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Abstract Amongst follicular lymphoma that transforms into a high-grade lymphoma, majority are diffuse large B cell lymphoma. Here we reported a rare atypical Burkitt's lymphoma transformation from an asymptomatic follicular lymphoma. Lymph node biopsy showed a composite lymphoma with infiltration of the inter-follicular areas by high grade small non-cleaved lymphoma cells amongst neoplastic follicles. Moreover, FISH and molecular genetic study confirmed concomitant MYC translocations and t(14;18) in the high-grade component, thereby suggesting the transformation of atypical Burkitt's lymphoma from an undiagnosed antecedent follicular lymphoma. The disease followed an aggressive clinical course, terminating in refractory disease 13 months after diagnosis. This is followed by a comprehensive review of the literature on lymphoma transformations from underlying follicular lymphoma after acquisition of MYC translocation, using Burkitt's lymphoma, follicular lymphoma, transformation and MYC translocations as keywords.

Summary: miR‐1258 is localised to the first intron of ZNF385B at chromosome 2q31.3. miR‐1258 promoter methylation was studied in 147 samples including 10 normal buffy coat, eight normal bone marrow plasma cells, 16 human myeloma cell lines (HMCLs), 20 MGUS, 63 diagnostic myeloma, and 30 relapsed myeloma samples by methylation‐specific PCR. In myeloma lines, miR‐1258 methylation, verified by pyrosequencing, was detected in 62·5% HMCLs but not normal controls, and expression of miR‐1258 correlated with that of ZNF385B. 5‐Aza‐2′‐deoxycytidine resulted in promoter demethylation and ZNF385B/miR‐1258 re‐expression. Luciferase assay confirmed programmed cell death ligand‐1 (PDL1) as a direct target of miR‐1258. Over‐expression of miR‐1258 in completely methylated myeloma cells led to reduced cellular proliferation and enhanced apoptosis, hence a tumour suppressor role, in addition to repression of PDL1. In primary samples, miR‐1258 methylation, with lower expression of miR‐1258, was detected in 49·2% diagnostic myeloma, imparting an inferior PFS (P = 0·034) in addition to 50·0% relapsed myeloma but not MGUS. Therefore, miR‐1258 is a tumour suppressor miRNA co‐regulated with its host gene, and frequently hypermethylated in active myeloma instead of MGUS, hence acquired during myeloma progression. Methylation‐mediated miR‐1258 silencing led to overexpression of PDL1 and inferior PFS, implicating miR‐1258 in the modulation of myeloma‐specific cytotoxicity. [ABSTRACT FROM AUTHOR]

FLT-3 aberrations that occur as an internal tandem duplication (ITD) or a mutation at the activation-loop position 835, D835, are common in acute promyelocytic leukaemia (APL). We investigated the clinicopathological associations and prognostic impact of FLT-3 aberrations in a cohort of APL patients. FLT-3 exons 11 and 12 were amplified by polymerase chain reaction (PCR), and the lTD was recognized as an increase in the size of the PCR product. FLT-3 exon 17 was amplified, and D835 mutation was identified by loss of an EcoRV site, followed by DNA sequencing. Of 82 patients studied, FLT-3 aberrations were detected in 35 cases (43%) at diagnosis (ITD: 16; D835 mutation: 18; lTD + D835 mutation: 1). FLT-3 ITD, but not D835 mutations, was significantly associated with higher presentation white blood cell count (WBC) and microgranular morphology. Early/induction deaths were related to male sex and high presentation WBC. There was a trend for FLT-3 lTD to be associated with non-remission (P = 0.06). For disease-free survival, high WBC was the only significant adverse factor. Male sex, high WBC and FLT-3 lTD were significant adverse factors for overall survival. These findings have important implications on the possible use of FLT-3 inhibitors in the treatment of APL. [ABSTRACT FROM AUTHOR]

The treatment results of indolent lymphoid malignancies in Chinese are poorly reported. The efficacy of FND (fludarabine 25 mg/m2/d, ×3; mitoxantrone 10 mg/m2/d, ×1; dexamethasone 20 mg/d, ×5; monthly cycles, ×6) in 95 Chinese patients with indolent B-cell malignancies (at diagnosis: 55, relapse/refractory disease: 40) and nine Chinese patients with T-cell large granular lymphocyte leukaemia (T-LGL leukaemia) (at diagnosis: two, refractory disease: seven) was evaluated. For B-cell malignancies, the complete response (CR), partial response (PR) and overall response (OR) rates were 50·5%, 18% and 68·5% respectively. Better results were obtained for primary versus relapse/refractory disease (CR: 60% vs. 37·5%, P = 0·03; OR: 84% vs. 47·5%, P < 0·001; median progression-free survival (PFS): 44 months vs. 22 months; 2-year PFS: 66% vs. 47%, P = 0·039; overall survival (OS): not reached vs. 32%; 2-year OS: 92% vs. 58%, P < 0·001). Responsive patients (CR/PR) had a better median PFS (44 months vs. 5 months, P < 0·001) and OS (67 months vs. 13 months, P < 0·001) than unresponsive patients. For T-LGL leukaemia, the CR and molecular-remission rates were 56% and 67% (median follow-up: 23 months). FND is an active regimen for the treatment of indolent B- and T-cell malignancies in Chinese patients, with results comparable with Western patients with similar indolent lymphomas. [ABSTRACT FROM AUTHOR]

