A 15-year-old boy with homozygous S sickle cell disease presents to the emergency department with chest pain and low-grade fever three days after he had a mild vasoocclusive crisis that was treated ...with ibuprofen and morphine. His oxygen saturation level is 95% in room air, his blood pressure is normal, he has a heart rate of 126 beats/min, and his body temperature is 38.1°Celsius. Chest auscultation shows rales on the right lower side. A complete blood cell count analysis reports a hemoglobin level of 68 (normal range 12.9-16.7) g/L, absolute reticulocyte count of 365 (normal range 50-150) x 109/L, leukocyte count of 18 (normal range according to age and ethnicity 3-9.7) x 109/L and a platelet count of 486 (normal range 165-360) x 109/L. The patient with acute chest syndrome was admitted to hospital and the hematology service was consulted. Given that this patient had infiltrate in the lung and low-grade fever, we started treatment with ceftriaxone administered intravenously along with azithromycin taken orally.
An international, multicenter registry was established to collect retrospective and prospective clinical data on patients with pyruvate kinase (PK) deficiency, the most common glycolytic defect ...causing congenital nonspherocytic hemolytic anemia. Medical history and laboratory and radiologic data were retrospectively collected at enrollment for 254 patients with molecularly confirmed PK deficiency. Perinatal complications were common, including anemia that required transfusions, hyperbilirubinemia, hydrops, and prematurity. Nearly all newborns were treated with phototherapy (93%), and many were treated with exchange transfusions (46%). Children age 5 years and younger were often transfused until splenectomy. Splenectomy (150 59% of 254 patients) was associated with a median increase in hemoglobin of 1.6 g/dL and a decreased transfusion burden in 90% of patients. Predictors of a response to splenectomy included higher presplenectomy hemoglobin (P = .007), lower indirect bilirubin (P = .005), and missense PKLR mutations (P = .0017). Postsplenectomy thrombosis was reported in 11% of patients. The most frequent complications included iron overload (48%) and gallstones (45%), but other complications such as aplastic crises, osteopenia/bone fragility, extramedullary hematopoiesis, postsplenectomy sepsis, pulmonary hypertension, and leg ulcers were not uncommon. Overall, 87 (34%) of 254 patients had both a splenectomy and cholecystectomy. In those who had a splenectomy without simultaneous cholecystectomy, 48% later required a cholecystectomy. Although the risk of complications increases with severity of anemia and a genotype-phenotype relationship was observed, complications were common in all patients with PK deficiency. Diagnostic testing for PK deficiency should be considered in patients with apparent congenital hemolytic anemia and close monitoring for iron overload, gallstones, and other complications is needed regardless of baseline hemoglobin. This trial was registered at www.clinicaltrials.gov as #NCT02053480.
•PK deficiency manifests a broad spectrum in anemia severity that moderately improves after splenectomy.•Close attention to monitoring for iron overload, gallstones, and other complications is recommended in all patients with PK deficiency.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mutations in
are associated with inherited bleeding disorders called
-related thrombocytopenias. We show here that mice with a megakaryocyte-specific
deletion exhibit a macrothrombocytopenic ...phenotype along a megakaryocytic dysplasia reminiscent of
-related thrombocytopenia. GFI1B deficiency increases megakaryocyte proliferation and affects their ploidy, but also abrogates their responsiveness towards integrin signaling and their ability to spread and reorganize their cytoskeleton.
-null megakaryocytes are also unable to form proplatelets, a process independent of integrin signaling. GFI1B-deficient megakaryocytes exhibit aberrant expression of several components of both the actin and microtubule cytoskeleton, with a dramatic reduction of α-tubulin. Inhibition of FAK or ROCK, both important for actin cytoskeleton organization and integrin signaling, only partially restored their response to integrin ligands, but the inhibition of PAK, a regulator of the actin cytoskeleton, completely rescued the responsiveness of
-null megakaryocytes to ligands, but not their ability to form proplatelets. We conclude that
controls major functions of megakaryocytes such as integrin-dependent cytoskeleton organization, spreading and migration through the regulation of PAK activity whereas the proplatelet formation defect in GFI1B-deficient megakaryocytes is due, at least partially, to an insufficient α-tubulin content.
