Establishing a diagnosis in patients suspected of having a myelodysplastic syndrome (MDS) can be challenging and could be informed by the identification of somatic mutations. We performed a ...prospective study to examine the frequency and types of mutations encountered in 144 patients with unexplained cytopenias. Based on bone marrow findings, 17% were diagnosed with MDS, 15% with idiopathic cytopenias of undetermined significance (ICUS) and some evidence of dysplasia, and 69% with ICUS and no dysplasia. Bone marrow DNA was sequenced for mutations in 22 frequently mutated myeloid malignancy genes. Somatic mutations were identified in 71% of MDS patients, 62% of patients with ICUS and some dysplasia, and 20% of ICUS patients and no dysplasia. In total, 35% of ICUS patients carried a somatic mutation or chromosomal abnormality indicative of clonal hematopoiesis. We validated these results in a cohort of 91 lower-risk MDS and 249 ICUS cases identified over a 6-month interval. Mutations were found in 79% of those with MDS, in 45% of those with ICUS with dysplasia, and in 17% of those with ICUS without dysplasia. The spectrum of mutated genes was similar with the exception of SF3B1 which was rarely mutated in patients without dysplasia. Variant allele fractions were comparable between clonal ICUS (CCUS) and MDS as were mean age and blood counts. We demonstrate that CCUS is a more frequent diagnosis than MDS in cytopenic patients. Clinical and mutational features are similar in these groups and may have diagnostic utility once outcomes in CCUS patients are better understood.
•Over 30% of patients with unexplained cytopenias who do not meet diagnostic criteria for MDS carry MDS-associated somatic mutations.•Clonal cytopenias of undetermined significance are more common than MDS and show comparable variant allele frequencies and blood counts.
Introduction
The clinical course of chronic lymphocytic leukemia (CLL) is heterogeneous, ranging from indolent disease with essentially normal life expectancy to rapidly progressive disease with ...significantly decreased survival. Traditional risk stratification is dependent in large part on cytogenetic analysis by fluorescence in situ hybridization (FISH), with del(13q) as a sole abnormality associated with a favorable prognosis, trisomy 12 or normal cytogenetics associated with an intermediate prognosis, and del(11q) or del(17p) associated with an unfavorable prognosis.1 In the last few years, recurrent mutations in key genes including TP53, BIRC3, NOTCH1, SF3B1, and ATM have also been identified as unfavorable prognostic indicators in CLL.2-4 In a study by Rossi et al, integration of mutations and cytogenetic abnormalities was found to significantly improve the accuracy of survival prediction in CLL beyond that of FISH alone.2 The aim of this study is to evaluate the frequency of these unfavorable mutations in an unselected cohort of CLL patients seen in the community setting, and to determine the percentage of lower-risk patients with a worse than expected prognosis who may potentially benefit from earlier and/or novel therapy.
Methods
An unselected cohort of 633 CLL patients seen in the community setting was included in this study. Demographic data included a mean age of 69 years, male to female ratio of 1.8:1, and mean WBC count of 48 g/dL. DNA sequences of key exons in TP53, BIRC3, NOTCH1, SF3B1, and ATM were determined from peripheral blood or bone marrow aspirates using a clinically validated next-generation sequencing (NGS) assay with a 5% lower limit of detection for single nucleotide variants. Results were compared between duplicate samples and annotated using software that queried databases containing known somatic mutations and germline variants. FISH analysis utilized probes specific for 11q22.3 (ATM), chromosome 12, 13q14.3/13q34, and 17p13.1 (TP53). CLL diagnoses were confirmed by flow cytometry, with FISH for t(11;14)(IGH-CCND1) also performed to exclude mantle cell lymphoma. The percentage of CLL cells by flow cytometry ranged from 18-98%, with a mean of 69%.
Results
Cytogenetic abnormalities were detected in 85% of CLL patients in this study, with del(13q) the most frequent (65%), followed by trisomy 12 (19%), del(11q) (17%), and del(17p) (10%). Mutations in any one of the 5 genes were detected in 37% of patients, with TP53 mutation the most frequent (12%), followed by mutations in NOTCH1 (11%), SF3B1 (10%), ATM (7%), and BIRC3 (3%). TP53 disruption as a whole was found in 14% of patients, consisting of del(17p) only (2%), TP53 mutation only (5%), and biallelic TP53 disruption (7%). ATM disruption as a whole was found in 21% of patients, consisting of del(11q) only (14%), ATM mutation only (4%), and biallelic ATM disruption (4%). Lower-risk patients, as defined by FISH showing either isolated del(13q), trisomy 12, or normal results, comprised 75% of patients, with 29% showing one or more unfavorable mutation: NOTCH1 (12%), SF3B1 (8%), TP53 (6%), ATM (4%), and BIRC3 (3%).
