Myeloid sarcoma as the only manifestation in a rare mixed lineage leukemia-fusion-driven acute myeloid leukemia: A case report.

BACKGROUND: The mixed lineage leukemia (MLL)-eleven-nineteen lysine-rich leukemia (ELL) fusion gene is a rare occurrence among the various MLL fusion genes. We present the first case in which myeloid sarcoma (MS) was the only manifestation of adult MLL-ELL-positive acute myeloid leukemia (AML). CASE SUMMARY: We report a case of a 33-year-old male patient who was admitted in June 2022 with a right occipital area mass measuring approximately 7 cm × 8 cm. Blood work was normal. The patient underwent right occipital giant subscalp mass excision and incisional flap grafting. Immunohistochemistry was positive for myeloperoxidase, CD43 and CD45 and negative for CD3, CD20, CD34, and CD56. The bone marrow aspirate showed hypercellularity with 20% myeloblasts. Flow cytometry showed that myeloblasts accounted for 27.21% of the nucleated cells, which expressed CD33, CD38, and CD117. The karyotype was 46, XY, t (11, 19) (q23; p13.1), -12, + mar/46, XY. Next-generation sequencing showed a fusion of MLL exon 7 to exon 2 of ELL. A diagnosis of MLL-ELL-positive AML (M2 subtype) with subcutaneous MS was made. CONCLUSION: MLL-ELL-positive AML with MS is a rare clinical entity. Additional research is needed to elucidate the molecular mechanisms of the pathogenesis of MS.

Additional cytogenetic abnormalities in patients with newly diagnosed acute promyelocytic leukemia predict inferior event-free survival.

BACKGROUND: The innovative combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has established a new chapter of curative approach in acute promyelocytic leukemia (APL). The disease characteristics and prognostic influence of additional cytogenetic abnormalities (ACA) in APL with modern therapeutic strategy need to be elucidated. METHODS: In the present study, we retrospectively investigated disease features and prognostic power of ACA in 171 APL patients treated with ATRA-ATO-containing regimens. RESULTS: Patients with ACA had markedly decreased hemoglobin levels than that without ACA (p = 0.021). Risk stratification in the ACA group was significantly worse than that in the non-ACA group (p = 0.032). With a median follow-up period of 62.0 months, worse event-free survival (EFS) was demonstrated in patients harboring ACA. Multivariate analysis showed that ACA was an independent adverse factor for EFS (p = 0.033). By further subgroup analysis, in CD34 and CD56 negative APL, patients harboring ACA had inferior EFS (p = 0.017; p = 0.037). CONCLUSIONS: To sum up, ACA remains the independent prognostic value for EFS, we should build risk-adapted therapeutic strategies in the long-term management of APL when such abnormalities are detected.

Clonal evolution in a chronic neutrophilic leukemia patient.

Objectives and importance: Chronic neutrophilic leukemia (CNL) is a distinct myeloproliferative neoplasm with a high prevalence (>80%) of mutations in the colony-stimulating factor 3 receptor (CSF3R); these mutations activate the receptor, leading to the proliferation of neutrophils that are a hallmark of CNL. Clinical presentation: We present a male patient who presented peripheral blood leukocytosis. On the basis of his morphological appearances and molecular findings he was determined to have a diagnosis of chronic neutrophilic leukemia. At a follow-up at 7 months, in addition to the CSF3R c.2373G > A (p.W791*) truncated mutation, another CSF3R mutation appeared as c.1853C > T(p.T618I). Discussion and conclusion: We present the first patient with a diagnosis of chronic neutrophilic leukemia with a c.2373G > A (p.W791*) truncated mutation of CSF3R. These findings elucidate a novel paradigm of CNL pathogenesis and explain how mutations drive the development of the disease. The order of acquisition of CSF3R mutations relative to mutations in epigenetic modifiers and the spliceosome have been determined only in isolated case reports; thus, further work is needed to understand the impact of mutation chronology on the clonal evolution and progression of CNL.

Prognostic value of expression of nuclear factor kappa-B/p65 in non-GCB DLBCL patients.

