The Non-Langerhans Cell Histiocytoses (Rare Histiocytoses) - Clinical Aspects and Therapeutic Approaches.

Rare histiocytoses, also called non-Langerhans cell histiocytoses, include all proliferative disorders of histiocytes, macrophages and dendritic cells that are not classified as Langerhans cell histiocytosis (LCH) and do not belong to the hemophagocytic lymphohistiocytosis (HLH) group of diseases. Thus, the term includes numerous benign or malignant, localized or systemic, adult or pediatric diseases. The classification of the histiocytic disorders has been revised several times. Here, we follow the classification recently published by Jean Francois Emile and an international expert panel, defining subgroups of histiocytoses described as L-Group, C-Group, M-Group, R-Group, and H-Group, which stands for LCH-like, cutaneous or mucocutaneous, malignant, Rosai-Dorfman-Disease like and HLH like. Some of the diseases have an excellent prognosis after resection or even disappear spontanously, others progress rapidly, requiring intensive systemic therapies. The malignant non-Langerhans cell histiocytoses in general have a poor prognosis, here, complex chemotherapy protocols are usually applied, with inconsistant results. An interesting perspective in non-malignant rare histiocytoses might be small molecular inhibitors, in particular BRAF inhibitors, since BRAF mutations have been found in some subtypes of non-Langerhans cell histiocytoses. By prospective and retrospective collection of experiences in a new registry (the "International Rare Histiocytic Disorders Registry", IRHDR), knowledge about these rare diseases might hopefully be improved.

Ferritin concentrations correlate to outcome of hematopoietic stem cell transplantation but do not serve as biomarker of graft-versus-host disease.

Clinical presentation and laboratory data are often too unspecific to distinguish the onset or activity of graft-versus-host disease (GvHD) from infections or toxicity. Antigen-presenting cells such as monocytes/macrophages and dendritic cells are involved in GvHD pathogenesis after allogeneic hematopoietic stem cell transplantation (HSCT). To test whether ferritin, an iron storage marker and macrophage activation-linked acute-phase protein, represents a candidate biomarker for acute or chronic GvHD in pediatric HSCT, we retrospectively evaluated a 2-year follow-up data from 131 eligible consecutive patients with different malignant and nonmalignant diseases who underwent allogeneic HSCT. Thirteen patients (10 %) suffered from acute GvHD II-IV°, 18 (14 %) had limited, and 14 (11 %) had extensive chronic GvHD. In extension of previous studies in adults investigating pre-transplant ferritin, our data show that post-HSCT hyperferritinemia (analyzed on days 0, +30, +60, +100, +180, +360, and +720) was significantly associated with decreased long-term survival (p < 0.001-0.03) in children and adolescents. Increased ferritin concentrations were associated with number and timing of red blood cell transfusions and toxic or infectious multi-organ failure but did not show significant differences between patients without GvHD and with acute grades II-IV, limited, or extensive chronic GvHD. Thus, our data do not identify ferritin as specifically GvHD-linked biomarker; however, they support the prognostic value of ferritin levels for outcome after HSCT in children.

Clinical and immunological overlap between autoimmune lymphoproliferative syndrome and common variable immunodeficiency.

Autoimmune lymphoproliferative syndrome (ALPS) is mainly caused by defects in the CD95 pathway. Raised CD3+TCRαß+CD4-CD8- double negative T cells and impaired T cell apoptosis are hallmarks of the disease. In contrast, the B cell compartment has been less well studied. We found an altered distribution of B cell subsets with raised transitional B cells and reduced marginal zone B cells, switched memory B cells and plasma blasts in most of 22 analyzed ALPS patients. Moreover, 5 out of 66 ALPS patients presented with low IgG and susceptibility to infection revealing a significant overlap between ALPS and common variable immunodeficiency (CVID). In patients presenting with lymphoproliferation, cytopenia, hypogammaglobulinemia and impaired B cell differentiation, serum biomarkers were helpful in addition to apoptosis tests for the identification of ALPS patients. Our observations may indicate a role for apoptosis defects in some diseases currently classified as CVID.

Evaluating bleeding severity in children with newly diagnosed immune thrombocytopenia: a pilot study.

