Influence of glutathione S-transferase gene polymorphisms on busulfan pharmacokinetics and outcome of hematopoietic stem-cell transplantation in thalassemia pediatric patients.

Hematopoietic stem-cell transplantation (HSCT) is currently the only curative therapeutic option for the treatment of thalassemia. In spite of the high cure rate, HSCT can lead to life-threatening adverse events in some patients. Busulfan (Bu) is a key component of the conditioning regimen prior to HSCT. Inter-individual differences in Bu pharmacokinetics (PK) are hypothesized to influence Bu efficacy and toxicity. Since Bu is mainly metabolized by glutathione S-transferase (GST), we investigated the relationship of GSTA1 and GSTM1 genotypes with first-dose PK and HSCT outcomes in 44 children with thalassemia intermedia and thalassemia major. All children received a myeloablative conditioning regimen with IV Bu. Association analysis revealed a relationship between GSTA169C>T (or haplotype *A/*B) and first Bu dose PK that was dependent on sex and Pesaro risk classification (PRC). Among female patients and patients with PRC I-II, homozygous individuals for the GSTA1T-69 allele defining haplotype *B, had higher Bu exposure and lower clearance (P⩽0.01). Association with HSCT outcomes showed that patients with the GSTM1 null genotypes had higher occurrence of regimen-related toxicity (P=0.01). These results suggest that GST genotypes could be useful to tailor the first Bu dose accordingly to improve HSCT outcome.

Relationship between clinical and BK virological response in patients with late hemorrhagic cystitis treated with cidofovir: a retrospective study from the European Group for Blood and Marrow Transplantation.

To investigate the relationship between clinical response and modification of BK viremia, we assessed retrospectively 32 cases of hemorrhagic cystitis (HC) after allogeneic hematopoietic SCT that were treated with i.v. cidofovir (CDV). They were 22 men (69%) and 10 women (31%) with a median age of 24 years, range 3-62. The median number of CDV doses was 3, range 1-8, and the treatment lasted for a median of 3 weeks, range 1-10. Clinical improvement of HC was observed in 27 patients (84%). In 12 of 32 episodes (37.5%), BK viremia was determined before every CDV administration and a complete clinical response was observed in 10 of 12 patients (83%), the reduction of BK viremia load being 1 log by 2 weeks after starting CDV. Nephrotoxicity related to CDV was observed in nine patients. Among 26 patients with 100-day follow-up, 4 of 4 patients who had a complete clinical response by 30 days were alive vs 16 of 22 (73%) who did not have the resolution of HC in this time frame. We conclude that in patients with HC, the response to CDV treatment is usually associated with a significant reduction of BK viremia load.

Escalating doses of donor lymphocytes for incipient graft rejection following SCT for thalassemia.

Mixed chimerism (MC) and secondary graft failure are frequent events following SCT for thalassemia. There is limited information regarding the outcome of donor lymphocyte infusion (DLI) to prevent rejection, mainly from case reports describing only successful cases. We describe a series of seven children affected by beta-thalassemia treated with escalating doses of DLI for level 2-3 MC (donor<90%) following myeloablative SCT from a matched family donor. The infusions were safe and no acute or chronic GVHD were documented; five patients experienced neutropenia and thrombocytopenia resolving spontaneously. DLI was successful in converting to full donor chimerism two patients stratified in the low-risk class (Pesaro class II). Conversely, for five high-risk patients, DLI was not effective in preventing secondary graft failure. This limited series suggests that escalating doses of DLI are safe in thalassemia patients post myeloablative therapy but efficacy may be jeopardized by rapidly growing anti-donor alloimmunity in high-risk patients. We suggest giving escalating doses of donor T cells to attempt a graft-versus-thalassemia as soon as level 2-3 MC is detected.

Hepatitis B reactivation in allogeneic hemopoietic stem cell transplantation setting: a pediatric experience.

Reactivation of HBV is a well known complication in patients undergoing HSCT. Lamivudine treatment appears to prevent hepatitis B virus reactivation and to decrease the mortality in at risk HSCT patients. We describe HBV reactivation occurred in three allogeneic HSCT pediatric patients coming from Eastern Europe, one of whom was successfully treated with lamivudine. Our experience confirms that HBV-DNA may persist as intra-hepatic infection or in extra-hepatic sites and that HBV reactivation may appear during immunodepression. Careful and complete screening for HBV markers is mandatory before HSCT, especially in children coming from countries at risk for HBV. Furthermore, a treatment with lamivudine could also represent an efficacious prophylaxis in pediatric patients to avoid HBV reactivation and to decrease the development of severe hepatic disease.

