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Nature Communications Oct 2017Chronic lymphocytic leukaemia (CLL) is a clonal disorder of mature B cells. Most patients are characterised by an indolent disease course and an anergic phenotype of...
Chronic lymphocytic leukaemia (CLL) is a clonal disorder of mature B cells. Most patients are characterised by an indolent disease course and an anergic phenotype of their leukaemia cells, which refers to a state of unresponsiveness to B cell receptor stimulation. Up to 10% of CLL patients transform from an indolent subtype to an aggressive form of B cell lymphoma over time (Richter´s syndrome) and show a significantly worse treatment outcome. Here we show that B cell-specific ablation of Nfat2 leads to the loss of the anergic phenotype culminating in a significantly compromised life expectancy and transformation to aggressive disease. We further define a gene expression signature of anergic CLL cells consisting of several NFAT2-dependent genes including Cbl-b, Grail, Egr2 and Lck. In summary, this study identifies NFAT2 as a crucial regulator of the anergic phenotype in CLL.NFAT2 is a transcription factor that has been linked with chronic lymphocytic leukaemia (CLL), but its functions in CLL manifestation are still unclear. Here the authors show, by analysing mouse CLL models and characterising biopsies from CLL patients, that NFAT2 is an important regulator for the anergic phenotype of CLL.
Topics: Adaptor Proteins, Signal Transducing; Animals; Clonal Anergy; Early Growth Response Protein 2; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocyte Specific Protein Tyrosine Kinase p56(lck); Mice; NFATC Transcription Factors; Phenotype; Proto-Oncogene Proteins c-cbl; Ubiquitin-Protein Ligases
PubMed: 28970470
DOI: 10.1038/s41467-017-00830-y -
Breast (Edinburgh, Scotland) Feb 2024Breast cancer (BC) risk prediction models consider cancer family history (FH) and germline pathogenic variants (PVs) in risk genes. It remains elusive to what extent...
BACKGROUND
Breast cancer (BC) risk prediction models consider cancer family history (FH) and germline pathogenic variants (PVs) in risk genes. It remains elusive to what extent complementation with polygenic risk score (PRS) and non-genetic risk factor (NGRFs) data affects individual intensified breast surveillance (IBS) recommendations according to European guidelines.
METHODS
For 425 cancer-free women with cancer FH (mean age 40·6 years, range 21-74), recruited in France, Germany and the Netherlands, germline PV status, NGRFs, and a 306 variant-based PRS (PRS) were assessed to calculate estimated lifetime risks (eLTR) and estimated 10-year risks (e10YR) using CanRisk. The proportions of women changing country-specific European risk categories for IBS recommendations, i.e. ≥20 % and ≥30 % eLTR, or ≥5 % e10YR were determined.
FINDINGS
Of the women with non-informative PV status, including PRS and NGRFs changed clinical recommendations for 31·0 %, (57/184, 20 % eLTR), 15·8 % (29/184, 30 % eLTR) and 22·4 % (41/183, 5 % e10YR), respectively whereas of the women tested negative for a PV observed in their family, clinical recommendations changed for 16·7 % (25/150), 1·3 % (2/150) and 9·5 % (14/147). No change was observed for 82 women with PVs in high-risk genes (BRCA1/2, PALB2). Combined consideration of eLTRs and e10YRs identified BRCA1/2 PV carriers benefitting from IBS <30 years, and women tested non-informative/negative for whom IBS may be postponed.
INTERPRETATION
For women who tested non-informative/negative, PRS and NGRFs have a considerable impact on IBS recommendations. Combined consideration of eLTRs and e10YRs allows personalizing IBS starting age.
FUNDING
Horizon 2020, German Cancer Aid, Federal Ministry of Education and Research, Köln Fortune.