BACKGROUND: Childhood immune thrombocytopenia (ITP) is a bleeding disorder characterized by decreased platelet counts. Assessment of the individual bleeding risk during the course of the disease would allow more accurately guiding treatment-related decisions in these patients. PATIENTS AND METHODS: We conducted a pilot study and prospectively evaluated platelet counts and bleeding signs using an established bleeding (Buchanan) score in 30 patients with newly diagnosed ITP at 3 different time points (at diagnosis [TP1], on day 2-3 [TP2], and on day 5-8 [TP3]) during the first week after diagnosis. 15 patients received immune modulatory therapy. RESULTS: Median platelet counts at the 3 different time points were 13, 19, 32×10 (9)/L (untreated patients) and 2, 7, 37×10 (9)/L (treated patients). Corresponding median cumulative bleeding scores were 5, 2, 0 (untreated patients) and 7, 6, 2 (treated patients). Cumulative median bleeding scores and platelet counts were inversely correlated in treated and untreated patients at all 3 time points. Cumulative median bleeding scores significantly decreased in both groups. CONCLUSIONS: Bleeding signs in children with newly diagnosed ITP rapidly improve within one week after diagnosis. Serial grading of bleeding severity seems to be useful to comprehensively assess and monitor the individual bleeding risk in these patients, but has to be evaluated and validated in a larger cohort.

Importance of allogeneic T-cells for disease control after stem cell transplantation for high-risk Langerhans cell histiocytosis.

Reduced intensity conditioning followed by allogeneic SCT (RIC-SCT) has recently emerged as promising new salvage option for children suffering from Langerhans cell histiocytosis (LCH) with risk organ involvement and failure to conventional therapy. We report on the posttransplant course of female toddler with high-risk LCH, who achieved complete remission after RIC-SCT, despite a posttransplant chimerism constellation, in which only the T-cell subset proved to be of donor origin in the long-term. We therefore suggest that allogeneic T-cells have played a crucial role in controlling disease activity in this patient and may exert the major curative effect after RIC-SCT for LCH.

NADPH-diaphorase-positive neurons in the human inferior colliculus: morphology, distribution and clinical implications.

Using the nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) reaction with nitroblue tetrazolium, we provided a detailed investigation of the distribution, dimensional characteristics and morphology of NADPH-d-positive neurons in the three main subdivisions of the human inferior colliculus (IC): central nucleus, pericentral nucleus, and external nucleus. In accordance with their perikaryal diameter, dendritic and axonal morphology, these neurons were categorized as large (averaging up to 45 µm in diameter), medium (20-30 µm), small (13-16 µm) and very small (7-10 µm). Their morphological differences could contribute to varying functionality and processing capacity. Our results support the hypothesis that large and medium NADPH-d-positive cells represent projection neurons, while the small cells correspond to interneurons. Heretofore, the very small NADPH-d-positive neurons have not been described in any species. Their functions-and if they are, indeed, the smallest neurons in the IC of humans-remain to be clarified. Owing to their location, we posit that they are interneurons that connect the large NADPH-d-positive neurons and thereby serve as an anatomical substrate for information exchange and processing before feeding forward to higher brain centers. Our results also suggest that the broad distribution of nitric oxide (NO) synthesis in the human IC is closely tied to the neuromodulatory action of NO on collicular neurotransmitters such as GABA and glutamate, and to calcium-binding proteins such as parvalbumin. A deeper understanding of the relationship between NADPH-d-positive fibers in all IC connections and their co-localization with other neurotransmitters and calcium-binding proteins will assist in better defining the function of NO in the context of its interplay with the cerebral cortex, the sequelae of the aging process and neurodegenerative disorders.

Management of chronic immune thrombocytopenia in children and adolescents: lessons from an Austrian national cross-sectional study of 81 patients.

Chronic immune thrombocytopenia (cITP) is often associated with an underlying predisposition towards autoimmunity, recognition of which is relevant to guide treatment. International recommendations on diagnostic steps and therapeutic measures of cITP in childhood exist. However, due to the low prevalence (1-2/100,000) and a variation of availability of immunological and hematological tests and treatments across pediatric units, we postulated that these guidelines are not uniformly adhered to and that immune dysregulation syndromes remained undiscovered. To delineate the current management of children and adolescents with cITP in Austria, we performed a nationwide cross-sectional study. Between 2011 and 2014, 81 children with cITP were seen at seven centers (median age 8.75 years; range 1-17; female:male ratio 47:34) at 641 visits during 180 patient years after diagnosis of cITP (>12 months ITP duration). Additional diagnoses were noted, most frequently immune or autoimmune disorders, hematologic diseases, or infections (in 37.3%, including Evans syndrome, autoimmune lymphoproliferative syndrome, systemic lupus erythematosus, and Fanconi anemia), or other symptoms like bi- or pancytopenia (n=9), lymphoproliferation or granulomatous inflammation (n = 3). Both decision to treat as well as choice of treatment varied: smaller centers tended to observe more frequently, larger centers applied a pattern of treatment modalities that appeared to depend less on bleeding tendency than on center policy. More than 50% of therapeutic interventions occurred in bleedings scores ≤2 (of 5), suggesting a strong psychosocial intention to treat. Platelet increment upon 479 therapeutic interventions of eight types was evaluated, with multiple treatment approaches being pursued sequentially in refractory patients. These data confirm the hypothesis of heterogeneous diagnostic and therapeutic management of cITP in Austrian children and corroborate the need for (1) a precise panel of parameters to exclude underlying disorders and (2) for biomarkers to predict treatment response.

