Linking the KIR phenotype with STAT3 and TET2 mutations to identify chronic lymphoproliferative disorders of NK cells.

Distinguishing chronic lymphoproliferative disorders of NK cells (CLPD-NK) from reactive NK-cell expansion is challenging. We assessed the value of killer immunoglobulin-like receptor(KIR) phenotyping and targeted high-throughput sequencing in a cohort of 114 consecutive patients with NK cell proliferation, retrospectively assigned to a CLPD-NK group (n = 46) and a reactive NK group (n = 68). We then developed an NK-cell clonality score combining flow cytometry and molecular profiling with a positive predictive value of 93%. STAT3 and TET2 mutations were respectively identified in 27% and 34% of the patients with CLPD-NK, constituting a new diagnostic hallmark for this disease. TET2-mutated CLPD-NK preferentially exhibited a CD16low phenotype, more frequently displayed a lower platelet count, and was associated with other hematologic malignancies such as myelodysplasia. To explore the mutational clonal hierarchy of CLPD-NK, we performed whole-exome sequencing of sorted, myeloid, T, and NK cells and found that TET2 mutations were shared by myeloid and NK cells in 3 of 4 cases. Thus, we hypothesized that TET2 alterations occur in early hematopoietic progenitors which could explain a potential link between CLPD-NK and myeloid malignancies. Finally, we analyzed the transcriptome by RNA sequencing of 7 CLPD-NK and evidenced 2 groups of patients. The first group displayed STAT3 mutations or SOCS3 methylation and overexpressed STAT3 target genes. The second group, including 2 TET2-mutated cases, significantly underexpressed genes known to be downregulated in angioimmunoblastic T-cell lymphoma. Our results provide new insights into the pathogenesis of NK-cell proliferative disorders and, potentially, new therapeutic opportunities.

Quantifying infective endocarditis risk in patients with predisposing cardiac conditions.

Aims: There are scant comparative data quantifying the risk of infective endocarditis (IE) and associated mortality in individuals with predisposing cardiac conditions. Methods and results: English hospital admissions for conditions associated with increased IE risk were followed for 5 years to quantify subsequent IE admissions. The 5-year risk of IE or dying during an IE admission was calculated for each condition and compared with the entire English population as a control. Infective endocarditis incidence in the English population was 36.2/million/year. In comparison, patients with a previous history of IE had the highest risk of recurrence or dying during an IE admission [odds ratio (OR) 266 and 215, respectively]. These risks were also high in patients with prosthetic valves (OR 70 and 62) and previous valve repair (OR 77 and 60). Patients with congenital valve anomalies (currently considered 'moderate risk') had similar levels of risk (OR 66 and 57) and risks in other 'moderate-risk' conditions were not much lower. Congenital heart conditions (CHCs) repaired with prosthetic material (currently considered 'high risk' for 6 months following surgery) had lower risk than all 'moderate-risk' conditions-even in the first 6 months. Infective endocarditis risk was also significant in patients with cardiovascular implantable electronic devices. Conclusion: These data confirm the high IE risk of patients with a history of previous IE, valve replacement, or repair. However, IE risk in some 'moderate-risk' patients was similar to that of several 'high-risk' conditions and higher than repaired CHC. Guidelines for the risk stratification of conditions predisposing to IE may require re-evaluation.

Genetics and epigenetics of CLL.

Chronic lymphocytic leukemia (CLL) has a heterogeneous biological behavior, which is highly influenced by its immunogenetic, epigenetic, and genomic properties. The remarkably variable clinical course of the disease has been associated with genetic features such as chromosomal abnormalities, the presence of either high or low numbers of somatic hypermutations (SHM) in the variable region of the immunoglobulin heavy chain locus (IGHV), and somatic mutations of several specific driver genes. Next-generation sequencing (NGS) technologies have provided a comprehensive characterization of the genomic and epigenomic landscape in CLL, elucidating important underlying mechanisms of the disease's biology. The scope of this review is to summarize the most recent discoveries about novel genetic and epigenetic alterations, discussing their impact on clinical outcomes and response to currently available therapy.

Myeloid sarcoma with NPM1 mutation may be clinically and genetically distinct from AML with NPM1 mutation: a study from the Bone Marrow Pathology Group.