Topics: Female; Humans; Young Adult; Adult; Middle Aged; Aged; Breast Neoplasms; BRCA1 Protein; BRCA2 Protein; Genetic Testing; Risk Factors; Genetic Predisposition to Disease
PubMed: 38061307
DOI: 10.1016/j.breast.2023.103615 -
Acta Dermato-venereologica Apr 2020
Topics: Dermoid Cyst; Ectodermal Dysplasia; Eye Diseases; GTP Phosphohydrolases; Humans; Infant, Newborn; Lipomatosis; Magnetic Resonance Imaging; Male; Membrane Proteins; Mutation; Neurocutaneous Syndromes
PubMed: 31633190
DOI: 10.2340/00015555-3358 -
BMJ (Clinical Research Ed.) Jul 2012To evaluate the effect of different treatment strategies on enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome.
OBJECTIVE
To evaluate the effect of different treatment strategies on enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome.
DESIGN
Multicentre retrospective case-control study.
SETTING
23 hospitals in northern Germany.
PARTICIPANTS
298 adults with enterohaemorrhagic E coli induced haemolytic uraemic syndrome.
MAIN OUTCOME MEASURES
Dialysis, seizures, mechanical ventilation, abdominal surgery owing to perforation of the bowel or bowel necrosis, and death.
RESULTS
160 of the 298 patients (54%) temporarily required dialysis, with only three needing treatment long term. 37 patients (12%) had seizures, 54 (18%) required mechanical ventilation, and 12 (4%) died. No clear benefit was found from use of plasmapheresis or plasmapheresis with glucocorticoids. 67 of the patients were treated with eculizumab, a monoclonal antibody directed against the complement cascade. No short term benefit was detected that could be attributed to this treatment. 52 patients in one centre that used a strategy of aggressive treatment with combined antibiotics had fewer seizures (2% v 15%, P = 0.03), fewer deaths (0% v 5%, p = 0.029), required no abdominal surgery, and excreted E coli for a shorter duration.
CONCLUSIONS
Enterohaemorrhagic E coli induced haemolytic uraemic syndrome is a severe self limiting acute condition. Our findings question the benefit of eculizumab and of plasmapheresis with or without glucocorticoids. Patients with established haemolytic uraemic syndrome seemed to benefit from antibiotic treatment and this should be investigated in a controlled trial.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Anti-Bacterial Agents; Antibodies, Monoclonal, Humanized; Case-Control Studies; Child; Combined Modality Therapy; Diarrhea; Disease Outbreaks; Disease Progression; Drug Therapy, Combination; Enterohemorrhagic Escherichia coli; Escherichia coli Infections; Female; Germany; Glucocorticoids; Hemolytic-Uremic Syndrome; Humans; Immunologic Factors; Infant; L-Lactate Dehydrogenase; Male; Mice; Middle Aged; Multivariate Analysis; Plasmapheresis; Platelet Count; Renal Dialysis; Respiration, Artificial; Retrospective Studies; Treatment Outcome; Young Adult
PubMed: 22815429
DOI: 10.1136/bmj.e4565 -
Cureus May 2020Richter's transformation (RT) is defined as the transition of chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) into an aggressive lymphoma. The...
Richter's transformation (RT) is defined as the transition of chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) into an aggressive lymphoma. The conversion generally leads to diffuse large B-cell lymphoma (DLBCL), but more aggressive forms such as Hodgkin lymphoma (HL) can also occur. RT is a rare complication of CLL. RT can be confused with CLL progression. Its identification is crucial because the management of lymphoma and CLL differ from each other. Furthermore, the use of certain agents for CLL such as venetoclax increases the risk of tumor lysis syndrome (TLS) in neoplasms with rapid replication such as DLBCL or CLL with hyperleukocytosis (blast crisis). We present the case of a 76-year-old man with a history of CLL on chemotherapy who developed fatigue, malaise, night sweats, chills, and unintentional weight loss for which he was started on treatment with venetoclax due to suspected clinical progression of his disease. The patient developed TLS, requiring hospitalization, and he was found to have an acute blast crisis. Also, his CLL was found to have been transformed into an aggressive DLBCL. This case highlights the importance of differentiating a true progression of CLL from RT into an aggressive lymphoma given that treatment would be different for the two and the prognosis with the transformation is worse.