PURPOSE: We estimated the expression of nuclear factor kappa B/p65 in non-germinal center B-cell-like subtype diffuse large B-cell lymphoma, to investigate its relationship to clinicopathological features, and to further evaluate its prognostic value and clarify its impact on survival. RESULTS: Among the 49 patients enrolled in this study, 14 (28.6%) had positive p65 expression. The negative p65 group had significantly better survival compared to the positive p65 group in terms of both the 3-year estimated OS (91.2% vs. 39.3%, p = 0.003) and PFS (75.6% vs. 26.5%, p = 0.002). In patients with 4 or more risk factors, p65 was an independent prognostic factor of OS (HR 5.99, 95%CI=1.39-25.75, p=0.016) and PFS (HR 4.01, 95%CI=1.15-14.00, p=0.029). MATERIALS AND METHODS: The expression of the NF-κB/p65 protein was deteremined by immunohistochemistry in 49 non-GCB DLBCL. Survival was assessed by the Kaplan-Meier method and Cox multivariate analysis. The median patient follow-up period was 24 months. CONCLUSIONS: The expression of NF-κB/p65 has prognostic value in high risk non-GCB DLBCL, and it is a suitable target for the development of new therapies.

JAK2, MPL, and CALR mutations in Chinese Han patients with essential thrombocythemia.

BACKGROUND: Mutations in Janus kinase 2 (JAK2), myeloproliferative leukemia (MPL), and CALR are highly relevant to Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms. METHODS: Assessing the prevalence of molecular mutations in Chinese Han patients with essential thrombocythemia (ET), and correlating their mutational profile with disease characteristics/phenotype. RESULTS: Of the 110 subjects studied, 62 carried the JAK2 V617F mutation, 21 had CALR mutations, one carried an MPL (W515) mutation, and 28 had non-mutated JAK2, CALR, and MPL (so-called triple-negative ET). Mutations in JAK2 exon 12 were not detected in any patient. Two ET patients had both CALR and JAK2 V617F mutations. Comparing the hematological parameters of the patients with JAK2 mutations with those of the patients with CALR mutations showed that the ET patients with CALR mutations were younger (p = 0.045) and had higher platelet counts (p = 0.043). CONCLUSION: Genotyping for CALR could be a useful diagnostic tool for JAK2/MPL-negative ET, since the data suggest that CALR is much more prevalent than MPL, therefore testing for CALR should be considered in patients who are JAK2 negative as its frequency is almost 20 times that of MPL mutation.

Prognostic role of pretreatment neutrophil-lymphocyte ratio in patients with diffuse large B-cell lymphoma treated with RCHOP.

This study aims to investigate whether neutrophil to lymphocyte ratio (NLR) is an independent predictor in newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients in the rituximab era. Data from newly diagnosed DLBCL patients at Nanjing Drum Tower Hospital from 2006 to 2015 were retrospectively reviewed. We used the receiver operating characteristic (ROC) curve analysis to generate the optimal cutoff value for NLR. Among those 156 patients enrolled, the NLR was < 3.0 in 46.8% (73/156) of the patients, and the remaining 53.2% (83/156) had an NLR ≥ 3.0. Patients with higher pretreatment NLR were found to correlate with poorer OS and PFS than these with lower NLR (hazard ratio [HR] = 2.66, 95% confidence interval [CI] = 1.43-4.97, P = 0.002 and HR = 1.79, 95% CI = 1.05-3.07, P = 0.034, respectively). The multivariate Cox proportional hazard model analysis further showed that high NLR was found independently predictive of poor OS (HR = 0.40; CI = 0.19-0.84, P = 0.015) and PFS (HR = 0.57; CI = 0.33-0.98, P = 0.042). Consequently, pretreatment NLR was an independent prognostic predictor in patients with DLBCL in the rituximab era.

The level of peripheral blood circulating CD34+ cells is higher in acute promyelocytic leukemia patients with adverse prognostic factors.