Myeloid sarcoma (MS) is currently considered equivalent to de novo acute myeloid leukemia (AML); however, the relationship between these entities is poorly understood. This retrospective multi-institutional cohort study compared 43 MS with NPM1 mutation to 106 AML with NPM1 mutation. Compared to AML, MS had more frequent cytogenetic abnormalities including complex karyotype (p = .009 and p = .007, respectively) and was enriched in mutations of genes involved in histone modification, including ASXL1 (p = .007 and p = .008, respectively). AML harbored a higher average number of gene mutations (p = .002) including more frequent PTPN11 mutations (p < .001) and mutations of DNA-methylating genes including DNMT3A and IDH1 (both p < .001). MS had significantly shorter overall survival (OS) than AML (median OS: 44.9 vs. 93.2 months, respectively, p = .037). MS with NPM1 mutation has a unique genetic landscape, and poorer OS, compared to AML with NPM1 mutation.

First study comparing genetic profiles of MS and AML with a common disease-defining lesion.NPM1^Mut MS may be genetically distinct from NPM1^Mut AML.NPM1^Mut MS may have inferior overall survival compared to NPM1^Mut AML.

Clinical guideline variability in the diagnosis of hereditary hematopoietic malignancy syndromes.

A growing understanding of the complexities of hematopoietic malignancies necessitates the existence of clinical recommendations that are sufficiently comprehensive. Although hereditary hematopoietic malignancies (HHMs) are increasingly recognized for conferring risk of myeloid malignancy, frequently utilized clinical recommendations have never been appraised for the ability to reliably guide HHM evaluation. We assessed established society-level clinical guidelines for inclusion of critical HHM genes and graded the strength of testing recommendations. We uncovered a substantial lack of consistency of recommendations guiding HHM evaluation. Such heterogeneity in guidelines likely contributes to refusal by payers to support HHM testing, leading to underdiagnoses and lost opportunities for clinical surveillance.

Cutaneous myiasis in cats and dogs: Cases, predisposing conditions and risk factors.

Two cases of cutaneous myiasis diagnosed in 2018 in Emilia-Romagna region (northern Italy) were reported. The first one, described in a domestic cat Felis silvestris catus L. (Carnivora: Felidae) and caused by Calliphora vicina Robineau-Desvoidy (Diptera: Calliphoridae), was the first one of this type ever reported in Italy in cats. The second one was described in a domestic dog Canis lupus familiaris L. (Carnivora: Canidae) and caused by Lucilia sericata (Meigen) (Diptera: Calliphoridae) and was unusual because it occurred in absence of lesions. An extensive literature search on cutaneous myiasis in these two domestic animal species was performed in order to draw attention to predisposing conditions and risk factors.

Cereblon (CRBN) gene polymorphisms predict clinical response and progression-free survival in relapsed/refractory multiple myeloma patients treated with lenalidomide: a pharmacogenetic study from the IMMEnSE consortium.

Cereblon (CRBN) is crucial for antiproliferative and immunomodulatory properties of immunomodulatory drugs. The objective of this study was to verify whether germline single nucleotide polymorphisms (SNPs) in the CRBN gene may influence response to lenalidomide in multiple myeloma (MM). Fourteen tagging SNPs covering the genetic variability in the CRBN gene region were genotyped in 167 Polish patients with refractory/relapsed MM treated with lenalidomide-based regimens. We found that carriers of minor alleles of two studied CRBN SNPs rs1714327G > C (OR = 0.26; 95% CI = 0.1-0.67; p = .0055, Bonferroni corrected p = .033) and rs1705814T > C (OR = 0.22; 95% CI = 0.07-0.65; p = .0063, Bonferroni corrected p = .037) were significantly associated with lower probability of achievement at least partial remission while treated with lenalidomide-based regimens, using the dominant inheritance model. Moreover, one of these SNPs, namely rs1705814T > C, was correlated with shorter progression-free survival (HR = 2.49; 95%CI = 1.31-4.74, p = .0054, Bonferroni corrected p = .033). It is suggested that selected germline CRBN allelic variants (rs1714327G > C and rs1705814T > C) affect lenalidomide efficacy in patients with relapsed/refractory MM.

Mortality and risk factor analysis for Candida blood stream infection: A three-year retrospective study.