ObjectivesTo assess the feasibility and acceptability of a mindfulness-based stress reduction (MBSR)-based intervention and determine if the intervention is associated with a significant signal on ...empathy and emotional competencies.DesignTwo pre–post proof-of-concept studies.SettingParticipants were recruited at the University of Montreal’s Psychology Department (Study 1) and the CHU Sainte-Justine Department of Hematology-Oncology (Study 2).ParticipantsStudy 1: 12 students completed the 8-week programme (mean age 24, range 18–34). Study 2: 25 professionals completed the 8-week programme (mean age 48, range 27–63).InterventionStandard MBSR programme including 8-week mindfulness programme consisting of 8 consecutive weekly 2-hour sessions and a full-day silent retreat.Outcomes measuresMindfulness as measured by the Mindful Attention Awareness Scale; empathy as measured by the Interpersonal Reactivity Index (IRI)’s Perspective Taking and Empathic Concern subscales; identification of one’s own emotions and those of others as measured by the Profile of Emotional Competence (PEC)’s Identify my Emotions and Identify Others’ Emotions subscales; emotional acceptance as measured by the Acceptance and Action Questionnaire-II (AAQ-II) and the Emotion Regulation Scale (ERQ)’s Expressive Suppression subscale; and recognition of emotions in others as measured by the Geneva Emotion Recognition Test (GERT).ResultsIn both studies, retention rates (80%–81%) were acceptable. Participants who completed the programme improved on all measures except the PEC’s Identify Others’ Emotions and the IRI’s Empathic Concern (Cohen’s d median=0.92, range 45–1.72). In Study 2, favourable effects associated with the programme were maintained over 3 months on the PEC’s Identify my Emotions, the AAQ-II, the ERQ’s Expressive Suppression and the GERT.ConclusionsThe programme was feasible and acceptable. It was associated with a significant signal on the following outcomes: perspective taking, the identification of one’s own emotions and emotional acceptance, thus, justifying moving towards efficacy trials using these outcomes.
Immune thrombocytopenia (ITP), an acquired autoimmune disorder of low platelets and risk of bleeding, has a substantial impact on health‐related quality of life (HRQoL). Patients with ITP often ...report significant fatigue, although the pathophysiology of this is poorly understood. In this observational cohort of 120 children receiving second‐line therapies for ITP, we assessed reports of fatigue using the Hockenberry Fatigue Scale. Children and adolescents with ITP reported a similarly high level of fatigue with 54% (29/54) of children and 62% (26/42) of adolescents reporting moderate‐to‐severe fatigue. There was no correlation between fatigue and age or gender. Adolescents with newly diagnosed and persistent ITP had higher mean fatigue scores than those with chronic ITP (P = 0·03). Fatigue significantly improved in children and adolescents by 1 month after starting second‐line treatments, and this improvement continued to be present at 12 months after starting treatment. Fatigue scores at all time‐points correlated with general HRQoL using the Kids ITP Tool, but did not correlate with bleeding symptoms, platelet count, or platelet response to treatment. Fatigue is common in children and adolescents with ITP and may benefit from ITP‐directed treatment even in the absence of bleeding symptoms.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Hypoxia-inducible factor-1 (HIF-1) regulates the transcription of genes whose products play critical roles in energy metabolism, erythropoiesis, angiogenesis, and cell survival. Limited information ...is available concerning its function in mammalian hematopoiesis. Previous studies have demonstrated that homozygosity for a targeted null mutation in the Hif1α gene, which encodes the hypoxia-responsive α subunit of HIF-1, causes cardiac, vascular, and neural malformations resulting in lethality by embryonic day 10.5 (E10.5). This study revealed reduced myeloid multilineage and committed erythroid progenitors in HIF-1α-deficient embryos, as well as decreased hemoglobin content in erythroid colonies from HIF-1α-deficient yolk sacs at E9.5. Dysregulation of erythropoietin (Epo) signaling was evident from a significant decrease in mRNA levels of Epo receptor (EpoR) in Hif1α-/- yolk sac as well as Epo and EpoR mRNA in Hif1α-/- embryos. The erythropoietic defects in HIF-1α-deficient erythroid colonies could not be corrected by cytokines, such as vascular endothelial growth factor and Epo, but were ameliorated by Fe-SIH, a compound delivering iron into cells independently of iron transport proteins. Consistent with profound defects in iron homeostasis, Hif1α-/- yolk sac and/or embryos demonstrated aberrant mRNA levels of hepcidin, Fpn1, Irp1, and frascati. We conclude that dysregulated expression of genes encoding Epo, EpoR, and iron regulatory proteins contributes to defective erythropoiesis in Hif1α-/- yolk sacs. These results identify a novel role for HIF-1 in the regulation of iron homeostasis and reveal unexpected regulatory differences in Epo/EpoR signaling in yolk sac and embryonic erythropoiesis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Data to inform surveillance and treatment for leukaemia predisposition syndromes are scarce and recommendations are largely based on expert opinion. This study aimed to investigate the clinical ...features and outcomes of patients with myelodysplastic syndrome or acute myeloid leukaemia and Shwachman-Diamond syndrome, an inherited bone marrow failure disorder with high risk of developing myeloid malignancies.
