Low/intermediate affinity Fc-gamma receptors (FcγR) are crucial for the recognition of immune complexes and IgG-sensitized microorganisms by phagocytic and cytotoxic effector cells. In all mammalian ...species studied so far, their genes are clustered in a single locus. However, this locus differs between humans and mice, both in the number of genes and the structure/function of the encoded receptors. We show that murine fcgr3 evolved through several steps into FCGR2A, its ortholog, which is specific to primates. One of these steps was the insertion of a retroviral element bringing a new intracellular exon comprising a non-canonical ITAM motif. We also show that the fcgr3-hspa6-fcgr4-fcgr2b module in mammals that has evolved in a FCGR2A-HSPA6-FCGR4-FCGR2B module in primates, was subsequently duplicated in apes through a Non-Allelic Homologous Recombination (NAHR), giving birth to FCGR2C, a hybrid gene between FCGR2B and FCGR2A. The FCGR4 duplication, which occurred simultaneously, eventually resulted in the emergence of FCGR3B, while FCGR3A remained the true FCGR4 ortholog. FCGR2C and FCGR3B, markers of this NAHR, are present in gorillas and chimpanzees, whereas they are absent in orangutans and more distant primates, such as gibbons and macaques. These data need to be taken into account when testing IgG-based therapies in animal species.
Complete STAT1 deficiency is an autosomal recessive primary immunodeficiency caused by null mutations that abolish STAT1-dependent cellular responses to both IFN-alpha/beta and IFN-gamma. Affected ...children suffer from lethal intracellular bacterial and viral diseases. Here we report a recessive form of partial STAT1 deficiency, characterized by impaired but not abolished IFN-alpha/beta and IFN-gamma signaling. Two affected siblings suffered from severe but curable intracellular bacterial and viral diseases. Both were homozygous for a missense STAT1 mutation: g.C2086T (P696S). This STAT1 allele impaired the splicing of STAT1 mRNA, probably by disrupting an exonic splice enhancer. The misspliced forms were not translated into a mature protein. The allele was hypofunctional, because residual full-length mRNA production resulted in low but detectable levels of normally functional STAT1 proteins. The P696S amino acid substitution was not detrimental. The patients' cells, therefore, displayed impaired but not abolished responses to both IFN-alpha and IFN-gamma. We also show that recessive STAT1 deficiencies impaired the IL-27 and IFN-lambda1 signaling pathways, possibly contributing to the predisposition to bacterial and viral infections, respectively. Partial recessive STAT1 deficiency is what we believe to be a novel primary immunodeficiency, resulting in impairment of the response to at least 4 cytokines (IFN-alpha/beta, IFN-gamma, IFN-lambda1, and IL-27). It should be considered in patients with unexplained, severe, but curable intracellular bacterial and viral infections.
Treatment summaries and a personalized survivorship care plans based on internationally approved, organ-specific follow-up care recommendations are essential in preserving the health and quality of ...life for cancer survivors. Cohorts made up of survivors of childhood cancer have made significant contributions to the understanding of early mortality, somatic late complications, and psychosocial outcomes among former patients. New treatment protocols are needed to enhance survival and reduce the potential risk and severity of late effects, and working with treatment databases is crucial in doing so.
In the GOCE (Grand Ouest Cancer de l'Enfant Western Region Childhood Cancer) network, in a participative approach, we developed the LOG-after medical tool, on which health data are registered and can be extracted for analysis. Its name emphasizes the tool's goal, referring to 'logiciel' (the French word for software) that focuses on the period "after" the acute phase. This tool is hosted on a certified health data server. Several interfaces have been developed that can be used depending on the user's profile. Here we present this innovative co-constructed tool that takes national aspects into account, including the results of the feasibility/satisfaction study and its perspective.
The database contains data relating to 2558 patients, with samples from 1702 of these (66.54%) being held in a tumor bank. The average year in which treatment started was 2015 (ranging from December 1967 to November 2022: 118 patients were treated before 2012 and registered retrospectively when seen in long-term follow-up consultations or for another cancer since November 2021). A short questionnaire was distributed to healthcare professionals using the tool (physicians and research associates or technicians, n = 14), of whom 11 answered and were all satisfied. Access to the patient interface is currently open to 124 former patients. This was initially offered to 30 former patients who were over 15 years old, affected by the disease within the last 5 years, and had agreed to test it. Their opinions were collected by their doctor by e-mail, telephone, or during a consultation in an open-ended question and a non-directive interview. All patients were satisfied with the tool, with interest in testing it in the long term. Some former patients found that the tool provided them with some ease of mind; one, for instance, commented: "I feel lighter. I allow myself to forget. I know I will get a notification when the time comes."
Freely available to all users, LOG-after: (1) provides help with determining personalized survivorship care plans for follow-up; (2) builds links with general practitioners; (3) empowers the patient; and (4) enables health data to be exported for analysis. Database URL for presentation: https://youtu.be/2Ga64iausJE.