BACKGROUND: The aim of this study was to evaluate the possible risk factors for mortality in adult patients with candidemia by investigating the causative agents, underlying conditions and predisposing factors. MATERIAL AND METHODS: The data including causative Candida species, predisposing factors, and underlying conditions of candidemia patients between the years 2015-2017 were collected and the impact of these factors on mortality was evaluated. Patients were divided into two groups as died (died patients within 30 days of the onset of candidemia) and survived and risk factors were evaluated for each group. RESULTS: We found 163 adult candidemia cases during the study period. Overall 30-day mortality was 40.5%. Candida parapsilosis was the most frequent causative agent (49.1%). C. parapsilosis candidemia was more common in the survived group compared with the died group (n: 49 (61.3%) vs. n: 31 (38.8%), P=0.888). Mortality rates were significantly higher in patients with dialysis (n: 27 (69.2%) vs. n: 12 (30.8%), P<0.00) and concurrent bacteremia (n: 20 (57.1%) vs. n: 15 (42.9%), P=0.024). Survival rates were significantly higher in patients with follow-up blood cultures (n: 75 (65.8%) vs. n: 39 (34.2%), P=0.013). The most important source of candidemia was catheter (49.7%), and C. parapsilosis was the most common causative agent (58%). The catheter was removed in 96.3% of these patients and the mortality rate was 38.5%. All of the patients received antifungal therapy and there was no significant difference between the effects of antifungals on mortality (n: 65 (39.9%) vs. 98 (60.1%), P=0.607). CONCLUSIONS: Dialysis and concurrent bacteremia are strong predictors of mortality in 30 days within patients with candidemia, whereas follow-up blood cultures have a protective role with lower mortality rates. In our study, the most important source of candidemia was catheter, and C. parapsilosis was the most common causative agent. The catheter was removed in almost all patients and the mortality rate was almost one third among these patients.

Telomere biology disorder prevalence and phenotypes in adults with familial hematologic and/or pulmonary presentations.

Telomere biology disorders (TBDs) present heterogeneously, ranging from infantile bone marrow failure associated with very short telomeres to adult-onset interstitial lung disease (ILD) with normal telomere length. Yield of genetic testing and phenotypic spectra for TBDs caused by the expanding list of telomere genes in adults remain understudied. Thus, we screened adults aged ≥18 years with a personal and/or family history clustering hematologic disorders and/or ILD enrolled on The University of Chicago Inherited Hematologic Disorders Registry for causative variants in 13 TBD genes. Sixteen (10%) of 153 probands carried causative variants distributed among TERT (n = 6), TERC (n = 4), PARN (n = 5), or RTEL1 (n = 1), of which 19% were copy number variants. The highest yield (9 of 22 [41%]) was in families with mixed hematologic and ILD presentations, suggesting that ILD in hematology populations and hematologic abnormalities in ILD populations warrant TBD genetic testing. Four (3%) of 117 familial hematologic disorder families without ILD carried TBD variants, making TBD second to only DDX41 in frequency for genetic diagnoses in this population. Phenotypes of 17 carriers with heterozygous PARN variants included 4 (24%) with hematologic abnormalities, 67% with lymphocyte telomere lengths measured by flow cytometry and fluorescence in situ hybridization at or above the 10th percentile, and a high penetrance for ILD. Alternative etiologies for cytopenias and/or ILD such as autoimmune features were noted in multiple TBD families, emphasizing the need to maintain clinical suspicion for a TBD despite the presence of alternative explanations.

Epidemiological analysis of 9,596 patients with acute lung injury at Chinese Military Hospitals.

Acute lung injury (ALI) is a common and severe disease that has been associated with significant morbidity and mortality. Understanding the epidemiology of ALI is vital for its prevention and treatment. The present study aimed to analyze the epidemiology of ALI by collecting data from patients that were submitted between 2000 and 2008 into the 'No. 1 Military Medical Project' information system. A total of 9,596 ALI patients were analyzed retrospectively, including 7,284 males (75.91%) and 2,312 females (24.09%). The median age of the patients was 44 years (interquartile range, 31-63 years), and there was a significant difference between the median ages of male and female patients (P<0.01). The number of patients with ALI admitted to the hospitals showed an increasing trend over time. However, there was no significant difference in the annual gender distribution (P>0.05). In addition, ALI was more prevalent in May, July, August, October, November and December, as compared with the other months. ALI occurred at any age, although 40-years-old was the peak age. There was a significant difference in the age group distributions of male and female ALI patients (P<0.01). Among the predisposing conditions, pulmonary contusion represented the highest proportion (45.71%), followed by pneumonia or respiratory tract infection (23.68%) and pulmonary malignant tumor (6.30%). Of the 581 (6.05%) mortalities, pneumonia was the most common cause (37.87%), followed by malignancies (16.87%) and pulmonary embolism (11.02%). However, the highest mortality rate was associated with cardiopulmonary resuscitation (48.28%). In conclusion, the results of the present study suggested that ALI should be increasingly monitored in the future, and predisposing conditions should be regarded as one of the most important features determining the management of ALI.

