Hypercalcemia is a frequent side effect of 13-cis-retinoic acid treatment in patients with high-risk neuroblastoma.

PURPOSE: 13-cis-Retinoic acid (13-cisRA) is used as a postconsolidation treatment in patients with high-risk neuroblastoma. Hypercalcemia is a known side effect of retinoids. Frequency, symptoms, treatment, and risk factors for hypercalcemia were analyzed. PATIENTS: Data were retrospectively analyzed for 350 patients registered in the German Neuroblastoma trials NB97 and NB04 who were treated with high-risk protocols-including myeloablative chemotherapy with autologous stem cell transplantation (SCT) or maintenance therapy-and had received 13-cisRA between January 1, 2000 and December 31, 2010. RESULTS: Hypercalcemia was reported in 78 patients (22.3%), and 37 patients (10.6%) developed Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or 4 hypercalcemia. The calcium levels were 2.5-4.6 mmol/L (median 3.1 mmol/L). Patients with a single kidney were at a higher risk of developing hypercalcemia (p = .001). Regarding postinduction treatment, 69 of 280 patients with SCT (24.6%) and nine of 70 patients without SCT (12.9%) developed hypercalcemia during 13-cisRA treatment (p = .037). Most patients developed hypercalcemia in the first cycle of 13-cisRA, and only in a single cycle. Hypercalcemia symptoms were frequent but moderate. In most patients, treatment with 13-cisRA was continued without dose reduction in subsequent cycles. CONCLUSION: In this cohort, grades 3 and 4 hypercalcemia were observed more often than previously reported. A single kidney and pretreatment with myeloablative chemotherapy with stem cell transplantation were identified as potential risk factors for the development of hypercalcemia.

Baclofen intoxication: a "fun drug" causing deep coma and nonconvulsive status epilepticus--a case report and review of the literature.

UNLABELLED: The number of reports on baclofen intoxication has increased in recent years. We report a 15-year-old boy who was referred in a state of deep coma (Glasgow Coma Scale = 3). On clinical examination, he showed sinus bradycardia with normal blood pressure. On admission to the hospital, he presented intermittent short episodes of generalized tonic-clonic seizures. While results of imaging procedures and initial toxicological screening (including standard HPLC analysis and urine test) were negative, a nonconvulsive status epilepticus was diagnosed by electroencephalography (EEG). Identification of baclofen as causative agent was possible after the boy's father reported abusive baclofen intake. Subsequent toxicological target analysis of blood and urine samples confirmed the excessive intake of baclofen and showed a typical elimination pattern with a secondary release. Following 112 h of mechanical ventilation, the boy rapidly regained consciousness and recovered normal neurological behavior. CONCLUSIONS: The present case demonstrates the importance of considering baclofen overdosage in cases of severe coma in combination with an abnormal EEG pattern and sinus bradycardia with normal blood pressure levels, in particular as the substance is popular in internet reports promoting baclofen as a rather harmless "fun drug." Furthermore, it underlines the difficulty to identify baclofen as a causative agent without anamnestic information. Nevertheless, by reviewing existing literature on oral baclofen overdosage, it is possible to picture a nearly specific pattern of clinical symptoms in baclofen intoxication.

Corrigendum: Clinical and Molecular Heterogeneity of RTEL1 Deficiency.

[This corrects the article on p. 449 in vol. 8, PMID: 28507545.].

Clinical and Molecular Heterogeneity of RTEL1 Deficiency.