The prognostic significance of hypercalcemia in lymphoma has only been studied on small series to date. We conducted a retrospective, monocentric, matched-control study that aimed to compare the ...outcome of patients diagnosed with any histological subtype of lymphoma associated with hypercalcemia, at diagnosis or relapse, with a group of controls matched for histological and prognostic factors. Sixty-two and 118 comparable patients treated between 2000 and 2016 were included in hypercalcemia and control cohorts, respectively. Hypercalcemia was found mainly at diagnosis (71%) in higher-risk patients (prognosis scores ≥ 3, 76%) and those with diffuse large B cell lymphoma (67.7%), stage III/IV disease (91.9%), and elevated LDH (90.3%). Two-year progression-free survival (PFS) was shorter in the hypercalcemia than control cohort 30.1% (95% confidence interval (95% CI) 18.3–41.9) vs 63.9% (95% CI 5.1–72.7),
p
< 0.001. Two-year overall survival (OS) was 40.6% (95% CI 28.1–53.1) and 77.7% (95% CI 70.1–85.3) in the hypercalcemia and control cohorts, respectively (
p
< 0.001). Hypercalcemia was independently associated with poor PFS HR = 2.5 (95% CI 1.4–3.5) and OS HR = 4.7 (95% CI 2.8–7.8) in multivariate analysis. Among the 40 patients who received autologous stem cell transplantation (ASCT), hypercalcemia was still associated with shorter OS 2-year OS: 65% (95% CI 40.1–89.9) vs 88.0 (95% CI 75.3–100),
p
= 0.04. Hypercalcemia may be associated with chemo-resistance, given its impact on PFS and OS. Hence, these data suggest that alternate strategies for lymphoma patients with hypercalcemia should be developed.
The incidence of myelodysplastic syndrome increases with aging and the early diagnosis enables optimal care of these diseases. The DxH 800 hematology analyzer measures and calculates 126 cytological ...parameters, but only 23 are used for routine CBC assessment. The goal of this study was to use the 103 unexploited "research parameters" to develop an algorithm allowing for an early detection of subclinical MDS patients by triggering morphological analysis. Blood sample parameters from 101 MDS patients and 88 healthy volunteers were analyzed to identify the critical "research parameters" with: (i) the most significant differences between MDS patients and healthy volunteers, (ii) the best contributions to principal component analysis (PCA), first axis, and (iii) the best correlations with PCA, first two axes (cos
> 0.6). Ten critical "research parameters" of white blood cells were identified, allowing for the calculation of an MDS-likelihood score (MDS-LS), based on logistic regression. Automatic calculation of the MDS-LS is easily implementable on the middleware system of the DxH 800 to generate a flag for blood smear review, and possibly early detection of MDS patients in the general population.
Childhood immune thrombocytopenia (ITP) is a rare autoimmune disorder characterized by isolated thrombocytopenia. Prolonged ITP (persistent and chronic) leads to a reduced quality of life for ...children in many domains. To provide optimal support for children, with ITP, it is important to be able to predict those who will develop prolonged ITP. This study aimed to develop a mathematical model based on platelet recovery that allows the early prediction of prolonged ITP. In this retrospective study, we used platelet counts from the 6 months following the diagnosis of ITP to model the kinetics of change in platelet count using a pharmacokinetic–pharmacodynamic model. In a learning set (n = 103), platelet counts were satisfactorily described by our kinetic model. The Kheal parameter, which describes spontaneous platelet recovery, allowed a distinction between acute and prolonged ITP with an area under the curve (AUC) of 0.74. In a validation set (n = 58), spontaneous platelet recovery was robustly predicted using platelet counts from 15 (AUC = 0.76) or 30 (AUC = 0.82) days after ITP diagnosis. In our model, platelet recovery quantified using the kheal parameter allowed prediction of the clinical course of ITP. Future prospective studies are needed to improve the predictivity of this model, in particular, by combining it with the predictive scores previously reported in the literature.
Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm characterized by the infiltration of blood and bone marrow by immature monocytes, in which extra‐hematopoietic ...localization is uncommon. We report the case of a 69‐year‐old‐man with highly likely ectopic brain CMML involvement by MRI. Without the possibility of cerebral biopsy and with a negative infectious disease assessment, high‐dose cytarabine‐based chemotherapy was successfully administered. The favorable evolution in this case highlights the potential benefit of such treatment, even without a cerebral biopsy to confirm the disease. This case can aid clinical decision‐making in the future.
The FCGR3A-V158F and FCGR2A-H131R polymorphisms are associated with clinical responses to therapeutic mAbs and with immune thrombocytopenic purpura (ITP). The FCGR2C-ORF/STOP polymorphism, ...controlling FcγRIIC expression on natural killer cells and therefore FcγRIIC-mediated antibody dependent cell-mediated cytotoxicity, is also associated with ITP. Using a new pyrosequencing assay to determine this polymorphism in a control population, we observed the expected allele frequencies (ORF:12.6%) and percentages of individuals with a single copy (10.0%) or 3 copies (12.1%) of FCGR2C, or with at least one FCGR2C-ORF allele (20.1%). No association of FCGR2C copy number variations with the FCGR3A-V158F or FCGR2A-H131R genotype was detected. More importantly, our results demonstrate a strong and a weaker linkage disequilibrium associating the FCGR2C-ORF allele with the FCGR3A-158V and the FCGR2A-131H allele, respectively.
Abstract Objective Oncologists' psychological health is a major challenge due to the consequential concerning the quality of the care they provide. However, only critical states of their health have ...been really examined by scientists. This study sought to plug this gap by investigating the mediating role of psychological flourishing in the relationship between the perception of the professional social context ( i.e., perceived workplace isolation and organizational support) and positive attitudes at work among oncologists ( i.e., work engagement, task adjustment and empathy). Methods The study was a cross‐sectional, including 541 French oncologists. Participants completed a self‐report questionnaire. Structural Equation Modeling was employed to test the hypotheses. Results The analysis revealed that workplace isolation and organizational support perceptions were related to oncologists' work engagement, task adjustment and empathy. Additionally, psychological flourishing acted as a partial mediator between these perceptions of professional social context and oncologists' work‐related attitudes. Conclusions This research underlined the potential of enhancing the psychological flourishing of oncologists by improving organizational support and mitigating their sense of isolation, and in turn, to enhance some dimensions of their positive attitudes at work.
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