Improved outcome of treatment-resistant high-risk Langerhans cell histiocytosis after allogeneic stem cell transplantation with reduced-intensity conditioning.

Children with multisystem Langerhans cell histiocytosis (LCH) and risk organ involvement who fail to respond to conventional chemotherapy have an extremely poor prognosis. Myeloablative stem cell transplantation (SCT) as a possible salvage approach for these patients has been associated with a high risk of transplant-related mortality. Therefore, allogeneic stem cell transplantation following a reduced-intensity conditioning regimen (RIC-SCT) has recently been performed as an alternative salvage approach. We report on the experience with allogeneic RIC-SCT in nine pediatric high-risk LCH patients. Conditioning regimen included fludarabine in all patients, melphalan in eight patients, total lymphoid irradiation in six patients, total body irradiation in two, antithymocyte globulin in five, and Campath in four patients. RIC-SCT was well tolerated with regard to common procedure-related complications. Two patients died 50 and 69 days after RIC-SCT, respectively. Seven out of the nine patients survived and showed no signs of disease activity (including one with nonengraftment and full autologous hematopoietic recovery) after median follow-up of 390 days post-SCT. Based on this observation, we conclude that RIC-SCT is a feasible procedure with low transplant-related morbidity and mortality and a promising new salvage approach for high-risk LCH patients with resistant risk organ involvement.

Proposal for standard recommendations for prophylaxis of graft-versus-host disease in children. European Group for Blood and Marrow Transplantation (EBMT) Working Party Paediatric Diseases and the International Study Committee of the BFM family-subcommittee Bone Marrow Transplantation (IBFM-STG).

Great variations exist in the practices of graft-versus-host disease prophylaxis for children undergoing allogeneic stem cell transplantation. It was the aim of the EBMT Working Party on Paediatric Diseases and the International Study Group of the BFM-Family, subcommittee bone marrow transplantation (IBFM-SG) to define standard recommendation for prevention of GVHD. Thus a survey was carried out among the local representatives of the EBMT WP and IBFM-SG members to define standards for GVHD prophylaxis basing on available literature data, discussion with colleagues and their own experience. Presently the majority of regimen for GVHD prophylaxis are centred on CsA and a short course of MTX with addition of some other immunosuppression (eg ATG or ALG) in patients with high risk for severe GVHD. The proposal defined different category of patients: patients with malignant disease who are either transplanted from HLA matched sibling donors or HLA mismatched family donors (or volunteer unrelated donors) and patients with non malignant disease who might not benefit from graft-versus-leukaemia effect having either an HLA matched sibling donor or an HLA mismatched family donor (or volunteer unrelated donor). Homogeneous GVHD prophylaxis for defined patient groups should provide better information to optimise strategies in reducing treatment related toxicity and incidence of relapse by increasing GVL effect.

Statement of current majority practices in graft-versus-host disease prophylaxis and treatment in children.

Great variations exist in the prophylaxis and treatment of GVHD in children undergoing allogeneic stem cell transplantation (SCT). The EBMT Working Party Paediatric Diseases (EBMT-WP PD) and the International BFM Study Group--Subcommittee Bone Marrow Transplantation (IBFM-SG), aimed at evaluating current local standards in the prevention and treatment of GVHD and steps which can be taken to achieve a uniform policy for the individual methods. Several conferences with their members assessed practices which are mainly applied or under investigation in children and identified where additional information is needed. For prevention of GVHD, the majority of the paediatric centres prefer CsA +/- MTX. Addition of folinic acid to MTX was considered for reduction of side-effects. During treatment of acute GVHD most centres administer prednisolone and whole blood level-adjusted CsA as medications of first choice. In cases of poor or no response to this therapy, additional immunosuppressive agents such as ATG, mycophenolate-mofetile and tacrolimus are being increasingly used. The treatment of chronic GVHD usually consists of various combinations of prednisolone and CsA. In severe cases, extracorporeal photopheresis, psoralene-UVA (PUVA) and thalidomide are administered.

Transplantation activities and treatment strategies in paediatric stem cell transplantation centres: a report from the EBMT Working Party on Paediatric Diseases. European Group for Blood and Marrow Transplantation.

