No improvement of survival with reduced- versus high-intensity conditioning for allogeneic stem cell transplants in Ewing tumor patients.

BACKGROUND: Outcomes of Ewing tumor (ET) patients treated with allogeneic stem cell transplantation (allo-SCT) were compared regarding the use of reduced-intensity conditioning (RIC) and high-intensity conditioning (HIC) regimens as well as human leukocyte antigen (HLA)-matched and HLA-mismatched grafts. PATIENTS AND METHODS: We retrospectively analyzed data of 87 ET patients from the European Group for Blood and Marrow Transplantation, Pediatric Registry for Stem Cell Transplantations, Asia Pacific Blood and Marrow Transplantation and MetaEICESS registries treated with allo-SCT. Fifty patients received RIC (group A) and 37 patients received HIC (group B). Twenty-four patients received HLA-mismatched grafts and 63 received HLA-matched grafts. RESULTS: Median overall survival was 7.9 months [±1.24, 95% confidence interval (CI) 5.44-10.31] for group A and 4.4 months (±1.06, 95% CI 2.29-6.43) for group B patients (P = 1.3). Death of complications (DOC) occurred in 4 of 50 (0.08) and death of disease (DOD) in 33 of 50 (0.66) group A and in 16 of 37 (0.43) and 17 of 37 (0.46) group B patients, respectively. DOC incidence was decreased (P < 0.01) and DOD/relapse increased (P < 0.01) in group A compared with group B. HLA mismatch was not generally associated with graft-versus-Ewing tumor effect (GvETE). CONCLUSIONS: There was no improvement of survival with RIC compared with HIC due to increased DOD/relapse incidence after RIC despite less DOC incidence. This implicates general absence of a clinically relevant GvETE with current protocols.

High-performance laterally-arranged multiple-bandgap solar cells using spatially composition-graded CdxPb1-xS nanowires on a single substrate: a design study.

In this paper, laterally arranged multiple bandgap (LAMB) solar cells based on CdxPb1-xS alloy nanowires of varying composition on a single substrate are designed to be used together with a dispersive concentrator. Simulation results for a design with six subcells in series connection are presented. The design is based on a unique materials capability achieved in our recent research. An efficiency of 34.9% was obtained for operation without solar concentration, which increased to 40.5%, 41.7%, and 42.7% for concentration ratios of 25, 100, and 240 respectively. The device was also simulated with decreased carrier mobilities to model the possible reduction in absorber conductivity, depending on the nanowire geometry and configuration. For a concentration ratio of unity, decreasing the mobilities to 25% of their original values caused less than a 2.5% absolute drop in efficiency. The LAMB design offers the advantages of an integrated cell platform and the potential for low-cost, high efficiency photovoltaic systems.

The role of BMT in childhood histiocytoses.

Childhood histiocytoses comprise two main diseases, Langerhans cell histiocytosis (LCH) and hemophagocytic lymphohistiocytosis (HLH). LCH is a rare disorder with obscure pathogenesis. Data on clonality suggested neoplastic origin, yet were not convincing. Dysregulation of cytokines and of DC trafficking and cross-talk are documented. Clinical manifestations and course are highly variable, ranging from self-healing solitary bone lesion to disseminated, multi-organ involvement with 20% fatality rate despite standard chemotherapy. HSCT has been applied in less than 50 cases, outside any trial, with good disease control but elevated early toxicity. The familial form of HLH (FHL) has been recognized as congenital immune deficiency, with mutations of PRF1, Munc13-4, syntaxin11 genes resulting in defective cellular cytotoxicity machinery. Chemo-immunotherapy allows temporary disease control, but HSCT holds as the only procedure with potential for cure. Rapid identification of genetic defects allows differential diagnosis from transient, virus-associated HLH, thus indicating early HSCT. The role of HSCT in childhood histiocytoses is thus very important. Better understanding of the pathogenesis, in particular of genetic and immune function defects, will help to tailor indications and, possibly less toxic, conditioning regimens, reducing treatment-related mortality, and thus disclosing the way to final cure.

Human immunodeficiency virus-related cancer in children: incidence and treatment outcome--report of the Italian Register.