INTRODUCTION: The increased flow cytometry enumeration of peripheral blood circulating CD34+ cells in patients with acute leukemia has been found in our previous work. In this study, we also demonstrated that acute promyelocytic leukemia (APL) patients not only had elevated CD34+ cell count, but also had some clinical features. METHODS: Fifty APL patients and 19 healthy volunteers were included in the study. The enumeration of circulating CD34+ cells, cytogenetic subgroup, immunophenotype analysis, and leukemic-related gene mutation detection were performed. RESULTS: Some APL patients with higher count of CD34+ cells (≤10 × 10(6)/l) usually possessed one or more poor prognostic factors (higher WBCs count, PML/RARa gene complex fusion, chemotherapy-related APL, normal karyotype/complex karyotype abnormalities, CD56/CD34 antigen positive expression, FLT3-ITD positive mutation, myelofibrosis, and marrow necrosis). A cut-off value of 10 × 10(6)/l CD34+ cells may have the power to distinguish APL patients with above adverse clinical prognostic factor from other APL subjects. CONCLUSION: The circulating CD34+ cell count appears to increase in some APL patients and a higher CD34+ cell count may be indicative of inferior survival and serve as an adverse biomarker for APL.

MYC and BCL-2 adjusted-International Prognostic Index (A-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP.

The International Prognostic Index (IPI) has been the basis for determining prognosis in patients with diffuse large B-cell lymphoma (DLBCL) for the past 20 years. The utility of the IPI must be reassessed in the era of immunochemotherapy. Seven risk factors at diagnosis were identified, and a maximum of 7 points were assigned to each patient. Four risk groups were created: low (0-1), low-intermediate (2-3), high-intermediate (4), and high (5-7). Using MYC and BCL-2 clinical data from the Drum Tower Hospital collected during the rituximab era, we performed a retrospective analysis of patients with DLBCL treated with R-CHOP and built an biological markers adjusted IPI with the goal of improving risk stratification.Clinical features from 60 adults with de novo DLBCL diagnosed from 2008-2013 were assessed for their prognostic significance. The IPI remains predictive, but it cannot identify the high-risk subgroup. Compared with the IPI, the MYC and BCL-2 adjusted-IPI (A-IPI) better discriminated patients in the high-risk subgroup (4-year overall survival [OS]: 33.3%) than did the IPI (4 year OS: 48.0%). In the era of R-CHOP treatment, MYC and BCL-2 adjusted-IPI is more powerful than the IPI for helping guide treatment planning and interpretation of clinical trials.

Splicing mutation in MVK is a cause of porokeratosis of Mibelli.

Porokeratosis is a chronic skin disorder characterized by the presence of patches with elevated, thick, keratotic borders, with histological cornoid lamella. Classic porokeratosis of Mibelli (PM) frequently appears in childhood with a risk of malignant transformation. Disseminated superficial actinic porokeratosis (DSAP) is the most common subtype of porokeratosis with genetic heterogeneities, and mevalonate kinase gene (MVK) mutations have been identified in minor portion of DSAP families of Chinese origin. To confirm the previous findings about MVK mutations in DSAP patients and test MVK's role(s) in PM development, we performed genomic sequence analysis for 3 DSAP families and 1 PM family of Chinese origin. We identified a splicing mutation of MVK gene, designated as c.1039+1G>A, in the PM family. No MVK mutations were found in three DSAP families. Sequence analysis for complementary DNA templates from PM lesions of all patients revealed a mutation at splice donor site of intron 10, designated as c.1039+1G>A, leading to the splicing defect and termination codon 52 amino acids after exon 10. Although no MVK mutations in DSAP patients were found as reported previously, we identified MVK simultaneously responsible for PM development.

MYC protein expression is associated with poor prognosis in diffuse large B cell lymphoma patients treated with RCHOP chemotherapy.

This study aims to investigate the prognostic significance of the MYC protein expression in diffuse large B cell lymphoma (DLBCL) patients treated with RCHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). A total of 60 patients with DLBCL from 2008 to 2013 were included. Formalin-fixed, paraffin-embedded DLBCL samples were analyzed for MYC protein expression and divided into high or low MYC group. The MYC protein expression and the international prognostic variables were evaluated. The high MYC protein expression predicted a shorter 3-year estimated overall survival (OS) and progression-free survival (PFS) versus the low MYC protein expression (57 % vs. 96 %, P < 0.001 and 50 % vs. 96 %, P = 0.001, respectively). Multivariate analysis confirmed the prognostic significance of the MYC protein expression for both OS (HR, 11.862; 95 % CI, 1.462-96.218; P = 0.021) and PFS (HR, 6.073; 95 % CI, 1.082-34.085; P = 0.040). MYC protein expression with International Prognostic Index (IPI) score distinguished patients into three risk groups with different 3-year OS rates (χ (2) 23.079; P < 0.001) and distinct 3-year PFS rates (χ (2) 15.862; P < 0.001). This study suggests that the MYC protein expression is an important inferior prognostic factor for survival in patients with DLBCL treated with RCHOP. The combinative model with IPI score and MYC protein expression could stratify DLBCL patients into prognostically relevant subgroups more effectively than either the IPI or the MYC alone.