Typical features of dyskeratosis congenita (DC) resulting from excessive telomere shortening include bone marrow failure (BMF), mucosal fragility, and pulmonary or liver fibrosis. In more severe cases, immune deficiency and recurring infections can add to disease severity. RTEL1 deficiency has recently been described as a major genetic etiology, but the molecular basis and clinical consequences of RTEL1-associated DC are incompletely characterized. We report our observations in a cohort of six patients: five with novel biallelic RTEL1 mutations p.Trp456Cys, p.Ile425Thr, p.Cys1244ProfsX17, p.Pro884_Gln885ins53X13, and one with novel heterozygous mutation p.Val796AlafsX4. The most unifying features were hypocellular BMF in 6/6 and B-/NK-cell lymphopenia in 5/6 patients. In addition, three patients with homozygous mutations p.Trp456Cys or p.Ile425Thr also suffered from immunodeficiency, cerebellar hypoplasia, and enteropathy, consistent with Hoyeraal-Hreidarsson syndrome. Chromosomal breakage resembling a homologous recombination defect was detected in patient-derived fibroblasts but not in hematopoietic compartment. Notably, in both cellular compartments, differential expression of 1243aa and 1219/1300aa RTEL1 isoforms was observed. In fibroblasts, response to ionizing irradiation and non-homologous end joining were not impaired. Telomeric circles did not accumulate in patient-derived primary cells and lymphoblastoid cell lines, implying alternative pathomechanisms for telomeric loss. Overall, RTEL1-deficient cells exhibited a phenotype of replicative exhaustion, spontaneous apoptosis and senescence. Specifically, CD34+ cells failed to expand in vitro, B-cell development was compromised, and T-cells did not proliferate in long-term culture. Finally, we report on the natural history and outcome of our patients. While two patients died from infections, hematopoietic stem cell transplantation (HSCT) resulted in sustained engraftment in two patients. Whether chemotherapy negatively impacts on the course and onset of other DC-related symptoms remains open at present. Early-onset lung disease occurred in one of our patients after HSCT. In conclusion, RTEL deficiency can show a heterogeneous clinical picture ranging from mild hypocellular BMF with B/NK cell lymphopenia to early-onset, very severe, and rapidly progressing cellular deficiency.

Influence of isotypes of disease-associated autoantibodies on the expression of natural autoantibody repertoires in humans.

Current understanding of immune network interactions mediated by immunoglobulins focuses on the role of idiotypes expressed on antibody variable regions. Idiotype interactions account significantly for the functional integrity of natural self-reactive antibody repertoires, whereas immunoglobulin isotypes are not considered to direct natural autoimmunity. Autoimmune thrombocytopenic purpura (AITP), a bleeding disorder caused by clonally restricted platelet-specific autoantibodies of the IgM or IgG isotype, is an excellent model to investigate the impact of isotype differences of immunoglobulins on the selection of natural self-reactive antibody repertoires in humans. Using specific analytical techniques to characterize the natural self-reactive antibody repertoire (i.e. quantitative immunoblotting, affinity biosensor technology), we here demonstrate that isotype differences of disease-associated autoantibodies are associated with altered natural self-reactive antibody repertoires in humans. Our data suggest that regulation of natural autoreactivity by antibody isotype might occur under certain conditions. The control of natural self-reactive antibody repertoires by immunoglobulin isotypes at a supraclonal level may provide a structural basis for non-organ-specific broad alterations of natural self-reactive antibody repertoires in organ-specific autoimmune diseases.

Evidence that human autoimmune thrombocytopenia mediated by both immunoglobulin isotypes IgM and IgG is an independent disease entity.

Autoimmune thrombocytopenic purpura (AITP) is a bleeding disorder caused by clonally restricted self-reactive antibodies with specificity for platelet glycoproteins. Anti-platelet autoantibodies in AITP mainly belong to the IgG class. The occurrence of anti-platelet autoantibodies of the IgM isotype has been reported, and AITP is partially mediated by antibodies of both isotypes, IgM and IgG. Using a technique of quantitative immunoblotting of immunoglobulins on self-tissues, followed by multiparametric statistical analysis of the data, we here demonstrate that patients with IgM- and IgG-mediated AITP are readily discriminated from patients with IgM-mediated AITP as well as from patients with IgG-mediated AITP at the basis of self-reactive antibody repertoires of isotypes IgM and IgG toward non-platelet antigens of human origin. Our data suggest that, in view of the important physiological functions of self-reactive antibody repertoires, human AITP mediated by both immunoglobulin isotypes IgG and IgM may be an independent disease entity. The role of autoantibody isotype for the pathophysiology of AITP might currently be underestimated, and diagnostic and therapeutic procedures in AITP might profit from considering autoantibody isotype more carefully.