PURPOSE: To outline the incidence, presenting features, treatment response, and outcome of human immunodeficiency virus (HIV)-associated malignancies in infancy and childhood, together with the estimated risk of HIV-associated cancer in children born to mothers infected with HIV. PATIENTS AND METHODS: The Italian Register for HIV Infection in Children collected data by specific registration and follow-up forms. By March 1999, 5,060 children were recruited, including 4,889 with perinatal exposure to HIV-1. Overall, 1,331 infected children were enrolled onto the Register and classified according to current Centers for Disease Control criteria; of them, 1,163 were vertically infected (24% of those with perinatal exposure). Of these 1,163, 569 (49%) were considered to have been prospectively followed-up since they had been registered at birth or within the first 3 months of age. RESULTS: Of the 1,331 children observed for a median time of 6.5 years, 35 developed 36 malignancies, four of which occurred in patients with blood-borne risk. For the 1,163 vertically infected children, the cumulative number of years of observation was 7,178 child-years and the cumulative incidence of HIV-associated tumors was 4.18 per 1,000 children/yr (95% confidence interval [CI], 2.92 to 5.98). When only the 569 vertically infected children prospectively followed up since birth were considered, the cumulative number of years of observation was 2,803 child-years. In this group, 10 tumors were observed, with a cumulative incidence of HIV-associated tumors of 3.57 per 1,000 children per year (95% CI, 1.92 to 6.63). CONCLUSION: The risk of cancer was significantly higher but not restricted to symptomatic and/or immune-compromised children. Cancer-directed treatment should be given promptly to these patients, who have a fair chance to survive their tumor in view of potential highly aggressive antiretroviral therapy-associated improvement in survival and quality of life.

Immunoglobulin G3-specific antibodies as a marker for early diagnosis of HIV infection in children.

Early diagnosis of HIV infection in the child of an HIV-infected mother may be difficult as HIV-specific immunoglobulin (Ig) G antibodies are transmitted to the fetus transplacentally. In an attempt to provide a new, simpler tool for early identification of HIV-infected children we analysed the HIV-specific IgG subclass pattern during the first year of life. One hundred and one samples were collected from 35 children born to HIV-seropositive mothers, among whom 18 seroreverted during follow-up and 17 were HIV-infected (two P1 and 15 P2 according to the Centers for Disease Control classification). Serum HIV-specific IgG3 was detectable at least in one sample in 26 out of 35 children. All 17 HIV-infected children showed persistently detectable specific IgG3, both with stable or progressive disease. Out of the 18 uninfected children who seroreverted during follow-up, nine were HIV-specific IgG3-negative when first tested and nine lost HIV-specific-IgG3 within 28 weeks after birth. The correlation of the serological results with clinical information and any other diagnostic tool on each child suggests that the clearance of specific-IgG3 antibodies heralds seroconversion in uninfected passive antibody-carrier children. This observation provides the basis for a new, simple and effective method for early diagnosis of HIV infection in children born to seropositive mothers.

HIV-1 transmission through breast-milk: appraisal of risk according to duration of feeding.

OBJECTIVES: To estimate the risk of HIV-1 transmission through breast-milk in children born to infected mothers, and to determine the relationship between duration of breast-feeding and risk. DESIGN AND METHODS: The study population included 168 breast-fed and 793 bottle-fed children born to seropositive mothers. All subjects were enrolled and followed-up in the Italian Register for HIV Infection in Children; HIV sero-status was defined in all children. Multivariate analysis was performed using a logistic regression model. Independent variables included biological factors (duration of breast-feeding, gestational age, clinical condition of mother at delivery, mode of delivery, birth-weight and sex). Year of birth and age when HIV infection was diagnosed were also considered in the analysis attempting to control for possible selection biases. RESULTS: Breast-feeding increased the risk of HIV-1 transmission. The estimated adjusted odds ratio for 1 day of breast- versus bottle-feeding was 1.19 (95% confidence interval, 1.10-1.28). The infection odds ratio of breast- versus bottle-feeding increased with the natural logarithm of the duration of practice. CONCLUSIONS: These results are the first to provide an appraisal of the additional risk of HIV-1 transmission associated with a seropositive mother breast-feeding her child. Biological significance of this route of transmission was supported by demonstration of a relationship between duration of breast-feeding and risk of HIV-1 transmission.

Viral phenotype and host-cell susceptibility to HIV-1 infection as risk factors for mother-to-child HIV-1 transmission.