Multiple BM harvests in pediatric donors for thalassemic siblings: safety, efficacy and ethical issues.

Allogeneic BMT represents the only chance of cure for beta-thalassemia. Occasionally, two affected individuals from the same family share a matched healthy sibling. Moreover, a high incidence of transplant rejection is still observed in Pesaro class III patients, requiring a second BMT procedure. In these settings, one option is to perform a second BM harvest from the same donor. Although BM harvest is a safe procedure in children, ethical issues concerning this invasive practice still arise. Here, we describe our series of seven pediatric, healthy donors, who donated BM more than once in favor of their beta-thalassemic HLA-identical siblings between June 2005 and January 2008. Three donors donated BM twice to two affected siblings and four donors donated twice for the same sibling following graft rejection of the first BMT. All donors tolerated the procedures well and no relevant side effects occurred. There was no significant difference between the two harvests concerning cell yield and time to engraftment. Our experience shows that for pediatric donors, a second BM donation is safe and feasible and good cellularity can be obtained. We suggest that a second harvest of a pediatric donor can be performed when a strong indication for BMT exists.

Incidence of bacteremias and invasive mycoses in children undergoing allogeneic hematopoietic stem cell transplantation: a single center experience.

We performed a retrospective single center study to define the epidemiology of bacteremias or invasive mycoses in pediatric allogeneic hematopoietic SCT (HSCT) from matched related donors (MRD) or alternative donors (AD). During 119 213 days of follow-up, 156 infections were observed: 130 bacteremias (27 in MRD-HSCT and 103 in AD-HSCT recipients) and 26 invasive mycoses (8 in MRD-HSCT and 18 in AD-HSCT recipients). Overall, the risk of bacteremia was fivefold that of invasive mycosis (P<0.001). AD-HSCT recipients had a higher percentage of infections (89 vs 27%; P<0.001), a higher rate/100 days of immunosuppression (infection rate (IR): 0.21 vs 0.06; P<0.001) and a higher proportion of repeated infections (44 vs 9%; P=0.001). In AD-HSCT, the relative risk of bacteremia was 2.87 in the pre-engraftment period, 5.84 in the early post-engraftment period and 6.46 in the late post-engraftment period (P<0.001) compared to MRD-HSCT. Only after 1 year did the epidemiology become similar. The epidemiology of invasive mycoses did not differ significantly between the two types of transplant.

Nebulized liposomal amphotericin B and combined systemic antifungal therapy for the treatment of severe pulmonary aspergillosis after allogeneic hematopoietic stem cell transplant for a fatal mitochondrial disorder.

Nebulized liposomal amphotericin B (20-15 mg twice daily by nebulizer) was combined with high dose intravenous liposomal amphotericin B (10 mg/kg/day) and high dose caspofungin (100 mg/m(2)) for the treatment of severe, recurrent pulmonary aspergillosis following allogeneic hematopoietic stem cell transplantation from alternative donor in a patient with mitochondrial disease (Pearson's syndrome). This combined treatment was administered for 8 days. Nebulized liposomal amphotericin B was well tolerated. Since severe transplant complications developed, nebulized administration was withdrawn and intravenous doses of liposomal amphotericin B and caspofungin were tapered to usual schedules. Pulmonary aspergillosis responded well to 45 days of combined intravenous antifungal therapies which were maintained for 2 years with secondary prophylaxis, because of persistent immunosuppressive treatment.

Nitazoxanide or CD3+/CD4+ lymphocytes for recovery from severe Cryptosporidium infection after allogeneic bone marrow transplant?

We describe a case of Cryptosporidium infection occurring in a child after allogeneic SCT for acute non-lymphoblastic leukemia. This patient presented an intestinal, biliar, and pancreatic Cryptosporidium disease associated with an intestinal aGvHD. The increase in CD3+/CD4+ cells secondary to the reduction of steroid therapy associated with the improvement of aGvHD and the use of antiparasitic treatments (especially nitazoxanide) improved the infection-related symptoms and led to a complete clearance of the Cryptosporidium.

Evolving role of myeloablative chemotherapy in the treatment of childhood brain tumours.

