Search

Systematic data on the ability of pegfilgrastim to mobilize stem cells after chemotherapy are scarce. We evaluated the efficacy of a single 6 mg dose of pegfilgrastim for mobilizing peripheral blood stem cells (PBSC) in aggressive lymphoma patients. Between July 2004 and October 2005, 17 aggressive non-Hodgkin's lymphoma and 11 poor-risk Hodgkin's lymphoma were treated with cycles containing cisplatin-aracytin. At the end of chemotherapy, the patients received 6 mg of pegfilgrastim. Duration of grade 4 neutropenia, adverse events, time to neutrophil recovery, peak and harvest of CD34+ cells were recorded. Twenty-seven out of 28 patients harvested a median of 17.3 x 10(6)/CD34+ cells (range 2.5-28.9) after a median of 9 days (range 8-12 days), with a single apheresis procedure in 25 cases. All patients had grade 3-4 neutropenia, median duration 3 days. The only adverse event was mild bone pain. To date, 13 patients have been autografted with a median of 15.4 x 10(6) CD34+ pegfilgrastim-mobilized cells per kg (range 2.5-28.9) with rapid and sustained engraftment. Mobilization, harvesting and autografting of pegfilgrastim-mobilized PBC can be successfully achieved in pretreated patients with aggressive lymphoma.

To assess burden and clinical features of type 1 diabetes in migrant with respect to Italian children. Prevalent children with type 1 diabetes were identified through a multicenter study, including 46 pediatric outpatients diabetic clinics. A nested case–control study was also performed, comparing features at diabetes onset and after 1 year of insulin treatment in 84 migrants and 75 Italian children with onset in 2011, matched for age and sex. Out of 7,812 children cared for by pediatric diabetologists, 761 (10 %) were migrant and 548 of them were born in Italy. Age at diagnosis was lower in migrants born in Italy (5.1 years, interquartile range (IQR) 2.2–7.7) than in those born in their original countries (7.8 years, IQR 5.3–10.3) and in Italians (9.8 years, IQR 5.9–13.0, p\0.001). At diabetes onset, migrants had lower frequencies of positivities of markers of b-cell autoimmunity (96 vs. 99.5 %, p\0.01), higher values of weight loss (11 vs. 7 %, p\0.01), HbA1c (70 vs. 58 mmol/mol, p\0.001), and insulin requirement (0.70 ± 0.03 vs. 0.63 ± 0.10 UI/kg/die, p = 0.05) and lower levels of 25-OH vitamin D3 (15.0 ± 2.8 vs. 20.8 ± 1.3, p = 0.03). Moreover, they experienced higher frequencies of hospitalizations during the first year of disease (19.2 vs. 2.7 %, p\0.001). Burden of type 1 diabetes in migrant children is increasing in Italy, with younger age at onset and different clinical features than in Italian children. Higher hospitalization rates and poorer glycemic control over the first year underline that approach to diabetes care in migrants needs to be improved.

Background and aims: Evaluation of incidence and correlates of severe hypoglycemia (SH) and diabetes ketoacidosis (DKA) in children and adolescents with T1DM. Methods and results: Retrospective study conducted in 29 diabetes centers from November 2011 to April 2012. The incidence of SH and DKA episodes and their correlates were assessed through a questionnaire administered to parents of patients aged 0e18 years. Incidence rates and incident rate ratios (IRRs) were estimated through multivariate Poisson regression analysis and multilevel analysis. Overall, 2025 patients were included (age 12.4 � 3.8 years; 53% males; diabetes dura- tion 5.6 � 3.5 years; HbA1c 7.9 � 1.1%). The incidence of SH and DKA were of 7.7 and 2.4 events/ 100 py, respectively. The risk of SH was higher in females (IRR Z 1.44; 95%CI 1.04e1.99), in pa- tients using rapid acting analogues as compared to regular insulin (IRR Z 1.48; 95%CI 0.97e2.26) and lower for patients using long acting analogues as compared to NPH insulin (IRR Z 0.40; 95% CI 0.19e0.85). No correlations were found between SH and HbA1c levels. The risk of DKA was higher in patients using rapid acting analogues (IRR Z 4.25; 95%CI 1.01e17.86) and increased with insulin units needed (IRR Z 7.66; 95%CI 2.83e20.74) and HbA1c levels (IRR Z 1.63; 95% CI 1.36e1.95). Mother' sa ge was inversely associated with the risk of both SH (IRRZ 0.95; 95%CI 0.92e0.98) and DKA (IRR Z 0.94; 95%CI 0.88e0.99). When accounting for center effect, the risk of SH associated with the use of rapid acting insulin analogues was attenuated (IRR Z 1.48; 95%CI 0.97e2.26); 33% and 16% of the residual variance in SH and DKA risk was ex- plained by center effect. Conclusion: The risk of SH and DKA is mainly associated with treatment modalities and strongly depends on the practice of specialist centers.