OBJECTIVE: To investigate the role of maternal HIV-1 isolate phenotype and a child's cell susceptibility/resistance to viral infection in mother-to-child HIV-1 transmission. PATIENTS AND METHODS: Forty-nine women were studied at the time of delivery. Primary isolates, obtained by culturing patient peripheral blood mononuclear cells (PBMC) with PBMC from healthy donors, were characterized for tropism and syncytium-inducing capability in monocyte-derived macrophages (MDM), peripheral blood lymphocytes (PBL), and in the MT-2 and MOLT-3 T-cell lines. RESULTS: Seven women transmitted HIV-1 to their children. Primary isolates were obtained from six and 28 transmitting and non-transmitting mothers, respectively. All primary isolates from transmitting mothers and their infants but only 50% of those from non-transmitting mothers replicated in MDM, regardless of their replication capacity in T-cell lines. PBL and MDM cells from six uninfected children were exposed to the corresponding maternal isolates. Polymerase chain reaction analysis of HIV-1 DNA in cells and p24 antigen assay in culture supernatants disclosed that two PBL and five MDM cultures were resistant to viral infection; two other PBL cultures, although HIV-1-infected, were negative for p24 production. Depletion of CD8+ cells only partially restored productive infection in CD4+ cell cultures. Moreover, all six PBL but only one MDM cultures were productively infected by an isolate obtained from a transmitting mother, thus suggesting that MDM resistance to HIV-1 infection is not viral isolate-restricted. CONCLUSIONS: Our findings strongly suggest that mother-to-child HIV-1 transmission is influenced by both monocyte-macrophage tropism of the maternal isolate and susceptibility of the child's target cells, in particular monocyte-macrophages, to HIV-1 infection.

Involvement of hormonal circadian secretion in the growth of HIV-infected children.

OBJECTIVE: To evaluate the circadian secretion of hormones involved in the regulation of growth in childhood, namely growth hormone, insulin-like growth factor (IGF)-I, cortisol, adrenocorticotropin hormone (ACTH), and thyroid-stimulating hormone (TSH) in HIV-infected children. DESIGN: The circadian secretory pattern of growth hormone, IGF-I, cortisol, ACTH and TSH was evaluated in 14 HIV-infected children; 13 healthy age- and sex-matched children were chosen as controls. METHODS: Sampling was performed every 4 h from 0400 h to 2000 h and every 2 h from 2000 h to 0400 h. Rhythmometric data were analysed by single and population mean cosinor methods and by analysis of variance. RESULTS: A statistically significant circadian rhythm for growth hormone, IGF-I and cortisol was detectable in HIV-seropositive children, but the mean basal IGF-I levels were below the normal range for age in 12 patients. A statistically significant circadian rhythm was not detectable for ACTH or TSH. CONCLUSION: These results show that there is a loss of the physiological regulation of growth hormone-IGF-I axis and a modification of 24 h TSH profile in our HIV-infected children. These abnormalities might be involved in the altered growth mechanism leading to the failure to thrive that is a peculiar feature of HIV-infected children.

Puberty in perinatal HIV-1 infection: a multicentre longitudinal study of 212 children.

OBJECTIVE: To define age at entry into Tanner stages in children with perinatal HIV-1 infection. DESIGN: Multicentre longitudinal study including 212 perinatally HIV-1-infected children (107 girls and 105 boys) followed-up during puberty (from 8 and 9 years onwards in girls and boys, respectively). Healthy children (843 girls and 821 boys) provided reference percentiles. P2 or B2 stages in girls and P2 or G2 stages in boys defined onset of puberty. METHODS: The cumulative probability [95% confidence limit (CI)] of entry into each stage at different ages was estimated by the Kaplan-Meier product-limit method; differences were evaluated by log rank test. Relationships were tested using the Spearman's rank correlation coefficient. RESULTS: Ages of girls [years (95%CI)] at P2 [12.9 (12.6-13.2)], P3 [13.4 (13.0-13.8)], P4 [14.6 (14.0-15.2)], B2 [12.7 (12.2-13.2)], B3 [13.3 (12.8-14.0)] and B4 [14.6 (14.0-15.2)] stages were > 97th percentile (> or = 21 month delay) of controls. Ages of boys [years (95%CI)] at P2 [12.6 (12.1-13.1)], P3 [13.9 (13.4-14.4)], P4 [14.9 (14.2-15.6)], G2 [12.1 (11.5-12.7)], G3 [13.6 (13.1-14.1)] and G4 [14.9 (14.1-15.7)] stages were at the 75-97th percentiles (< or = 15 month delay). Age at onset of puberty was not related to clinical and immunological condition, antiretroviral treatment, weigh for height and age at onset of severe disease or immune suppression. CONCLUSION: Perinatal HIV-1 infection interferes with sexual maturation. The mechanisms by which this occurs should be elucidated and intervention strategies designed. Intervention could save much psychological distress, since associated linear growth failure can exacerbate adolescents' feelings of being different and unwell.

Once versus twice daily administration of didanosine in children with symptomatic HIV-associated disease who were intolerant to or clinically deteriorated on zidovudine. The Italian Pediatric Collaborative Study Group on Didanosine.