Conclusions
Mutations in TP53, BIRC3, NOTCH1, SF3B1, and ATM have previously been shown to be indicators of unfavorable prognosis in CLL. Using a clinically validated NGS assay, 37% of the CLL patients in our cohort were shown to have a mutation in any one of the 5 genes. In patients with lower-risk disease as defined by FISH, 29% showed one or more unfavorable mutation, including 6% with a TP53 mutation. Mutational profiling using NGS can thus help identify a significant proportion of lower-risk CLL patients with a worse than expected prognosis who may potentially benefit from earlier and/or novel therapy.
ReferencesDohner H, et al. N Engl J Med 2000;343:1910-1916Rossi D, et al. Blood 2013;121:1403-1412Austen B, et al. J Clin Oncol 2007;25:5448-5457Skowronska A, et al. J Clin Oncol 2012;30:4524-32
No relevant conflicts of interest to declare.
Introduction: Mantle cell lymphoma is characterized by the t(11;14)(q13;q32) and can usually be recognized by its typical CD5+/CD23- immunophenotype. However, phenotypic variations have been observed ...and such variants can resemble other types of B-cell neoplasms, including chronic lymphocytic leukemia (CLL/SLL) and marginal zone lymphoma. In particular, the CD5- variant is diagnostically challenging. Some CD5- mantle cell lymphomas have been reported to have an indolent clinical course, while others follow an aggressive course similar to typical mantle cell lymphoma. To our knowledge, CD5- mantle cell leukemia has not been fully characterized. To further our understanding of this disease entity for diagnostic workup and risk assessment, we evaluated clinical, morphologic, immunophenotypic, and genetic features in a cohort of CD5- mantle cell leukemia.
Methods: Among 111 cases of mantle cell leukemia identified from our database over a 2-year period, 12 were CD5- with t(11;14) and absolute peripheral lymphocytosis (>5,000/uL). Antigen expression was defined by flow cytometry as positive, dim positive, or negative. Conventional chromosome analysis and FISH were performed on all cases, including probes for 11q22.3 (ATM), 12 (CEP 12), 13q14, 13q34, 17p13 (TP53) and t(11;14) (IGH-CCND1). Other parameters obtained included age, gender, CBC, blood and bone marrow histology, and IgVH mutational status.
Results: Of the 12 patients, 7 were female with a median age of 67 years (range: 55-88 years). Patients presented with marked lymphocytosis (mean: 55 K/uL) and mild normocytic anemia (mean: 11.3 g/dL). The average platelet count was within the low normal range (mean: 173 K/uL). Flow cytometric analysis showed that all cases expressed CD19 and surface light chain restriction (10 kappa and 2 lambda), and lacked CD5 and CD10. All except one case expressed CD20. CD23 was negative in 8 cases and dim positive in 4 cases. Thus, the leukemic phenotype was suggestive of a marginal zone lymphoma. Morphologically, the leukemic cells were small to medium sized with round nuclei and scant to moderately abundant cytoplasm. Bone marrow biopsy was performed in 6 of 12 cases. All 6 cases showed marrow involvement (mean: 45%; range: 25-85%) with interstitial and intrasinusoidal distribution patterns. While the marrow histology was suggestive of involvement by marginal zone lymphoma, immunohistochemical testing for cyclin D1 revealed positive nuclear staining in the leukemic cells. FISH for t(11;14) was positive in all 12 cases. In contrast, conventional chromosome analysis detected t(11;14) in only 6 cases (3 blood and 3 marrow samples). Additional cytogenetic abnormalities were detected in 8 (67%) patients. Five (42%) cases showed 17p deletion. Other abnormalities included 13q- (3/12; 25%), 11q- (2/12; 17%), and trisomy 12 (1/12; 8%). IgVH analysis was performed in 2 cases, and both exhibited IgVH hypermutation.