We did a multicentre, retrospective, cohort study in collaboration with the North American Shwachman-Diamond Syndrome Registry. We reviewed patient medical records from 17 centres in the USA and Canada. Patients with a genetic (biallelic mutations in the SBDS gene) or clinical diagnosis (cytopenias and pancreatic dysfunction) of Shwachman-Diamond syndrome who developed myelodysplastic syndrome or acute myeloid leukaemia were eligible without additional restriction. Medical records were reviewed between March 1, 2001, and Oct 5, 2017. Masked central review of bone marrow pathology was done if available to confirm leukaemia or myelodysplastic syndrome diagnosis. We describe the clinical features and overall survival of these patients.
We initially identified 37 patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia. 27 patients had samples available for central pathology review and were reclassified accordingly (central diagnosis concurred with local in 15 56% cases), 10 had no samples available and were classified based on the local review data, and 1 patient was excluded at this stage as not eligible. 36 patients were included in the analysis, of whom 10 (28%) initially presented with acute myeloid leukaemia and 26 (72%) initially presented with myelodysplastic syndrome. With a median follow-up of 4·9 years (IQR 3·9-8·4), median overall survival for patients with myelodysplastic syndrome was 7·7 years (95% CI 0·8-not reached) and 0·99 years (95% CI 0·2-2·4) for patients with acute myeloid leukaemia. Overall survival at 3 years was 11% (95% CI 1-39) for patients with leukaemia and 51% (29-68) for patients with myelodysplastic syndrome. Management and surveillance were variable. 18 (69%) of 26 patients with myelodysplastic syndrome received upfront therapy (14 haematopoietic stem cell transplantation and 4 chemotherapy), 4 (15%) patients received no treatment, 2 (8%) had unavailable data, and 2 (8%) progressed to acute myeloid leukaemia before receiving treatment. 12 patients received treatment for acute myeloid leukaemia-including the two patients initially diagnosed with myelodysplastic who progressed- two (16%) received HSCT as initial therapy and ten (83%) received chemotherapy with intent to proceed with HSCT. 33 (92%) of 36 patients (eight of ten with leukaemia and 25 of 26 with myelodysplastic syndrome) were known to have Shwachman-Diamond syndrome before development of a myeloid malignancy and could have been monitored with bone marrow surveillance. Bone marrow surveillance before myeloid malignancy diagnosis was done in three (33%) of nine patients with leukaemia for whom surveillance status was confirmed and 11 (46%) of 24 patients with myelodysplastic syndrome. Patients monitored had a 3-year overall survival of 62% (95% CI 32-82; n=14) compared with 28% (95% CI 10-50; n=19; p=0·13) without surveillance. Six (40%) of 15 patients with available longitudinal data developed myelodysplastic syndrome in the setting of stable blood counts.
Our results suggest that prognosis is poor for patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia owing to both therapy-resistant disease and treatment-related toxicities. Improved surveillance algorithms and risk stratification tools, studies of clonal evolution, and prospective trials are needed to inform effective prevention and treatment strategies for leukaemia predisposition in patients with Shwachman-Diamond syndrome.
National Institute of Health.
Little data is available on the effect of mindfulness amongst pediatric hematology-oncology professionals. The purpose was to further document change in biological and psychological stress following ...a mindfulness-based stress reduction (MBSR) program.
We led two pre-post interventional studies (n = 12 and n = 25) and measured changes on hair cortisol concentrations, perceived stress, psychological distress and burnout.
Professionals did not change on biological stress (d = 0.04), but improved on self-reported measures (median d = 0.58). Effects were maintained over 3 months for psychological distress, anxiety, depression, and burnout (median d = 0.66). Effects were larger if trainees participated to the retreat and if they reported higher baseline perceived stress.
In pediatric hematology-oncology professionals, an MBSR program was related with improvements in self-reported stress over 3 months. Components of the program and characteristics of trainees may influence the impact of MBSR.
•We evaluated changes following a Mindfulness-Based Stress Reduction (MBSR) program in hematology-oncology professionals.•We observed improvements in psychological distress, anxiety, depression, and burnout, but no change in hair cortisol.•In this understudied population, MBSR may modify primarily the experience of stress.•Baseline stress and participation to a silent retreat may increase the effect of MBSR.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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