The objective of this study was to compare the safety, tolerability and clinical response of once- versus twice-daily administration of didanosine given at a dosage of 270 mg/m2/day in children with symptomatic HIV-associated disease who were intolerant to or clinically deteriorated on zidovudine monotherapy. We carried out a randomized, open-label multicentre trial. Didanosine was supplied in buffered tablets, which could be chewed or dispersed in liquid. The children were recruited from 16 paediatric departments participating in the Italian Register for HIV Infection in Children. A total of 53 children (median age 5.5 years) started trial treatment; 26 were given didanosine twice daily and 27 once daily; 85% had AIDS and 98% had clinically deteriorated while on zidovudine therapy. Similar safety and tolerability results were demonstrated for the two schemes of therapy. A total of 11 children (20.7%) required discontinuation of didanosine for severe adverse events (five children (19.2%) in the twice-daily group; six children (22.2%) in the once-daily group, log-rank P = 0.81). Severe hepatic toxicity was uncommon (5.6%) while mild to moderate hepatic dysfunction was demonstrated in about 17% of the participants, without any difference between the two groups. Haematological toxicity was common (about 40% of the children, 11 in the twice- and 19 in the once-daily group) but never severe. Clinical pancreatitis and retinal lesions were never demonstrated. There was no significant difference in progression to death or to a new opportunistic infection between the two treatment regimens (log-rank P = 0.54). The modification of surrogate efficacy parameters during the study period was similar in the two groups. However, weight gain was poorer in children treated once daily. This study suggests that the safety and tolerability of 270 mg/m2/day of didanosine given once daily is substantially similar to that of the traditionally recommended schedule of two divided doses. Owing to the small sample and to the severity of the clinical condition of the children enrolled, no definite conclusions on the comparative efficacy of the two regimens can be drawn.

Fluconazole versus amphotericin B as empirical antifungal therapy of unexplained fever in granulocytopenic cancer patients: a pragmatic, multicentre, prospective and randomised clinical trial.

Amphotericin B, despite its intrinsic servere toxicity, is the most commonly used empirical antifungal therapy in cancer patients with unexplained fever not responding to empirical antibacterial therapy. The aim of this study was to show whether fluconazole was as effective as, and less toxic than, amphotericin, with no effort made to compare the antifungal activity of the two drugs. A group of 112 persistently febrile (> 38 degrees C) and granulocytopenic (< 1000 cells/mm3) cancer patients, not receiving any absorbable antifungal antibiotic for prophylaxis, with a mean age of 27 years (range 1-73 years), undergoing chemotherapy for a variety of malignancies and with a diagnosis of unexplained fever after at least 96 h of empirical antibacterial therapy, were randomised to receive either fluconazole (6 mg/kg/day up to 400 mg/day) or amphotericin B (0.8 mg/kg/day) as empirical antifungal treatment. Patients were required to have normal chest X-rays at randomisation, no previous history of aspergillosis and negative surveillance cultures for Aspergillus. The intention-to-treat analysis showed defervescence and survival without treatment modification in 42 of 56 patients (75%) in the fluconazole group and in 37 of 56 (66%) in the amphotericin B group (P = 0.4). Duration of therapy was 6 days (95% CI = 4-8 days) in both groups. Death occurred in 3 patients (5%) in the fluconazole and in 2 (4%) in the amphotericin B group. No fungal death was documented in either group. Adverse events developed in 18 of 56 patients (32%) in the fluconazole group and in 46 of 56 (82%) in the amphotericin B group (P < 0.001). In the amphotericin B group, 5 patients had treatment discontinued because of toxicity, versus none in the fluconazole group, a difference which approached statistical significance (P = 0.06). This study shows that fluconazole is by far less toxic than amphotericin B and suggests that it might be as effective as amphotericin B, in pragmatical terms and for this specific indication. However, numbers are too small to allow definitive conclusions about efficacy, and the use of fluconazole for this indication remains experimental. Future studies should try to identify patients more at risk of fungal infections, with the aim of individualising antifungal approaches.

Successful treatment of Griscelli syndrome with unrelated donor allogeneic hematopoietic stem cell transplantation.

Griscelli syndrome (GS) is a rare autosomal recessive disorder, characterized by pigmentary dilution of the skin and hair and in most patients by abnormal regulation of the immune system, which results in a syndrome of macrophage hyperactivation, known as hemophagocytic lymophohistiocytosis (HLH). Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment available for genetically induced HLH. Few cases of successful HSCT from a compatible donor have been reported in children with GS. We describe the first patient with GS cured with an allograft from a compatible unrelated bone marrow donor. We used a novel preparative regimen consisting of busulfan, thiotepa and fludarabine. The demonstrated curative effect of HSCT from an unrelated donor in a patient with genetically determined HLH also supports the use of a systematic diagnostic approach in these patients, in order to identify those with a worse prognosis and needing an urgent allograft in a timely manner.