Conclusions: CD5- mantle cell leukemia comprised approximately 11% of mantle cell leukemia in our series. In addition to t(11;14), other chromosome abnormalities were identified in the majority of the cases (67%). Deletion of 17p was most frequent, likely representing a more aggressive form in contrast to the previously described indolent form. The leukemic immunophenotype and marrow infiltration features resembled marginal zone lymphoma, indicating the importance of detecting t(11;14) for proper classification and clinical management of the disease. We observed that FISH was much more sensitive in detecting t(11;14) than conventional chromosome analysis. Therefore, performing FISH for t(11;14) and 17p- would be useful for diagnostic workup of mature B-cell leukemia regardless of CD5 positivity. Our limited observation of IgVH hypermutation in CD5- mantle cell leukemia would suggest future studies to investigate this potential relationship for prognostic implications.
No relevant conflicts of interest to declare.
Introduction: The discovery of JAK2, MPL, and CALR mutations has significantly improved the diagnostic approach to BCR-ABL1-negative myeloproliferative neoplasms (MPN). Approximately 60% of patients ...with essential thrombocythemia (ET) and primary myelofibrosis (PMF) harbor a JAK2 or MPL mutation. CALR mutations account for the majority of the remaining cases, and are found in 50-70% of ET and 60-90% of PMF cases that are negative for JAK2 and MPL mutations. Most CALR mutations cause a 52-bp deletion (type 1) or a 5-bp insertion (type 2). These mutations are acquired early during disease evolution and activate JAK/STAT signaling. Prior studies have shown that CALR type 1 mutations are associated with a favorable impact on survival of PMF patients, but not those with ET. Some data also suggested that CALR type 2 mutations may be associated with unfavorable prognosis in PMF. To assess the clinicopathologic impacts of CALR mutation subtypes in ET and PMF, we evaluated a series of CALR-mutated cases and correlated subtypes of mutations with several clinical, laboratory, and genetic parameters.
Methods: MPN cases positive for CALR mutations were retrieved from our database over a period of 14 months. CALR, JAK2, and MPL mutation analyses were performed by either fragment analysis with Sanger sequencing confirmation or Next-Generation sequencing. Chromosome analysis and FISH with probes for 5p15/5q31, 7p11/7q31, 8cen, 20q, and t(9;22) were performed in all cases. Other parameters obtained included age, gender, hemoglobin, WBC, platelet count, bone marrow blasts and histology, and JAK2/MPL mutation status. The data were analyzed with independent sample t-tests and a 2-tailed chi-square test.
Results: A total of 100 consecutive cases of CALR mutated MPNs were identified, 86 of which had available marrow specimens for morphologic subclassification. We further studied the cohort of 86 cases, including 37 ET and 49 PMF patients. 49 were male and 37 female with a median age of 67 (range 31-88) years. 49 (57%) patients had type 1, 28 (33%) had type 2, and 9 (10%) exhibited other types of mutations. No JAK or MPL mutation was found in any cases. Among patients with type 1 mutations, 22 (46%) were ET and 27 (54%) were PMF. Type 2 mutations were seen in 9 (33%) ET and 19 (67%) PMF patients. Notably, 5 cases of ET with type 2 mutations displayed atypical megakaryocytic hyperplasia with variable size and tight aggregates. In contrast, ET with type 1 mutations generally exhibited large megakaryocytes with hyperlobated nuclei. Two cases of PMF with type 2 mutations had a remote history of ET and may represent myelofibrotic transformation. ET patients with type 2 mutations had lower marrow cellularity (mean: 40% vs. 57%; p=0.014) than those with type 1 mutations. There were no statistically significant differences in age, gender, average hemoglobin, WBC, platelet count, marrow blasts, or reticulin fibrosis between the two ET subgroups. While no significant differences in various parameters were observed between PMF patients with type 1 and type 2 mutations, type 2 mutations showed a trend toward a higher platelet count (mean: 714 K/uL vs. 513 K/uL; p=0.086). Chromosome abnormalities were seen in 12 cases (23%), including 11 cases of PMF and 1 case of ET. Among PMF cases, cytogenetic abnormalities were less frequently associated with type 1 mutation (3/27) than type 2 and other types of mutations (8/22) (6% vs. 36%; p=0.035). The number of cases with other types of CALR mutations was small (3 ET and 6 PMF); therefore, comparison of those cases with cases from type 1 or type 2 mutated groups was precluded.