The aim of our study was to evaluate the impact of an early intensification programme including chemotherapy (CHT), autologous stem cell transplantation (ASCT) and radiation therapy (RT) in patients with primary mediastinal large B cell lymphoma (MLCL) with sclerosis presenting with adverse prognostic factors. Between 1993 and 1999, 19 patients with MLCL were referred to our institution. Four patients were classified as low risk according to the age-adjusted International Prognostic Index (AA-IPI). Fifteen (79%) were categorised in the high–intermediate or high risk group and were considered eligible for ASCT. Induction therapy consisted of VACOP-B (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone and bleomycin) for 12 weeks. After induction therapy the four low risk patients achieved a complete remission (CR) and did not undergo ASCT. Of the 15 poor risk patients, five achieved CR, seven partial remission (PR), and three showed refractory disease (RD). All these patients received mobilising therapy consisting of high-dose cyclophosphamide. After peripheral stem cell (PSC) collection, to obtain a greater tumor mass reduction before transplantation, the seven patients in PR underwent further treatment with high-dose etoposide and those with RD received two cycles of DHAP (dexamethasone, cytarabine and cisplatin). At the time of ASCT, seven patients were in CR, six in PR and two had RD. After transplantation using BEAM as preparative regimen, all patients but one achieved a CR. Seven patients with minimal (

Context:The incidence of type 1 diabetes has been increasing over time.Objective:We estimated the genetic and environmental components of type 1 diabetes susceptibility in a twin cohort of recent-onset cases to explore the sources of changing disease epidemiology.Design:We linked the population-based Italian Twin Registry with 14803 type 1 diabetes records from 36 pediatric diabetes care centers throughout Italy, except Sardinia, and identified 173 diabetic twins. Patients were positive for at least one autoantibody to islet cell, glutamate decarboxylase, tyrosine phosphatase, insulin, or zinc transporter 8 and were insulin dependent since their diagnosis. Zygosity was determined by DNA genotyping or by questionnaire.Outcome Measures:We estimated proband-wise concordance, cotwin recurrence risk with Kaplan-Meier method, and genetic and environmental proportions of susceptibility variance by structural equation models.Results:We recruited 104 diabetic twins (53 males) from 88 pairs (34 monozygotic, 54 dizygotic) and one triplet. The mean age at diagnosis was 8.1 yr (range 1.1-20.5 yr), and the median year of diagnosis was 2002. Proband-wise concordances were 45.5 and 16.4% in monozygotic and dizygotic pairs (P = 0.01). Recurrence risks in monozygotic and dizygotic cotwins were 37 and 12% after 10 yr from the proband's diagnosis (P = 0.005). Genetic contribution to type 1 diabetes susceptibility was 40% (95% confidence interval 8-78), and the shared and individual-specific environmental components were 51% (14-77) and 9% (4-19), respectively.Conclusions:In addition to the moderate genetic effects on type 1 diabetes susceptibility, our results draw attention to the substantial shared environmental effects, suggesting that exposures in fetal or early postnatal life may contribute to the increasing incidence of the disease.

The aetiology of impaired growth hormone (GH) secretion in Prader-Willi syndrome (PWS) remains controversial due to the common occurrence of obesity. To further clarify whether suboptimal GH secretion in PWS is an artefact of excess weight, we evaluated both GH immunological activity and GH bioactivity after arginine administration in 23 non-obese PWS patients [seven females, aged 6.9 +/- 0.9 years, body mass index (BMI) SDS 0.63 +/- 0.26], in comparison with a control group of 32 healthy subjects, matched for age, gender and BMI (10 females, aged 7.9 +/- 0.3 years, BMI SDS 0.21 +/- 0.20). Serum GH concentration was measured with a time-resolved immunofluorometric assay (IFMA), while GH bioactivity was evaluated by the Nb2 cell bioassay. Serum IGF-I concentrations were measured by double-antibody RIA. GH mean peak after pharmacological stimulation was significantly lower in PWS individuals compared with controls when measured either by IFMA (6.05 +/- 1.23 microg/L vs. 23.7 +/- 1.06 microg/L, p < 0.0001) or by Nb2 (6.87 +/- 0.55 microg/L vs. 12.88 +/- 0.19 microg/L, p < 0.0001). Analysis of integrated GH secretion (AUC) confirmed that the PWS group differed significantly from the control subjects (387.9 +/- 76.1 microg/L/h vs. 1498.1 +/- 56.2 microg/L/h, p < 0.0001); the same result was obtained when the GH rise after arginine administration was expressed as nAUC (278.2 +/- 53.3 microg/L/h vs. 1443.6 +/- 52.5 microg/L/h, p < 0.0001). PWS patients had an IGF-I SDS significantly lower than those found in control subjects (p < 0.0001). Subnormal IGF-I values were present in 19 PWS individuals (82.6%) and two healthy controls (6.2%). These findings are in agreement with the hypothesis that a complex derangement of hypothalamus-pituitary axis occurs in PWS.