A patient with light chain myeloma complicated by simultaneous Herpes simplex and Aspergillus fischeri pneumonia is presented. Microscopic examination of her bronchoalveolar specimen showed bronchial cells with cytopathic effects and numerous cleistotheca, the sexual reproductive structures of Aspergillus. Culture was positive for Herpes simplex virus and Aspergillus fischeri. The initial partial response to amphotericin B followed by complete clinical response with addition of intravenous acyclovir emphasized the importance of recognition of simultaneous infection by these 2 pathogens. This is the first report of identifying cleistotheca in the bronchoalveolar lavage specimen. [ABSTRACT FROM AUTHOR]

The MAF translocations, t(14;16) and t(14;20), are considered as adverse prognostic factors based on few studies with small sample sizes. We report on their prognostic impact in a large group of 254 patients - 223 (87.8%) with t(14;16) and 31 (12.2%) with t(14;20). There were no intergroup differences in survival estimates. Median progression-free survival was 16.6 months for t(14;16) and 24.9 months for t(14;20) ( p  = 0.28). Median overall survival (OS) was 54.0 months and 49.0 months, respectively ( p  = 0.62). Median OS in patients who underwent double autologous stem cell transplantation (ASCT) was 107.0 months versus 60.0 months in patients who received single ASCT ( p  < 0.001). ISS 3 was associated with shorter OS (HR = 1.89; 95% CI 1.24-3.19; p  = 0.005) in Cox analysis. Our study suggests that t(14;20) should be considered as an adverse factor of equal prognostic implication to t(14;16).

The t(14;16) translocation, found in 3%-5% of newly diagnosed (ND) multiple myeloma (MM), has been associated with adverse outcomes. However, the studies establishing the characteristics of t(14;16) included solely small cohorts. The goal of the current international, multicenter (n = 25 centers), retrospective study was to describe the characteristics and outcomes of t(14;16) patients in a large, real-world cohort (n = 223). A substantial fraction of patients had renal impairment (24%) and hemoglobin <10 g/dL (56%) on initial presentation. Combined therapy of both immunomodulatory drug and proteasome inhibitor (PI) in the first line was used in 35% of patients. Autologous stem cell transplantation was performed in 42% of patients. With a median follow up of 4.1 years (95% CI 3.7-18.7), the median progression-free survival (PFS) and overall survival (OS) from first line therapy were 2.1 years (95% CI 1.5-2.4) and 4.1 years (95% CI 3.3-5.5), respectively. Worse OS was predicted by age > 60 years (HR = 1.65, 95% CI [1.05-2.58]), as well as revised International Scoring System (R-ISS) 3 (vs R-ISS 2; HR = 2.59, 95% CI [1.59-4.24]). In conclusion, based on the largest reported cohort of t(14;16) patients, quarter of this subset of MM patients initially presents with renal failure, while older age and the R-ISS 3 predict poor survival., (© 2020 Wiley Periodicals, Inc.)

Minimal residual disease (MRD) is one of the most powerful prognostic factors in multiple myeloma. Therefore, standardization and easy operation of MRD testing are crucial. Previously, we validated the sensitivity of 10 -5 with spike in of plasmid controls for a standardized next-generation sequencing (NGS) approach based on triplicate measurements of bone marrow by LymphoTrack-MiSeq platform. To improve the technique, we replaced spike-in plasmid controls by genomic DNA from myeloma cells. A spike-in control of 0.001% was consistently detected in all 19 samples tested, confirming a uniform sensitivity of 10 -5 of this upgraded protocol. MRD was detected in 14 of 19 patients (78%), with a significant (P = 0.04) impact on progression-free survival based on high versus low MRD levels. Reproducibility of detection was confirmed by the extremely small interrun variation tested in three patients. In nine patients, MRD was tested in parallel by allele-specific oligonucleotide real-time quantitative PCR. NGS showed an improved sensitivity and provided quantification of MRD for cases assigned positive but not quantifiable by real-time quantitative PCR, obviating the need of patient-specific probes/primers. In summary, the use of genomic DNA as spike-in control simplifies NGS detection of MRD while preserving the sensitivity of 10 -5 . Validity and reproducibility of the standardized procedure were verified, and the prognostic impact of NGS-based MRD in myeloma was confirmed., (Copyright © 2020 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Amongst follicular lymphoma that transforms into a high-grade lymphoma, majority are diffuse large B cell lymphoma. Here we reported a rare atypical Burkitt's lymphoma transformation from an asymptomatic follicular lymphoma. Lymph node biopsy showed a composite lymphoma with infiltration of the inter-follicular areas by high grade small non-cleaved lymphoma cells amongst neoplastic follicles. Moreover, FISH and molecular genetic study confirmed concomitant MYC translocations and t(14;18) in the high-grade component, thereby suggesting the transformation of atypical Burkitt's lymphoma from an undiagnosed antecedent follicular lymphoma. The disease followed an aggressive clinical course, terminating in refractory disease 13 months after diagnosis. This is followed by a comprehensive review of the literature on lymphoma transformations from underlying follicular lymphoma after acquisition of MYC translocation, using Burkitt's lymphoma, follicular lymphoma, transformation and MYC translocations as keywords.