Conclusions: ET patients with type 2 mutations showed less marrow cellularity and more megakaryocytic abnormalities associated with PMF compared to those with type 1 mutations. Our observations may raise the question whether ET patients with type 2 CALR mutations are more likely to progress to post-ET myelofibrosis. Type 2 mutations were also associated with a higher platelet count and higher frequency of cytogenetic abnormalities in PMF. Thus, CALR type 2 mutations may have a greater impact on megakaryocytic hyperplasia and platelet count production. We hypothesize that CALR type 1 and type 2 mutations represent different disease subgroups with pathogenic and prognostic implications.
No relevant conflicts of interest to declare.
Introduction
The term ICUS has been used to describe patients with persistent unexplained cytopenia(s) who do not meet the minimal diagnostic criteria for MDS. While studies on ICUS have been few and ...small to date, it is clear that a subset of patients do progress to overt MDS or acute myeloid leukemia (AML), supporting the concept of an early or pre-phase of MDS (Wimazal, Leuk Res 2007; Hanson, Leuk Res 2009; Schroeder, Ann Oncol 2010). Through the use of NGS-based profiling, the majority of patients with MDS are now known to harbor one or more somatic mutations in driver genes, with RNA splicing and epigenetic pathways most commonly altered (Haferlach, Leukemia 2014). The aim of this study is to elucidate the genomic landscape of ICUS and to evaluate its potential relationship to lower-risk MDS.
Methods
DNA exon sequences in SF3B1, SRSF2, U2AF1, ZRSR2, TET2, IDH1, IDH2, DNMT3A, EZH2, ASXL1, SETBP1, TP53, PHF6, RUNX1, ETV6, CBL1, NRAS, KIT, JAK2, MPL, and NPM1 were determined from the bone marrow aspirates of 250 patients with ICUS and 90 patients with lower-risk MDS (7 MDS with isolated del(5q), 7 MDS-unclassified, 12 refractory cytopenia with unilineage dysplasia, 27 refractory cytopenia with multilineage dysplasia, and 37 refractory anemia with ring sideroblasts) using a clinically validated and sensitive NGS assay on the Illumina MiSeq platform. The lower limit of detection of the assay was 5% with a minimum depth of coverage of 500x. Mutations were compared for concordance between duplicate samples and annotated using software that queried databases and published literature containing somatic mutations and germline variants.
Results
One or more somatic mutations were detected in 33% (82/250) of patients with ICUS. Among this mutated subgroup (ICUS-MUT), the mean number of mutations was 1.8 per patient. TET2 mutation, postulated to be an early genetic event in the pathogenesis of myeloid neoplasms, was the most common mutation detected (38%). DNMT3A (20%), ASXL1 (18%), SRSF2 (15%), and ZRSR2 (11%) mutations were the next most common, with the remaining mutations each detected in <10% of patients. The two most common pathways involved were epigenetic (65%) and RNA splicing (18%). The mean allele frequency for mutations was 33% (range 6-99%), with 14% of mutations having an allele frequency of <10%. The most common type of mutation was missense (60%), followed by frameshift (17%), nonsense (16%), splicing (4%), and other (3%). While no significant difference was observed in the median hemoglobin, absolute neutrophil count, and platelet count between the ICUS-MUT and wild-type (ICUS-WT) subgroups, the ICUS-MUT subgroup was significantly older (78 vs. 69 years, P < 0.0001) and more commonly male (male:female ratio of 1.3:1 vs. 0.8:1, P= 0.0139).
In lower-risk MDS, one or more somatic mutations were detected in 83% (75/90) of patients. The mean number of mutations was 1.8 per patient, identical to that observed in ICUS-MUT. SF3B1 mutation, which is highly associated with ring sideroblasts, was the most common mutation detected (47%). ASXL1 (16%), TET2 (14%), and DNMT3A (10%) mutations were the next most common, with the remaining mutations each detected in <10% of patients. The two most common pathways involved were RNA splicing (58%) and epigenetic (49%). The mean allele frequency for mutations was 32% (range 5-89%), with 6% of mutations having an allele frequency of <10%. The most common type of mutation was missense (66%), followed by frameshift (14%), nonsense (12%), splicing (7%), and other (1%). While no significant difference was observed in the median absolute neutrophil count, platelet count, age, and male:female ratio between lower-risk MDS and ICUS-MUT, lower-risk MDS patients were significantly more anemic (hemoglobin 9.7 vs. 10.5 g/dL, P= 0.0058).
