related AML, with short latency periods. All patients presented with thrombocytopenia and/or leukocytopenia. Bone marrow aspirates revealed atypical morphology and the detection of rare CBFB-MYH11 fusion transcripts. All 5 patients died, with a short mean overall survival of 5.8 months.
Our series suggests that the presence of high risk abnormalities confers distinct biological features and poor prognosis to inv(16) AML.
A newborn girl had typical “blueberry muffin” skin lesions, which shows histopathologic features of monocytic leukemia cutis. The systemic leukemia was demonstrated after one month of life. She was ...treated by chemotherapy, including induction and three consolidation cures, according to the ELAM02 protocol, which led to complete remission. This case report with congenital form of AML5 cutaneous localization, preceding systemic involvement, with a 5‐year follow‐up and positive outcome is remarkable.
IntroductionSuspicion of myelodysplastic syndromes (MDS) is the most common reason for bone marrow aspirate in elderly patients. Peripheral blood neutrophil myeloperoxidase expression quantified by ...flow cytometric analysis might rule out MDS for up to 35% of patients referred for suspected disease, without requiring bone marrow aspiration. Yet laboratory-developed liquid antibody cocktails have practical limitations, because of lack of standardisation and poor stability. This research project aims to estimate the level of agreement and comparative accuracy between a single-use flow cytometry tube of lyophilised reagents (BD Lyotube Stain 468) and its laboratory-developed liquid reagent counterpart in quantifying peripheral blood neutrophil myeloperoxidase expression, among adult patients referred for suspected MDS.Methods and analysisThe MPO-MDS-Develop project is a cross-sectional diagnostic accuracy study of two index tests by comparison with a reference standard in consecutive unselected adult patients conducted at a single university hospital. Flow cytometry analysis of peripheral blood samples will be performed by independent operators blinded to the reference diagnosis, using either Lyotube Stain 468 or laboratory-developed liquid reagent cocktail. The reference diagnosis of MDS will be established by cytomorphological evaluation of bone marrow aspirate by two independent haematopathologists blinded to the index test results. Morphologic assessment will be complemented by bone marrow flow cytometric score, karyotype and targeted next-generation sequencing panel of 43 genes, where relevant. The target sample size is 103 patients.Ethics and disseminationAn institutional review board (Comité de Protection des Personnes Sud Est III, Lyon, France) approved the protocol prior to study initiation (reference number: 2020-028-B). Participants will be recruited using an opt-out approach. Efforts will be made to release the primary results within 6 months of study completion.Trial registration numberNCT04399018.
Dendritic cells (DCs) are central cells in the development of antitumor immune responses, but the number and function of these cells can be altered in various cancers. Whether these cells are ...affected during the development of melanoma is not known. We investigated the presence, phenotype, and functionality of circulating myeloid DCs (MDCs) and plasmacytoid DCs (PDCs) in newly diagnosed melanoma patients, compared to controls. The frequencies of PDCs and MDCs were equivalent in melanoma patients as compared with normal subjects. Both circulating DC subsets were immature, but on ex vivo stimulation with R848 they efficiently upregulated their expression of costimulatory molecules. We found that circulating DCs from melanoma patients and controls displayed similar pattern of expression of the chemokine receptors CXCR3, CXCR4, CCR7, and CCR10. Strikingly, PDCs from melanoma patients expressed higher levels of CCR6 than control PDCs, and were able to migrate toward CCL20. Further data showed that CCR6-expressing PDCs were present in melanoma primary lesions, and that CCL20 was produced in melanoma tumors. These results suggest that PDCs and MDCs are functional in melanoma patients at the time of diagnosis, and that CCL20 may participate to their recruitment from the blood to the tumor.
We examined the electrophysiological correlates of retention in auditory short-term memory (ASTM) for sequences of one, two, or three tones differing in timbre but having the same pitch. We focused ...on event-related potentials (ERPs) during the retention interval and revealed a sustained fronto-central ERP component (most likely a sustained anterior negativity; SAN) that became more negative as memory load increased. Our results are consistent with recent ERP studies on the retention of pitch and suggest that the SAN reflects brain activity mediating the low-level retention of basic acoustic features in ASTM. The present work shows that the retention of timbre shares common features with the retention of pitch, hence supporting the notion that the retention of basic sensory features is an active process that recruits modality-specific brain areas.