Twenty-five medical centers and the Prader–Willi Syndrome (PWS) Association collaborated on a study which attempted to identify all people with genetically confirmed diagnosis of PWS living in Italy. Investigators of the participating centers contacted PWS subjects and/or their family, filled in a specially developed form with the required data and forwarded this information by email. The study identified 425 subjects (209 males and 216 females, between the ages of 0.4–46.7). Two hundred thirty-eight patients had del15, 104 had UPD15, 4 demonstrated a translocation affecting chromosome 15 and 79 showed a positive methylation test. There were fewer subjects found over the age of 35, probably due to the low rate of identification of older PWS patients as well as the high mortality rate. There were a greater number of male children and adolescents with PWS whilst, amongst adults, there were more females. As expected, the majority of subjects with PWS were obese, especially in adult life. Nevertheless, it is noteworthy that 26% of patients aged between 6 and 17 were normal weight. A total of 212 subjects had received GH treatment, of which 141 were still receiving therapy, while the remaining 71 had stopped. In children and adolescents (233 cases), 89 subjects had never undergone GH therapy. Eighteen PWS patients had died in the past 20 years. Obesity-related cardiovascular and respiratory diseases were the cause of death, both during childhood and after 18 years of age. Three children died suddenly whilst undergoing GH therapy. Respiratory infection and cardiac illness were the causes of death in two cases. There was no definitive cause of death found in the third case. Overall, there was no increase in number of deaths during GH treatment, suggesting that GH administration in patients with PWS, as a group, does not increase the risk of death. © 2008 Wiley-Liss, Inc.

The aim of this study was to evaluate the age of immigrants' children at diagnosis of Type 1 diabetes (T1DM) according to their country of birth. Immigration from developing countries to a westernised area causes rapid changes in the environmental conditions, and we investigated whether the location of birth, either inside or outside Italy, is associated with age at diagnosis of diabetes. Out of a prevalent hospital-based cohort of 5718 T1DM children cared for in 2002 in 47 Italian Pediatric Diabetes Units, we recruited 195 children (M: 97) of immigrants from developing countries--119 were born in Italy and 76 outside the European Union. Children with only one immigrant parent (no. 42) were also included. Age at diagnosis of T1DM, and other variables were compared with those of Italian children. Children of immigrated families born in Italy developed T1DM at a median age of 4.0 yr (IQR 2.2-6.9), whereas those born in developing countries and that had immigrated to Italy after birth developed T1DM at a median age of 7.9 yr (IQR 5.1-10.7, p < 0.001). Among the children born in Italy, 77 had parents who were both immigrants and the children's median age at diagnosis was 3.8 yr (IQR 2.1-6.3); 42 had only one immigrant parent and, when it was the father (no. = 23), median age was even younger (2.9 yr, IQR 2.0-8.2). Ten children had immigrated in their first yr of life and their median age was 9.1 yr (IQR 5.0-10.6). The median age of the Italian children was 6.6 yr (IQR 3.6-9.5). Results show that the outbreak of T1DM is earlier in immigrants' children born in Italy than in original countries.

Background Prader-Willi syndrome (PWS) is a genetic disorder due to loss of expression of paternally transcribed genes of the imprinted region of chromosome 15q11-13. PWS is characterized by peculiar signs and symptoms and many endocrine abnormalities have been described (growth hormone deficiency, hypogonadotropic hypogonadism). The abnormalities of thyroid function are discussed in literature and published data are discordant. The aim of our study was to report the thyroid function in patients with PWS to identify the prevalence of thyroid dysfunction. Methods Thyroid function tests were carried out in 339 patients with PWS, aged from 0.2 to 50 years. A database was created to collect personal data, anthropometric data, thyroid function data and possible replacement therapy with L-thyroxine. Subjects were classified according to thyroid function as: euthyroidism (EuT), congenital hypothyroidism (C-HT), hypothyroidism (HT – high thyroid-stimulating hormone [TSH] and low free thyroxine [fT4]), central hypothyroidism (CE-H – low/normal TSH and low fT4), subclinical hypothyroidism (SH – high TSH and normal fT4), and hyperthyroidism (HyperT – low TSH and high fT4). Results Two hundred and forty-three out of 339 PWS patients were younger than 18 years (71.7%). The prevalence of thyroid dysfunction was 13.6%. Specifically, C-HT was found in four children (1.18%), HT in six patients (1.77%), CE-H in 23 patients (6.78%), SH in 13 patients (3.83%), and HyperT in none. All other subjects were in EuT (86.4%). Conclusions Hypothyroidism is a frequent feature in subjects with PWS. Thyroid function should be regularly investigated in all PWS patients both at the diagnosis and annually during follow-up.