Conclusions
Through the use of NGS-based profiling, one or more somatic mutations were detected in 33% of patients with ICUS. The ICUS-MUT subgroup displayed clinical parameters that were more similar to lower-risk MDS than the ICUS-WT subgroup. The ICUS-MUT subgroup was also similar to lower-risk MDS at the genomic level, with similar pathways involved, mean number of mutations, mean allele frequency, and type of mutations observed. Prior studies have shown that a subset of patients with ICUS do progress to overt MDS or AML. NGS-based profiling may be helpful in identifying those patients with potential early or pre-phase of MDS.
Kwok:Genoptix, Inc., a Novartis company: Employment, Equity Ownership. Reddy:Genoptix, Inc., a Novartis company: Employment, Equity Ownership. Lin:Genoptix, Inc., a Novartis company: Employment, Equity Ownership. Flamholz:Genoptix, Inc., a Novartis company: Employment, Equity Ownership. Yung:Genoptix, Inc., a Novartis company: Employment, Equity Ownership. Dabbas:Genoptix, Inc., a Novartis company: Employment, Equity Ownership. McGinniss:Genoptix, Inc., a Novartis company: Employment, Equity Ownership. Nahas:Genoptix, Inc., a Novartis company: Employment, Equity Ownership. Kines:Genoptix, Inc., a Novartis company: Employment. Xu:Genoptix, Inc., a Novartis company: Employment, Equity Ownership.
Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy characterized by persistent monocytosis with features of a myelodysplastic syndrome (MDS) and/or myeloproliferative ...neoplasm (MPN). While most cases present as de novo disease, a subset of CMML has been described in the literature to evolve from a preexisting MDS (MDS-CMML). CMML with preexisting MPN (MPN-CMML) has not been characterized to our knowledge. It is uncertain whether CMML patients with preexisting MDS or MPN have one or more disease processes and if such patients behave differently from patients who present with de novo CMML. In an attempt to address these questions, we compared the clinicopathologic features between groups of MDS-CMML, MPN-CMML, and de novo CMML in the present study.
126 cases with newly diagnosed CMML were retrieved from our database over a 3-year period. 22 cases had preexisting MDS (n=15) or MPN (n=7). Prior diagnoses of MDS included refractory anemia (n=5), refractory anemia with ring sideroblasts (n=2), MDS with isolated 5q deletion (n=1), refractory cytopenia with multilineage dysplasia (n=6), and refractory anemia with excess blasts-1 (n=1). Prior diagnoses of MPN included essential thrombocythemia (n=1), primary myelofibrosis (n=3), and MPN NOS (n=3). Cytogenetic studies were performed in all cases. Other parameters obtained included age, gender, hemoglobin, white blood cell count, monocytes, platelets, bone marrow blasts and histology, and JAK2/MPL mutations. 22 consecutive cases of de novo CMML were included for comparative analysis.
CMML with preexisting MDS or MPN comprised 17% of CMML (22/126 patients). Among these 22 patients, 15 were male and 7 female with a median age of 79 (range 61-86) years. Median age of the patients at CMML stage was similar to that of patients with de novo CMML (77 years; range 65-89). The median time between disease presentation as MDS or MPN and CMML was 22 months. Patients presented with marked monocytosis at the CMML stage (mean: 23% and 4564/uL) as compared to the stage of MDS (mean: 13% and 794/uL; p<0.001) or MPN (mean: 6.4% and 1216/uL; p<0.001); and the monocyte count was similar to that present in de novo CMML (mean: 24% and 4313/uL). Marrow blasts were significantly increased at the CMML stage as compared to the stage of MDS (mean: 5.3 vs. 1.6; p=0.017), MPN (mean: 5.1 vs. 1.9; p=0.048), or de novo CMML (5.2 vs. 1.9; p=0.009). There was no significant difference in average hemoglobin, platelet count or marrow cellularity between cases at the two disease stages or among the MDS-CMML and MPN-CMML subgroups. However, the marrows of MPN-CMML showed significantly increased diffuse reticulin fibrosis (p=0.002) and marked megakaryocytic hyperplasia (p=0.002) as compared to MDS-CMML. CMML with preexisting MDS or MPN is more frequently associated with cytogenetic abnormalities than de novo CMML (50% vs. 23%), although this difference did not reach statistical significance (p=0.116). 8 (36%) cases had chromosome abnormalities at the MDS or MPN stages; 7 (87%) of the 8 cases demonstrated persistent chromosome abnormalities at the CMML stage. In addition, 4 (18%) patients acquired chromosome abnormalities at the CMML stage. JAK2 mutation was seen in 1 (7%) of 15 cases of MDS-CMML and 4 (57%) of 7 cases of MPN-CMML. Notably, 2 cases of JAK2 positive MPN became JAK2 negative at the CMML stage; one of the patients had been previously treated with a JAK2 inhibitor. No MPL mutation was found in any case.