Meta-analysis of randomised clinical trials comparing idarubicin + cytarabine with daunorubicin + cytarabine as the induction chemotherapy in patients with newly diagnosed acute myeloid leukaemia.

BACKGROUND: To determine whether the use of idarubicin+cytarabine (IA) is more effective than the use of daunorubicin+cytarabine (DA) as induction chemotherapy for patients with newly diagnosed acute myeloid leukaemia. METHODS: A computer-based search was performed. Randomised trials comparing IA with DA as induction therapy for newly diagnosed AML were included in this meta-analysis. The primary outcome of interest for our analysis was survival (disease-free survival, event-free survival and overall survival); the secondary endpoint was complete remission. RESULTS: Ten trials with 4,060 patients were eligible for this meta-analysis. Our pooled results suggest that IA is associated with a significant advantage in CR (RR = 1·23; 95% CI = 1·07-1·41, p = 0.004), EFS (HR = 0·64; 95% CI = 0·45-0·91, p = 0.013), and OS (HR = 0·88; 95% CI = 0·81-0·95, p = 0.02) but not in DFS (HR = 0·90; 95% CI = 0·80-1·00, p = 0.06). In the subgroup analysis, age had a significant interaction with OS and CR benefits. CONCLUSION: Our analysis indicated that IA could improve the duration of overall survival compared to DA as induction therapy for young patients with newly diagnosed AML. Further study is needed to determine whether IA can produce clinical benefits in selected genetic or molecular subgroups of young AML patients.

Methylenetetrahydrofolate reductase gene polymorphisms association with the risk of follicular lymphoma: a meta-analysis.

To date, case-control studies on the association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and follicular lymphoma have provided controversial results. To clarify the effect of MTHFR polymorphisms on the risk of follicular lymphoma, a meta-analysis of all case-control studies was performed. The fixed effects and random effects model showed that the C677T polymorphism was associated with a risk of follicular lymphoma among Caucasian populations, and A1298C polymorphism was associated with a risk of follicular lymphoma among Asian populations. Our pooled data suggest evidence for a major role of MTHFR polymorphisms in the carcinogenesis of follicular lymphoma.

[The relationship between polymorphism of genes XPA, XPC, XPD, XRCC1 and susceptibility to acute lymphoblastic leukemia].

OBJECTIVE: To study the relationship between polymorphism of genes XPA, XPC, XPD, XRCC1 and susceptibility to acute lymphoblastic leukemia (ALL) in a Chinese population. METHODS: Polymorphism were determined by a case-control study through matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry method of Mass-ASSAY platform in 114 confirmed ALL cases and 169 age- and sex-matched controls, so as to compare the relationship between different genotypes and ALL risk. RESULTS: Multivariate logistic regression analysis revealed that individuals carrying at least one 23G variant allele (AG/GG genotypes) had a significantly increased risk for ALL (adjusted OR 2.02; 95%CI 1.08 - 3.78) compared with the wild-type genotype (23AA), and evidence that positive interactions between the polymorphisms in XPC C499T and XPA A23G might occur. Furthermore, individuals with both putative risk genotypes had a significantly higher risk (adjusted OR 5.60; 95%CI 1.57 - 19.90), compared with those with both wild-genotypes. By contrast, no significant association was observed between the XPD T751G, XRCC1 G399A, C194T polymorphism and ALL risk. CONCLUSIONS: XPA A23G and XPC C499T polymorphism may contribute to the risk of developing ALL. There are significant combinations between XPC C499T and XPA A23G.

[Granulocytic sarcoma of oral cavity: report of two cases].

Granulocytic sarcoma of oral cavity is a kind of isolated tumor constructed by immature myeloid cells. Two cases of granulocytic sarcoma of oral cavity were analyzed. The literatures about granulocytic sarcoma were overviewed.