PubMed: 32550064
DOI: 10.7759/cureus.8145 -
International Journal of Cancer Nov 2016Richter syndrome represents the transformation of the chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most frequently the diffuse large B-cell lymphoma...
Mantle cell lymphoma-variant Richter syndrome: Detailed molecular-cytogenetic and backtracking analysis reveals slow evolution of a pre-MCL clone in parallel with CLL over several years.
Richter syndrome represents the transformation of the chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most frequently the diffuse large B-cell lymphoma (DLBCL). In this report we describe a patient with CLL, who developed a clonally-related pleomorphic highly-aggressive mantle cell lymphoma (MCL) after five cycles of a fludarabine-based second-line therapy for the first relapse of CLL. Molecular cytogenetic methods together with whole-exome sequencing revealed numerous gene alterations restricted to the MCL clone (apart from the canonical t(11;14)(q13;q32) translocation) including gain of one copy of ATM gene or emergence of TP53, CREBBP, NUP214, FUBP1 and SF3B1 gene mutations. Similarly, gene expression analysis revealed vast differences between the MCL and CLL transcriptome, including overexpression of cyclin D1, downregulation of cyclins D2 and D3, or downregulation of IL4R in the MCL clone. Backtracking analysis using quantitative PCR specifically detecting an MCL-restricted focal deletion of TP53 revealed that the pre-MCL clone appeared in the bone marrow and peripheral blood of the patient approximately 4 years before the clinical manifestation of MCL. Both molecular cytogenetic and sequencing data support the hypothesis of a slow development of the pre-MCL clone in parallel to CLL over several years, and thereby exclude the possibility that the transformation event occurred at the stage of the CLL relapse clone by mere t(11;14)(q13;q32) acquisition.
Topics: Biomarkers, Tumor; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 14; Female; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Leukemia, Lymphocytic, Chronic, B-Cell; Loss of Heterozygosity; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Middle Aged; Translocation, Genetic; Tumor Suppressor Protein p53
PubMed: 27407063
DOI: 10.1002/ijc.30263 -
Journal of the American Academy of... 1994Since its introduction into DSM-III, reactive attachment disorder has stood curiously apart from other diagnoses for two reasons; it remains the only diagnosis designed...
Since its introduction into DSM-III, reactive attachment disorder has stood curiously apart from other diagnoses for two reasons; it remains the only diagnosis designed for infants, and it requires the presence of a specific etiology. This paper describes the pattern of disturbances demonstrated by some children who meet DSM-III-R criteria for reactive attachment disorder. Three suggestions are made: (1) the sensitivity and specificity of the diagnostic concept may be enhanced by including criteria detailing the developmental problems exhibited by these children; (2) the etiological requirement should be discarded given the difficulties inherent in obtaining complete histories for these children, as well as its inconsistency with ICD-10; and (3) the diagnosis arguably is not a disorder of attachment but rather a syndrome of atypical development.
Topics: Adjustment Disorders; Caregivers; Child; Cognition Disorders; Developmental Disabilities; Female; Humans; Male; Object Attachment; Psychiatric Status Rating Scales
PubMed: 7513324
DOI: 10.1097/00004583-199403000-00005 -
Breast Care (Basel, Switzerland) Oct 2013Paraneoplastic hypoglycemia is a rare syndrome amoung tumorous diseases. It is often associated with a paraneoplastic secretion of 'big' insulin-like growth factor-II.
BACKGROUND
Paraneoplastic hypoglycemia is a rare syndrome amoung tumorous diseases. It is often associated with a paraneoplastic secretion of 'big' insulin-like growth factor-II.
METHODS
We describe this syndrome in a 60-year-old patient with advanced breast cancer 8 years after primary diagnosis.
RESULTS AND CONCLUSION
This non-islet cell tumor-induced hypoglycemia may be the only evidence for an otherwise clinically occult disease progression. Fast diagnosis and appropriate acute and causal treatment concepts should be part of oncological management.
PubMed: 24415991
DOI: 10.1159/000355702