CMML with preexisting MDS or MPN is not uncommon. The majority of cases exhibit persistent chromosomal abnormalities from the preexisting MDS or MPN, supporting the notion of one disease with two stages of presentation. The findings of a higher frequency of cytogenetic abnormalities and occasional cytogenetic evolution may suggest that chromosome alteration is one of the mechanisms involved in triggering disease progression to CMML. JAK2 V617F was more frequent in MPN-CMML, which correlated with myelofibrosis and megakaryocytic hyperplasia. However, loss of JAK2 mutation can occur at CMML stage. Loss/inhibition of JAK2 activity may contribute to a change in disease course. Our study revealed that CMML with preexisting MDS or MPN is characterized by more advanced disease with increased marrow blasts and therefore may be associated with a poorer prognosis.
No relevant conflicts of interest to declare.
Abstract 2478
Flow cytometric immunophenotyping is critical for accurate diagnosis of CD5-positive chronic lymphocytic leukemia (CLL). CLL is classically positive for CD23 and negative for FMC-7, ...which are useful markers for distinguishing it from CD5-positive mantle cell lymphoma (MCL). However, a subset of CLLs express FMC-7 and rare cases additionally lack CD23, exhibiting a classic MCL phenotype. While CLL generally has an indolent clinical course, the disease is heterogeneous in clinical behavior and several molecular genetic markers are identified that predict poor prognostic subgroups. Prior studies have shown CLL with atypical phenotypic and morphologic features to be associated with trisomy 12. In this retrospective study, we analyzed a large cohort of consecutive CLL cases to determine if expression of FMC-7 identifies a subset of CLL that differs clinically and genetically from typical CLL.
1848 cases of CLL with complete cytogenetics/FISH and IgVH studies were retrieved from our database over a 2-year period. These cases were divided into three groups based on their imunophenotypes: Group I (1562 cases) with a typical CLL phenotype (CD23+/FMC7-); Group II (238 cases) with co-expression of CD23 and FMC7; and Group III (48 cases) with a mantle-like phenotype (CD23-/FMC7+). Other clinicopathologic parameters obtained for those cases included age, gender, CBC, bone marrow (BM) tumor burden, Zap-70, CD38 and surface light chain intensity.
There were 1144 men and 704 women in age ranging from 30 to 99 years (mean: 70 years). Cytogenetic results showed that group II had a higher percentage of cases with trisomy 12 (50%; p<0.001) and complex cytogenetic abnormalities (9.6%; p=0.005) than group I(14% and 4.8%, respectively). Group III also had a higher percentage of cases with trisomy 12 (29%; p=0.005) and complex cytogenetic abnormalities (14.6%; p<0.001) as compared to group I. However, deletion of 17p was more frequently observed in group III (31%) than in groups I (9%; p<0.001) and II (6%; p<0.001). Deletion of 13q14 occurred more frequently in group I (59%) than in groups II (43%; p=0.002) and III (35%; p<0.001). IgVH hypermutation was more frequent in both groups II (65%; p<0.001) and III (71%; p=0.007) as compared to group I (51%). CD38 expression was higher in group II than group I (45% vs. 25%; p<0.001), but showed no significant difference between groups I and III. FMC7 expression correlated with higher light chain intensity in groups II (66%; p<0.001) and III (72%; p<0.001), compared to group I (43%). Average BM tumor burden was higher in group II than group I (63% vs. 56%; p=0.012) and no significant difference was seen between groups I and III. A low Hb subgroup was identified in the group III (10 vs. 14 g/dL), significantly associated with 17p deletion (p=0.012). In addition group III also showed a lower average platelet count than group I (166k/uL vs. 192k/uL; p=0.04). Notably, 17p deletion was not associated with lower Hb in group I and II CLLs. There was no significant difference in average Hb and platelet count between groups I and II, nor were there significant differences in age, gender, WBC and ZAP-70 between all three groups.