To determine the current approach to stem cell transplantation (SCT) in centres which treat predominantly paediatric patients, a questionnaire was sent to 67 centres known by the EBMT registry to perform SCT mainly in children. Fifty-five centres from 19 countries responded. Forty centres (75%) started their transplantation activities between 1980 and 1992. Median number of transplants/centre was 95 (range 8-400). Median number of transplants/centre/year was 18 (range 5-85). On average, there was one physician responsible for seven SCT/year while one nurse was involved for a median of 1.7 SCT/year. Median four rooms/centre (range 1-17) were available for paediatric SCT. The most common isolation facilities were rooms with high efficiency particulate air filtration (HEPA). Eighty-two percent (45/55) of the centres performed allogeneic as well as autologous SCT, while 5% (three centres) offered exclusively allogeneic SCT and 13% (seven centres) used only autologous stem cell rescue. Stem cell source for allogeneic SCT was bone marrow in 87%, peripheral blood (PB) in 10% and umbilical cord blood in 3%. Donors were HLA matched related in 57%, mismatched related in 13%, and matched unrelated in 30% of allogeneic SCT. PB was the most commonly used stem cell source for autologous SCT (48%), followed by BM (41%) and the two together (11%). Data analysis revealed substantial differences in protective care, stem cell processing and transplantation procedures within the centres, irrespective of the country, centre size and transplant type.

[Associated trauma with urinary tract injuries]. / Traumatismes généraux avec participation des voies urinaires.

The authors analyze the peculiarities in the diagnostic and curative behavior in cases of associated traumatic injuries with participation of the urinary system in adults and children. A trauma is defined as associated when one kind of traumatic agent affects more then one organ or system. The authors do not discuss the combined trauma where we observed different damaging agents as for example mechanical trauma plus radiation or burn. The experience of the treatment of 64 children and 109 adults suffering from associated traumatic injuries for the period 1981-1997 has been summarized. In cases of associated traumatic injuries the kidneys are the most common participants on the part of the urinary system (70.3% of the children and 51.4% of the adults). On the second place we witness bladder damages in adults and urethra damages in children. The data concerning the combination between urological trauma and other organs traumas are available in details--the most common are: bone fractures, lesions of intraabdominal organs, skull and brain traumas, etc. The three basic problems caused by such kind of trauma are also discussed--organizational, diagnostic and curative. At the end the authors present the most typical characteristics of associated traumatic injuries in children compared to those in adults.

Parvalbumin-immunoreactive neurons in the human claustrum.

The morphology and distribution of parvalbumin-immunoreactive neurons (PV-ir) were studied in the human claustrum. PV-ir neurons were observed throughout the claustrum, with the highest numbers noted in the central (broadest) portion as compared with the dorsal and ventral aspects. Reaction product was evident in the neuronal perikarya, dendritic processes, and spines. In the majority of these labeled neurons, the cytoplasm was devoid of lipofuscin pigment. Cell bodies varied widely in both shape and size, ranging from oval and small, to multipolar and large. PV-ir neurons were classified into two groups, primarily based on dendritic morphology: spiny neurons with long and straight dendrites, and aspiny neurons with thin and curving dendritic processes. PV-ir fibers were seen throughout the neuropil, with many immuno-positive puncta noted.

Neuropeptide Y immunoreactivity in the cat claustrum: A light- and electron-microscopic investigation.

The claustrum is a telencephalic nucleus located ventrolateral to the basal ganglia in the mammalian brain. It has an extensive reciprocal connectivity with most if not all of the cerebral cortex, in particular, primary sensory areas. However, despite renewed and growing interest amongst investigators, there remains a paucity of data concerning its peptidergic profile. The aim of the present study was to examine the presence, morphology, distribution and ultrastructure of neuropeptide Y-immunoreactive (NPY-ir) neurons and fibers in the claustrum of the cat. Ten adult healthy cats from both sexes were used. All animals received human and ethical treatment in accordance with the Principles of Laboratory Animal Care. Subjects were irreversibly anesthetized and transcardially perfused with fixative solution containing glutaraldehyde and paraformaldehyde. Brains were promptly removed, postfixed and sectioned. Slices were incubated with polyclonal anti-NPY antibodies according to the standard avidin-biotin-peroxidase complex method adopted by our Department of Anatomy, Histology and Embryology. NPY-ir neurons and fibers were found to be diffusely distributed throughout the claustrum, with no obvious topographic or functional patterning other than larger numbers in its central/broadest part (stereotaxic planes A12-A16). Neurons were generally classified by diameter into three sizes: small (under 17 µm), medium (17-25 µm) and large (over 25 µm). Staining density is varied with some neurons appearing darker than others. At the electron-microscopic level NPY immunoproduct was observed within neurons, dendrites and terminal boutons, each differing relative to their ultrastructural attributes. Two types of NPY-ir synaptic boutons were found. Lastly, it is of interest to note that gender-specific differences were not observed.