Primary brain tumours, a heterogeneous group of cancer that constitute the second most common cancer in childhood, were historically treated with neurosurgical resection and radiation therapy. Chemotherapy has proven to be beneficial for some histological types, which has since led to exploration of the role of high-dose chemotherapy and haematopoietic stem cell rescue. Patients with high-grade glial tumours, primitive neuroectodermal tumours and high-risk medulloblastoma usually fare poorly. The indicators of bad prognosis are metastatic status, extent of resection and age. Children <3 years at diagnosis carry worse prognosis. Rare cancers such as ependymoblastoma, atypical teratoid rhabdoid tumour and choroid plexus carcinoma have a dismal prognosis regardless of the above-mentioned indicators. The use of myeloablative therapy (MAT) has been investigated to improve the rate of long-term DFS, as well as to reduce and delay in the youngest children the use of the craniospinal irradiation associated with unacceptable late effects. We will overview the literature regarding patients with 'good and uncertain indications' to MAT. Ependymoma and brain stem tumours, for which the available data discourage the use of MAT, are excluded. Finally, we will summarize a single Institution experience (Giannina Gaslini Children's Hospital, Genoa) with MAT in the period 1997-2003.

Caspofungin associated with liposomal amphotericin B or voriconazole for treatment of refractory fungal pneumonia in children with acute leukaemia or undergoing allogeneic bone marrow transplant.

Caspofungin, in association with other antifungal drugs, was administered as rescue therapy in two cases of documented and one case of possible invasive fungal infection in children with acute leukaemia or undergoing allogeneic bone marrow transplant. The combined therapy was well-tolerated and seemed to be effective in all three patients. A combination antifungal therapy including caspofungin could represent an effective therapy for children with invasive mycoses refractory to single-agent antifungal therapy.

Mesial temporal sclerosis--a late complication in four allogeneic pediatric recipients with persistent seizures after an acute episode of cyclosporine-A neurotoxicity.

Mesial temporal sclerosis (MTS) is a common finding in patients with intractable temporal lobe epilepsy (TLE). In this report, we retrospectively reviewed the neuroimaging results of four children who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), and who developed recurrent, partial, intractable seizures following a first event caused by cyclosporine-A (CSA) neurotoxicity. Neuroradiologic findings of MTS were demonstrated in all these patients. We suggest that MTS may be a consequence of CSA neurotoxicity, which induces repeated seizures, associated with other predisposing conditions, as well as being a consequence of the underlying disease and its treatment, and of severe graft-versus-host disease (GvHD).

Systolic and diastolic cardiac function in acromegaly. An echocardiographic study.

The aim of this study was to establish the existence of primary acromegalic cardiomyopathy different from the cardiovascular complications often associated with acromegaly. Thirty-four acromegalic patients, referred to our non-invasive laboratory and divided into two groups on the basis of the presence of hypertension, underwent echocardiographic studies. A control group of 34 subjects individually matched with the patients for age, sex, and blood pressure values was also studied. To evaluate cardiac function during exercise, the normotensive acromegalics, the control group, and a group of 9 athletes with left ventricular mass comparable to that of the acromegalic subjects underwent a handgrip test. Cardiac mass was increased in all patients; hypertensive patients had a greater increase than normotensive patients (144.9 +/- 38 vs 120.9 +/- 20.8 g/m, p < 0.02). Systolic wall stress and percent fractional shortening, although similar to the values confirmed in controls, were modified in the hypertensive patients (wall stress 77.5 +/- 9.3 vs 60.8 +/- 9.4 dyne/cm2, p < 0.01). In all patients, diastolic function at rest was similar to that in controls, although the hypertensive patients had deteriorated diastolic function (E peak 56.9 +/- 12.4 vs 71 +/- 15 cm/s, p < 0.01; A peak 70.4 +/- 21.1 vs 52.3 +/- 16.4 cm/s, p < 0.03; E/A ratio 0.89 +/- 0.37 vs 1.38 +/- 0.35, p < 0.02). During handgrip testing, wall stress in both the normotensive acromegalics and the control subjects increased but remained unchanged in the athlete group; percent fractional shortening decreased in all patients and controls but increased slightly in the athlete group. In conclusion, cardiac hypertrophy caused by GH hyperincretion does not improve acromegalic heart activity: diastolic function, although normal at rest, appears deficient during isometric exercise.

Echocardiographic Doppler evaluation of left ventricular diastolic function in athletes' hypertrophied hearts.