We have identified three groups of CLL based on CD23 and FMC-7 expression. In contrast to group I with typical CLL phenotype, group II (13%) with CD23+/FMC7+ phenotype correlated significantly with higher light chain intensity, trisomy 12, and IgVH hypermutation. Furthermore, group II is more frequently associated with high CD38, complex cytogenetic abnormalities, and a higher BM tumor burden. Thus, FMC7 alone may be sufficient to identify phenotypically atypical CLL with features suggestive of a more aggressive behavior. Group III represents a small subset (2.6%) of CLL with mantle- like phenotype (CD23-/FMC7+). Similar to group II, group III correlated with higher light chain intensity, trisomy 12, complex cytogenetic abnormalities, and IgVH hypermutation. However, group III is highly associated with 17p deletion with lower platelet count and Hb. Group III CLL with mantle-like phenotype is likely biologically to be distinct from group II. Future clinical studies may be warranted to confirm inferior outcome in phenotypically atypical CLL in general and CLL with mantle-like phenotype in particular.
No relevant conflicts of interest to declare.
Background: Over the past several decades, dental researchers reported different aspects of oral submucous Fibrosis (OSMF). Yet, there is a big lacunae in the present scenario of evidence based ...dentistry which correlates the role of critical components of a habit such as duration, frequency, chewing time to the clinical grading of OSMF. Aims: To correlate the etiological factors to the severity of clinical grading along duration, frequency and style of chewing habit. Materials and Methods: A cross sectional study of 390 oral submucous fibrosis (OSMF) patients who attended the dental clinic in Central India, Indore, over a period of 3 years was done. Results: Among cases, grade I OSMF was seen in 50.51% (197), grade II OSMF in 28.20% (110) and grade III OSMF in 21.28% (83) subjects, with a male to female ratio of 2.3:1. Gutkha and other arecanut products was practiced most commonly and showed significant risk in the severity of OSMF. Conclusion: The relative risk of OSMF increased with duration, frequency and style of chewing habits for longer duration and swallowing it without spitting. Key words: Oral Submucous Fibrosis; Arecanut; Gutkha.
Nutritional intervention is a key strategy in the control and management of non-communicable diseases. Here, initially, we evaluated the effects of carrot juice (CJ) on some of the physical and ...biochemical parameters in rats fed with high-fructose diet, then in type 2 diabetic subjects. For the animal study, weanling male Wistar rats were given control (n = 6) or high fructose (HFr; n = 24) diet for 8 weeks. Then, the HFr group rats were subdivided into 4 groups (n = 6 in each) and continued either on HFr diet or shifted to control diet, with or without CJ (0.3 mg β-carotene) ingestion orally for 8 weeks. At the end, the ingestion of CJ reversed the HFr-induced adiposity (23 ± 1.6 vs 18 ± 1.1, P = .038), hypertriglyceridemia (182 ± 18.2 vs 90 ± 10.5 mg/dL, P<0.001), and hyperinsulinemia (81 ± 14.7 vs 40 ± 7.5 µU/mL, P = .014), while increased the retinol levels in liver (240 ± 38.4 vs 492 ± 61.2 µg/g, P = .002) and adipose tissue (1.8 ± 0.09 vs 2.5 ± 0.18 µg/g, P = .026). On the other hand, in the diabetic subjects (7 males and females each, n = 14) compared to their baseline, the daily consumption of 50 mL CJ (~2400 µg β-carotene) for 6 weeks significantly reduced the body weight (69.4 ± 4.13 vs 69.0 ± 4.09 kg, P = .014), BMI (27.4 ± 1.07 vs 27.2 ± 1.06 kg/m2, P = .007), and fat% (33.4 ± 1.87 vs 31.9 ± 2.13, P = .029) with an increase in plasma β-carotene levels (0.21 ± 0.045 vs 0.45 ± 0.089 µmol/L, P = .044). Although CJ increased the glucose (145 ± 10.4 vs 165 ± 11.4 mg/dL, P = .039), insulin, and glycated hemoglobin levels remained unaltered. In conclusion, the consumption of carrot juice reversed the HFr-induced metabolic abnormalities in a rat model and decreased body weight and BMI of diabetic subjects.
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