Risk factors for diabetes insipidus in langerhans cell histiocytosis.

BACKGROUND: Diabetes insipidus (DI) is the most frequent central nervous system (CNS)-related permanent consequence in Langerhans cell histiocytosis (LCH), which mostly requires life-long hormone replacement therapy. In an attempt to define the population at risk for DI, 1,741 patients with LCH registered on the trials DALHX 83 and DALHX 90, LCH I and LCH II were studied. RESULTS: Overall 212 of 1,741 patients (12%) was reported to have DI. In 102 of 1,741 patients (6%) DI was present at diagnosis of LCH. One thousand one hundred eighty three of 1,539 patients without DI at diagnosis had follow up information. One hundred ten of these (9%) later developed DI. The risk of developing DI was 20% at 15 years after diagnosis. Multisystem disease patients at diagnosis carried a 4.6-fold risk for DI compared to single system patients. Craniofacial lesions, in particular in the "ear," "eye," and oral region were associated with a significantly increased risk for DI (relative hazard rate, RHR 1.7), independent of the extent of disease. No influence of the duration of therapy could be determined, but the duration of initial disease activity (RHR 1.5) and the occurrence of reactivations (RHR 3.5) significantly increased the risk for DI. CONCLUSIONS: Patients with multisystem disease and craniofacial involvement at diagnosis, in particular of the "ear," "eye," and the oral region carry a significantly increased risk to develop DI during their course. This risk is augmented when the disease remains active for a longer period or reactivates.

Langerhans cell histiocytosis in neonates.

BACKGROUND: To study the incidence, clinical patterns, course, and outcome of neonatal Langerhans cell histiocytosis (LCH). PROCEDURE: Retrospective analysis of the data of the Austrian/German/Swiss/Netherlands LCH Study Group. The incidence of neonatal LCH was estimated with the data from the population-based German Childhood Cancer Registry. RESULTS: The estimated incidence of neonatal LCH (LCH diagnosed within 28 days after birth) in the population-based registry was 1-2/1,000,000. In 61/1,069 trial patients (6%), the first disease manifestations were observed in the neonatal period. However, in only 20 of them, the diagnosis was established within this period. There was a preponderance of multisystem (MS)-LCH 36/61 (59%). Cutaneous changes were the most common initial manifestation in both, single-system (SS)-LCH (92%), and MS-LCH (86%). In 72% of the MS-LCH patients, risk organs (ROs) were involved at diagnosis as well. The probability of survival at 5 years was 94% in SS-LCH and 57% in MS-LCH, which is significantly lower than in older age groups. CONCLUSIONS: In contrast to the available literature, neonatal LCH is characterized by a clear predominance of MS-LCH. Cutaneous changes are the most common initial manifestation in neonates with both SS-LCH and MS-LCH. Prompt evaluation of disease extent upon diagnosis is mandatory for risk-adapted treatment. The disease course is unpredictable upon diagnosis. Close monitoring for disease progression is mandatory if isolated cutaneous LCH is managed by the "wait and see" approach. Neonates with MS-LCH, especially those with RO involvement at diagnosis, have less favorable prognosis compared to infants and older children, and need systemic therapy.

[Integrating demographic and socioeconomic policies]. / Integrirane na demografskata sas sotsialno-ikonomicheskata politika.

"The article offers a theoretical model of integration between demographic and socioeconomic policy [in Bulgaria].... The author examines the changes in the population's demographic structures: changes in the sex ratio; ageing; [and] family nuclearisation.... The conclusion is drawn that in order to boost the effectiveness of the demographic policy, social practice and its scientific back-up should be even more fully integrated." (SUMMARY IN ENG)

[Demographic processes and problems in the Lovech area]. / Demografski protsesi i problemi v Loveshkiya krai.

PIP: The author analyzes demographic trends in Lovech, Bulgaria, with a focus on the impact of socioeconomic, psychological, social, and biological factors on fertility, mortality, and migration. Implications for population policy development are discussed. (SUMMARY IN ENG AND RUS)^ieng

[Population census--present and future]. / Prebroyavaneto na naselenieto--nastoyashche i perspektivi.

PIP: The theoretical basis of Bulgaria's population census is outlined. The author recommends the development of a system of sample surveys linked to the census in order to meet the country's statistical needs. (SUMMARY IN ENG AND RUS)^ieng