A deletion polymorphism in the RIZ gene is associated with increased progression of imatinib treated chronic myeloid leukemia patients.

RIZ1 encodes a retinoblastoma (Rb)-interacting zinc finger protein, is commonly lost or expressed at reduced levels in cancer cells. The RIZ1 gene locus commonly undergoes LOH in many cancers. Here, we analyzed Proline insertion-deletion polymorphism at amino acid position 704 in the RIZ1 gene and its association with CML. The RIZ1 pro-704 LOH genotypes were determined by AS-PCR in 100 CML patients among which 50 were in CP-CML, 25 in AP-CML, and 25 in BC-CML. Pro704 ins/del polymorphism (LOH) was detected in 27% CML patients. Proline ins-ins homozygosity, del-del homozygosity and ins-del heterozygosity was detected in 9%, 18%, and 73% CML patients compared with 3%, 3%, and 94% in healthy controls, respectively (p < .0003). A four-fold increased risk was found to be associated del-del genotype. We found a statistically significant association between RIZ1 LOH and stage (p > .01) and hematological resistance (p > .001). However, there were no correlations found with other clinical parameters like age, gender, thrombocytopia, type of BCR-ABL, and molecular response. Our findings suggest that proline 704 del-del homozygosity phenotype can play an important role in progression of CML.

Intracranial abscesses over the last four decades; changes in aetiology, diagnostics, treatment and outcome.

Background The development of modern medicine has resulted in changes in the predisposing conditions, clinical picture, treatment and results of treatment of intracranial abscesses. This study sought to evaluate these changes in a hospital district. Methods A retrospective analysis of the clinical data of all patients treated due to intracranial abscesses at a tertiary referral centre, between 1970-2012. Results The total number of intracranial abscesses was 166. The incidence of intracranial abscesses was 0.33/100 000/year (2000-2012). The most common predisposing conditions were infection of the ear-, nose- and throat region (22%), odontogenic infection (15%) and cardiac anomaly (13%). Lately (2000-2012), infections of the ear-, nose- and throat region (15%) and cardiac anomalies (5%) have become less common, whereas odontogenic infections (32%) have become more common. The most common pathogens belong to Streptococcus spp (42%), Fusobacteriae (14%), Actinomycetales (8%) and Staphylococcus spp (8%). Most patients (66%) experienced a favourable recovery; the proportion of patients with favourable outcome enabling return to prior occupation rose over time, from 12% in 1970-1989 to 24% in 1990-2012. Conclusions The predisposing conditions for intracranial abscesses have changed markedly within the study period. Odontogenic infections have become a common predisposing condition, whereas infections of the ear-, nose- and throat region and cardiac malformations are nowadays less common as predisposing conditions compared to at the beginning of the study period. The proportion of patients with favourable outcome enabling return to prior occupation seems to have increased with time.

Polymorphisms in GRIA1 gene are a risk factor for asparaginase hypersensitivity during the treatment of childhood acute lymphoblastic leukemia.

l-asparaginase is an effective antineoplastic agent used in chemotherapy of acute lymphoblastic leukemia. The drug effect may be compromised by an elicited immune response, resulting in the production of anti-asparaginase antibodies causing an anaphylactic reaction or silent inactivation of the enzyme. To elucidate possible genetic predisposition for inter-individual differences in asparaginase hypersensitivity, we studied single nucleotide polymorphisms (SNPs) in the GRIA1 gene in 146 pediatric patients treated with l-asparaginase. Allergic reaction to l-asparaginase occurred in 49.3% of patients. We observed a statistically significant association between SNPs in the GRIA1 gene and the occurrence of asparaginase allergy: rs4958351 with p = 0.003, rs4958676 with p = 0.005, rs6889909 with p = 0.005, rs6890057 with p = 0.005 and rs10070447 with p = 0.006. We found a statistically significant correlation between asparaginase allergy and event-free survival (p-value 0.005).

Src family kinases and their role in hematological malignancies.

The Src family protein tyrosine kinases (SFKs) are non-receptor intracellular kinases that have important roles in both hematopoiesis and leukemogenesis. The derangement of their expression or activation has been demonstrated to contribute to hematological malignancies. This review first examines the mechanisms of SFK overexpression and hyperactivation, emphasizing the dysregulation of the upstream modulators. Subsequently, the role of SFK up-regulation in the initiation, progression and therapy resistance of many hematological malignancies is also analyzed. The presented evidence endeavors to highlight the influence of SFK up-regulation on an extensive number of hematological malignancies and the need to consider them as candidates in targeted anticancer therapy.