•We investigated electrophysiological correlates of auditory short-term memory (ASTM).•Participants retained one, two, or three tones differing in timbre in ASTM.•Brain activity was measured with electroencephalography (EEG).•A load-sensitive sustained fronto-central component, a SAN, arose during retention.•The SAN represents the retention of acoustic features in a memory store.
R-CHOP immuno-chemotherapy significantly improved clinical management of diffuse large B-cell lymphoma (DLBCL). However, 30–40% of DLBCL patients still present a refractory disease or relapse. Most ...of the prognostic markers identified to date fail to accurately stratify high-risk DLBCL patients. We have previously shown that the nuclear protein CYCLON is associated with DLBCL disease progression and resistance to anti-CD20 immunotherapy in preclinical models. We also recently reported that it also represents a potent predictor of refractory disease and relapse in a retrospective DLBCL cohort. However, only sparse data are available to predict the potential biological role of CYCLON and how it might exert its adverse effects on lymphoma cells. Here, we characterized the protein interaction network of CYCLON, connecting this protein to the nucleolus, RNA processing, MYC signaling and cell cycle progression. Among this network, NPM1, a nucleolar multi-functional protein frequently deregulated in cancer, emerged as another potential target related to treatment resistance in DLBCL. Immunohistochemistry evaluation of CYCLON and NPM1 revealed that their co-expression is strongly related to inferior prognosis in DLBCL. More specifically, alternative sub-cellular localizations of the proteins (extra-nucleolar CYCLON and pan-cellular NPM1) represent independent predictive factors specifically associated to R-CHOP refractory DLBCL patients, which could allow them to be orientated towards risk-adapted or novel targeted therapies.
High-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 is an aggressive mature B-cell neoplasm, whereas B-lymphoblastic lymphoma is immature cell proliferation, with a frequent ...positivity for terminal deoxynucleotidyl transferase. The transformation of a low-grade follicular lymphoma into a lymphoblastic neoplasm expressing terminal deoxynucleotidyl transferase is a very rare event.
A 55-year-old Caucasian man was followed for a grade 1-2 follicular lymphoma carrying a t(14;18) IGH/BCL2+ and was initially treated with R-CHOP. The follicular lymphoma presented two relapses. In the third relapse, the patient had multiple lymphadenopathy and ascites, which motivated a retroperitoneal biopsy and an ascitic tap. These samples were analyzed by histological, cytological, flow cytometric, cytogenetic, and molecular assessments. The patient died of a multiple organ dysfunction syndrome 2 weeks after his third relapse. The biopsy revealed a diffuse proliferation made up of two types of tumor cells: centroblasts (Bcl-6-positive) and immature cells (terminal deoxynucleotidyl transferase-positive). Flow cytometric analysis confirmed the immature phenotype, with an expression of terminal deoxynucleotidyl transferase, combined with a loss of membrane immunoglobulins. The cytogenetic analysis performed on the ascites revealed a clonal evolution characterized by a t(8;22)(q24;q11) MYC+ translocation not previously detected in follicular lymphoma. Fluorescence in situ hybridization confirmed the double rearrangement of the BCL2 and MYC genes. Polymerase chain reactions and sequencing were used to study the clonal relationship between follicular lymphoma and the secondary tumors. The IGVH gene rearrangement revealed a unique clonal rearrangement involving an IGVH4-59 subset in all three specimens.
These findings suggest a clonal relationship between the two types of lymphoma cells. Furthermore, they support the transformation of an acute follicular lymphoma into a composite lymphoma combining a high-grade B-cell lymphoma and a lymphoblastic neoplasm expressing terminal deoxynucleotidyl transferase. This case report highlights the possible transformation of follicular lymphoma into a highly aggressive and immature proliferation.
PDF