It is well known that one of the most evident effects of prolonged and intense physical training is an increase of left ventricular mass. This increase could have a great influence on the diastolic properties of the heart, which can now be accurately evaluated by use of pulsed- and continuous-wave of Doppler echocardiography. The aim of this study was to evaluate the diastolic function of a group of superendurance athletes (professional bicyclists, exercising more than forty hours a week). Sixteen athletes (A), aged between twenty and thirty-one years, during the period of maximal training, and 16 age-matched controls (C) were studied. All subjects were evaluated at rest with mono-dimensional, two-dimensional, and Doppler echocardiography. Diastolic (DD) and systolic (SD) diameter, posterior wall (PW), and interventricular septum (IVS) thickness were also measured. The left ventricular mass (LVM) was calculated. Diastolic function was evaluated by calculating isovolumetric relaxation time (IVR) with continuous-wave Doppler, and deceleration time (DT), rapid filling flow peak (Ep), and atrial filling peak (Ap) were evaluated with pulsed Doppler echocardiography. The LVM (A: 354 +/- 47 g vs C: 170.6 +/- 33.4, p < 0.05), DD (A: 57.7 +/- 3.9 mm vs C: 50.5 +/- 2.7, p < 0.01), PW thickness (A: 11.9 +/- 0.7 mm vs C: 8.4 +/- 0.6, p < 0.05), and IVS thickness (A: 12.3 +/- 1 mm vs C: 8.2 +/- 0.9, p < 0.05) were significantly greater in the athletes than in the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

[The diameter of the common trunk of the left coronary artery and left ventricular mass in athletes. An echocardiographic study]. / Diametria del tronco comune della coronaria sinistra e massa ventricolare sinistra in atleti. Studio ecocardiografico.

The feasibility of two-dimensional echocardiographic visualization of the coronary artery was re-evaluated in adults in the light of technological advances and development of new imaging planes. Athletes are a good model for this type of study. The aim of our study was to visualize in athletes the coronary arteries, particularly the left main artery, and to see if a correlation exists between left-ventricular mass and coronary diameter. Twenty-one endurance athletes, aged between 17 and 30 years, and 21 control subjects, matched for age, sex and body surface area, were examined. All the subjects were examined with mono- and two-dimensional echocardiography, with annular array (3.5 and 5 MHz), with parasternal and apical projections modified in order to visualize the left main coronary artery. Wall thickness, left ventricular internal dimension and left ventricular mass were calculated. Interventricular septum thickness was 10.8 +/- 1.5 mm for athletes (A) versus 8.2 +/- 0.9 mm for controls (C); p less than 0.01. Posterior wall thickness was 10.4 +/- 1.5 mm (A) versus 8.2 +/- 0.6 mm (C); p less than 0.01. The left ventricular diastolic diameter was 54.6 +/- 5.1 mm (A) versus 49.5 +/- 3.4 mm (C); p less than 0.01. The mean left ventricular mass was 278.2 +/- 85.2 g (A) versus 165.6 +/- 35.4 g (C); p less than 0.01. The mean diameter of the left main coronary artery was 4.9 +/- 0.8 mm (A) versus 3.1 +/- 0.4 mm (C); p less than 0.01.(ABSTRACT TRUNCATED AT 250 WORDS)

[In vivo densitometry of the skeleton by single energy CT body scanner for clinical use. Technical procedure. Cross-sectional study of 124 subjects on the role of age and sex. Evaluation of the cortical/spongiosa ratio as a function of age]. / Densitometria "in vivo" dello scheletro con TC body a singola energia per uso clinico. Procedimento tecnico. Studio trasversale in 124 soggetti in funzione dell'età e del sesso. Valutazione del rapporto corticale/spongiosa in funzione dell'età.

CT 5005 EMI Scanner 140 kVp. Abstraction of the HN in the cortical of the right femural diaphysis and in the spongiosa of the vertebral body (L1). 124 clinically normal subjects of both sexes (63 males and 61 females), aged between 20 and 87 years were grouped into 7 categories according to age decade. Cortical-male - The variations of bone mineral content are not correlated either with age or with sex. Cortical-female - Modest correlation with age but not calculable with sex. Spongiosa-male - Excellent correlation with age (r = --0,975; (p less than 0,005). In each decade the average male values are superior to the female values. Spongiosa-female - Excellent linear correlation with age (r = --0,945; p less than 0,005). The average values for each decade are inferior to those of the males. The cortical/spongiosa ratio increases in relation to age: in males (r = --0,896; p less than 0,01) and in females (r = --0,885; p less than 0,01). The bone mineral content loss in the IX decade compared to the III decade is equal in males and in females in both the cortical (--20%) and the spongiosa (--65%). The reduction curves with the CT body scanner are not comparable to those obtained with other techniques. They result as being compatible with those obtained through histomorphometry (trabecular bone density).