[HIV infection and the endocrine system in children]. / Infezione da HIV e sistema endocrino nel bambino.

HIV infected children characteristically develop a failure to thrive in 25% to 100% of symptomatic cases, with a significantly reduced survival time. The pathogenic mechanism for HIV-driven failure to thrive is not yet understood. Likely it is multifactorial, endocrine dysregulation surely plays a major, even if not yet fully clarified, role in this complication. Global evaluation of endocrine data could allow to better understand the mechanisms underlying the failure to thrive in HIV-infected children, also in relationship with the current manifestations of the HIV infection. The results of the endocrine studies could also be related with additional features of the children, as their immunological status. It is well known that endocrine and immune functions are closely related in animals and in humans. Thus, the evaluation of the results of studies could provide some interesting information about the relationships between them in the HIV-infected child. Such relationships, if present, also could help to better define therapeutic interventions in these children.

Diagnostic value of viral culture, polymerase chain reaction and western blot for HIV-1 infection in 218 infants born to HIV-infected mothers and examined at different ages.

In a prospective longitudinal 10-year (1988 to 1998) study, 308 sequential blood samples from 218 infants born to HIV-1 seropositive women were examined by blood culture, polymerase chain reaction (PCR) and Western Blot (WB) for HIV-1 infection within the first month of life (no. 47 specimens), at 2-6 (no. 125), 7-18 (no. 80), and > 18 (no. 56) months after birth. Clinical status at follow-up after the initial diagnosis of HIV infection was also evaluated. Vertically transmitted HIV infection was diagnosed in 45 children (24 children were diagnosed before 18 months of age), whereas 173 were found to be uninfected (transmission rate 20.6%). Sensitivities of viral culture, PCR and WB were 95.2%, 97.8%, 94.4%, and specificities were 99.5%, 97.6% and 20.7%, respectively. Thus, cumulative positive predictive values (PPV) of blood culture, PCR and WB were 97.5%, 88.2% and 23.4%, while negative predictive values (NPV) were 99.0%, 99.6% and 100.0%, respectively. In view of defining the optimal time of sampling for a correct diagnosis of HIV infection, a PPV of 100.0% was achieved earlier by viral culture (2-6 months of age) than by PCR (7-18 months of age). Meanwhile, a NPV of 100% was obtained earlier by PCR (within the first month of age) than by viral culture (2-6 months). These results indicate that a combination test strategy requiring two blood samples analyzed by viral culture and PCR may confirm or exclude HIV perinatal infection within the first 2 months of life rather than being delayed to later times. Clinical follow-up was performed in 35 children, of whom 7 developed a rapidly progressive disease, 23 showed a slow progression, while 5 children are still younger than 5 years and do not present severe clinical symptoms.

[Course of mother-child relations in cases of maternal HIV infection]. / L'evoluzione della relazione madre-bambino in caso di infezione materna da HIV.

32 children born from HIV infected mothers (8 HIV infected and 24 seroreverted uninfected) were followed up from 1990 to 1995 at the Neurological Institute "C. Mondino" in Pavia to study the mother and baby relationship. At the end of the follow-up period, from the birth to the end of the second year of age, all children had psychosomatic disorders (repeated rejections, anorexia, sleep disturbances characterised by difficulty in falling asleep and frequent wake-ups, gaseous colics many times during the day). The psychosomatic disorders are considered as the result of an early distortion of the mother and baby relationship. Thus children born from HIV positive mothers are exposed to the possibility of developing psychological problems related to a distorted relationship with their mother.

[Neuropsychological development of children born to HIV-positive mothers]. / Lo sviluppo neuropsichico del bambino nato da madre HIV positiva.

138 children born to HIV infected mothers (58 HIV infected and 80 seroreverted uninfected) were followed up at the Institute of Infectious Diseases of the University of Pavia. All patients had an evaluation of neurological assessment every three months done by a pediatric neurologist (Amiel-Tison and Towen) and an evaluation of psychological assessment by observation of child-mother interaction. The development quotient was examined using the Griffiths Scales and mental development using the Wisc-R scale. The incidence of Central Nervous System involvement was 36% in children with symptomatic HIV infection, the hump of incidence of severe encephalopathy was in the first 4 or 5 year of life, another hump (smaller) was in preadolescence. Development deficit and psychological problems were discovered both in asymptomatic infected and in non infected children, without difference of percentage between the two groups.