Elevated serum concentrations of β-2-microglobulin are often found at the time of diagnosis of hemophagocytic lymphohistiocytosis in adults with lymphoid and myeloid malignancies

Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder of immune regulation. In patients over 60 years of age, HLH associated with hematological malignancies (hM-HLH) is the most prevalent. β-2-Microglobulin (B2M) plays an important role in antigen presentation and immunological regulation. Elevated B2M levels reflect T-cell activation. Objective: The aim of this study was to determine serum B2M concentrations in adults with hM-HLH and to interpret its significance in the context of overall survival (OS). Patients and methods: Serum B2M concentration was determined in 31 adults aged 22–84 years at the time of hM-HLH diagnosis. Lymphoid malignancy was diagnosed in 22 patients and myeloid malignancy in 9 patients. Results: The serum concentration of B2M was elevated in 100% of the examined patients. Mean and median serum B2M concentrations were 5.3 and 4.2mg/L, respectively (range 2–17mg/L). We have not found any significant differences in terms of the studied serum B2M concentrations between patients with T/NK-cell lymphomas, B-cell lymphomas, and myeloid malignancies. The outcome of HLH was poor in vast majority of patients with the median OS for the entire group of 46 days. Conclusions: Elevated serum B2M level is a frequent finding at the time of hM-HLH diagnosis in adults. It seems to be a useful indicator of HLH for its early detection and evaluation afterward, as well as for immediate therapeutic intervention. Further prospective studies answering the question whether serum B2M can be used as a prognostic factor in hM-HLH would be of interest

Atypical cytomorphology of Gaucher cells is frequently seen in bone marrow smears from untreated patients with Gaucher disease type 1

Introduction. Gaucher cells (GCs), the lipid-laden storage macrophages, are the pathologic hallmark of Gaucher disease (GD). They are typically 20–100 μm in diameter with eccentrically placed nuclei and cytoplasm with characteristic crinkles and striations. A few previous observations have indicated that sometimes GD patients may display morphology of GCs which is different from this classical description. The aim of our study was to explore the morphological polymorphism of GCs in patients with untreated GD type 1 (GD1). Material and methods. May-Grünwald Giemsa stained bone marrow smears (BM-S) from 6 patients with sporadic GD1 were analysed; each patient sample consisted of two slides where all GCs and non-Gaucher cell macrophages were counted. We have defined for the study purposes and examined the following features of GCs which were considered as atypical: (1) foamy cytoplasm, (2) centrally placed nucleus, (3) cell diameter > 100 μm, (4) multinuclearity, (5) syncytial morphology, (6) unusually large cytoplasmic projections, and (7) apparent haemophagocytosis. Results. All analysed patients showed 22–40% GCs with atypical cytomorphology (median 29%). The median number of atypical features of GCs was 10 per patient (range 6–13). Multinuclearity was the most common atypical feature of GCs, followed by erythrophagocytosis and foamy cytoplasm. There was a strong positive correlation between erythrophagocytosis and foamy cytoplasm in GCs (Spearman’s rank correlation coefficient: 0.9). Although majority of atypical GCs had one atypical feature, there was a considerable amount of GCs presenting ≥ 2 atypical features. Conclusions. Untreated patients with GD1 often show a considerable proportion of GCs with atypical cytomorphology. The knowledge of possible atypical variant forms of GCs can contribute to a quicker and accurate diagnosis of GD, and minimize the risk for misdiagnosis. To the best of our knowledge, this is the first published report on atypical cytomorphology of GCs in untreated patients with GD1.

Długotrwała pancytopenia po chemioterapii jako objaw demaskujący chorobę Gauchera u pacjentki z rakiem płuca

The diagnosis of congenital metabolic disease can be very difficult and often extends in time. This applies particularly to metabolic diseases of milder phenotype, such as an adult form (type 1) of Gaucher disease caused by the inherited (autosomal recessive) deficiency of the lysosomal enzyme glucocerebrosidase.In this work, we present a case of 48-year-old Polish patient (living in Sweden) with lung cancer, who developed a prolonged pancytopenia complicated by sepsis after each cycle of chemotherapy. These symptoms led to initiation of hematological diagnostic work-up and the assumption that the complications are caused by Gaucher disease. Definitive diagnosis of Gaucher disease was confirmed by results of enzymatic analyses, which revealed reduced activity of glucocerebrosidase in peripheral blood lymphocytes to 0.44μkat/kg protein (ref.: 2.1–3.8), increased activity of plasma chitotriosidase to 1241nkat/L (ref.: G (N370S), confirming diagnosis of type 1 Gaucher disease in the patient. The presence of the mutation c.604C>T has never been previously reported in a Polish patient with Gaucher disease. Administration of enzyme replacement therapy with imiglucerase (Cerezyme™) led to a rapid improvement of peripheral blood counts and enabled further continuation of intensive chemotherapy for lung cancer.In conclusion, the authors would like to emphasize that knowledge of the symptoms and the principles of diagnosis of Gaucher disease among hematologists is very important for efficient diagnostics of patients affected by this rare disease

Saccadic Impairments in Patients with the Norrbottnian Form of Gaucher’s Disease Type 3

BackgroundChronic neuronopathic Gaucher’s disease type 3 (GD3) is relatively frequent in northern Sweden. Besides multiple other neurological symptoms, horizontal gaze palsy or oculomotor apraxia is common in GD3.ObjectiveTo characterize the saccades in patients with Norrbottnian GD3 with respect to their neurological and cognitive status using a computer-based eye-tracking technique.MethodsHorizontal and vertical reflexive saccades as well as antisaccades of nine GD3 patients [4M/5F; 41.1 ± 11.0 years; modified severity scoring tool (mSST): 9.3 ± 5.4; Montreal Cognitive Assessment (MoCA): 24.0 ± 4.2] and age-matched controls were analyzed using EyeBrain T2, a head-mounted binocular eye tracker. Systematic clinical assessment included the mSST, a valid tool for monitoring the neurological progression in GD3 and MoCA.ResultsIn Norrbottnian GD3 patients, gain, peak, and average velocity (107.5°/s ± 41.8 vs. 283.9°/s ± 17.0; p = 0.0009) of horizontal saccades were reduced compared to healthy controls (HCs). Regarding vertical saccades, only the average velocity of downward saccades was decreased (128.6°/s ± 63.4 vs. 244.1°/s ± 50.8; p = 0.004). Vertical and horizontal saccadic latencies were increased (294.3 ms ± 37.0 vs. 236.5 ms ± 22.4; p = 0.005) and the latency of horizontal reflexive saccades was correlated with the mSST score (R2 = 0.80; p = 0.003). The latency of antisaccades showed association to MoCA score (R2 = 0.70; p = 0.009). GD3 patients made more errors in the antisaccade task (41.5 ± 27.6% vs. 5.2 ± 5.8%; p = 0.005), and the error rate tended to correlate with the cognitive function measured in MoCA score (p = 0.06).ConclusionThe mean age of 41 years of our GD3 cohort reflects the increased life expectancy of patients in the Norrbottnian area compared to other GD3 cohorts. Marked impairment of horizontal saccades was evident in all patients, whereas vertical saccades showed distinct impairment of downward velocity. Latency of reflexive saccades was associated with the severity of neurological symptoms. Increased latency and error rate in the antisaccade task were linked to cognitive impairment. The assessment of saccades provides markers for neurological and neuropsychological involvement in Norrbottnian GD3

Thirty-year clinical outcomes after haematopoietic stem cell transplantation in neuronopathic Gaucher disease.

BACKGROUND: Neuronopathic Gaucher Disease (nGD) describes the condition of a subgroup of patients with the Lysosomal Storage Disorder (LSD), Gaucher disease with involvement of the central nervous system (CNS) which results from inherited deficiency of β-glucosylceramidase. Although systemic manifestations of disease are now corrected by augmentation with macrophage-targeted therapeutic enzyme (enzyme replacement therapy, ERT), neurological disease progresses unpredictably as a result of failure of therapeutic enzyme to cross the blood-brain barrier (BBB). Without therapy, the systemic and neurological effects of the disease progress and shorten life: investigators, principally in Sweden and the UK, pioneered bone marrow transplantation (BMT; Haematopoietic Stem Cell Transplantation HSCT) to supply healthy marrow-derived macrophages and other cells, to correct the peripheral disease. Here we report the first long-term follow-up (over 20 years in all cases) of nine patients in the UK and Sweden who underwent HSCT in the 1970s and 1980s. This retrospective, multicentre observational study was undertaken to determine whether there are neurological features of Gaucher disease that can be corrected by HSCT and the extent to which deterioration continues after the procedure. Since intravenous administration of ERT is approved for patients with the neuronopathic disease and ameliorates many of the important systemic manifestations but fails to correct the neurological features, we also consider the current therapeutic positioning of HSCT in this disorder. RESULTS: In the nine patients here reported, neurological disease continued to progress after transplantation, manifesting as seizures, cerebellar disease and abnormalities of tone and reflexes. CONCLUSIONS: Although neurological disease progressed in this cohort of patients, there may be a future role for HSCT in the treatment of nGD. The procedure has the unique advantage of providing a life-long source of normally functioning macrophages in the bone marrow, and possibly other sites, after a single administration. HSCT moreover, clearly ameliorates systemic disease and this may be advantageous-especially where sustained provision of high-cost ERT cannot be guaranteed. Given the remaining unmet needs of patients with neuronopathic Gaucher disease and the greatly improved safety profile of the transplant procedure, HSCT could be considered to provide permanent correction of systemic disease, including bone disease not ameliorated by ERT, when combined with emerging therapies directed at the neurological manifestations of disease; this could include ex-vivo gene therapy approaches