ObjectiveTo define the appropriate diagnostic cut-off limits for the GH response to GHRH+arginine (ARG) test and IGF-I levels, using receiver operating characteristics (ROC) curve analysis, in late adolescents and young adults.Design and methodsWe studied 152 patients with childhood-onset organic hypothalamic–pituitary disease (85 males, age (mean±s.e.m.): 19.2±0.2 years) and 201 normal adolescents as controls (96 males, age: 20.7±0.2 years). Patients were divided into three subgroups on the basis of the number of the other pituitary hormone deficits, excluding GH deficiency (GHD): subgroup A consisted of 35 panhypopituitary patients (17 males, age: 21.2±0.4 years), subgroup B consisted of 18 patients with only one or with no more than two pituitary hormone deficits (7 males, age: 20.2±0.9 years); and subgroup C consisted of 99 patients without any known hormonal pituitary deficits (60 males, age: 18.2±0.2 years). Both patients and controls were lean (body mass index, BMI2). Patients in subgroup A were assumed to be GHD, whereas in patients belonging to subgroups B and C the presence of GHD had to be verified.ResultsFor the GHRH+ARG test, the best pair of highest sensitivity (Se; 100%) and specificity (Sp; 97%) was found choosing a peak GH of 19.0 μg/l. For IGF-I levels, the best pair of highest Se (96.6%) and Sp (74.6%) was found using a cut-off point of 160 μg/l (SDS: −1.3). Assuming 19.0 μg/l to be the cut-off point established for GHRH+ARG test, 72.2% of patients in subgroup B and 39.4% in subgroup C were defined as GHD. In patients belonging to group B and C and with a peak GH response ConclusionsIn late adolescent and early adulthood patients, a GH cut-off limit using the GHRH+ARG test lower than 19.0 μg/l is able to discriminate patients with a suspicion of GHD and does not vary from infancy to early adulthood.

Background: To evaluate the clinical outcome of patients with relapsed or refractory follicular lymphoma treated with immunochemotherapy, in vivo purging and high-dose therapy with autotransplant. Patients and methods: Sixty-four patients were enrolled in the trial. Primary end point was progression-free survival (PFS). Secondary end points were the in vivo purging effect on stem-cell harvest and the impact of molecular response on the outcome. Results: At enrollment, 59% of patients were PCR+ for bcl-2 rearrangement in bone marrow (PCR-informative). After the immunochemotherapy, before mobilization, 97% obtained complete response or partial response and 87% of patients informative for bcl-2 were molecularly negative. Sixty-one patients proceeded to in vivo purging and peripheral blood stem cell (PBSC) mobilization with rituximab and high-dose AraC. The median number of CD34+ cells collected was 16.6 · 10 6 /kg. Of 33 PCR-informative patients, the harvests resulted in PCR2 in all. Fifty-eight patients received high-dose therapy and autotransplant of in vivo purged PBSC. After a median follow-up of 3.5 years, 41 patients are in complete remission. Five-year PFS is 59%. Conclusion: This study demonstrates that patients with advanced relapsed or refractory follicular lymphoma treated with immunochemotherapy, in vivo purging and autotransplant may obtain long-lasting PFS. In bcl-2-positive patients, in vivo purging allows the harvest of lymphoma-free PBSC. Absence of the bcl-2 rearrangement after autotransplant is associated with persistent clinical remission.

Background. Pegfilgrastim is a polyethylene glycol (PEG)-conjugated form of G-CSF in which filgrastim is bound covalently to a 20kDa PEG molecule; this formulation increases serum half-life of G-CSF due to decreased renal elimination. Following the subcutaneous injection of a 6 mg single dose of pegfilgrastim, serum levels of G-CSF are maintained over a period of 2 weeks. In patients with lymphoma, pegfilgrastim is as effective as filgrastim in shortening the time of neutropenia after cytotoxic chemotherapy; however, the ability of pegfilgrastim to mobilize stem cells after chemotherapy is poorly understood and the optimal mobilization strategy remains controversial. Aims. We evaluate the efficacy of a single fixed 6 mg dose of pegfilgrastim after salvage therapy with cisplatin-containing chemotherapy regimens in mobilizing peripheral blood stem cells in aggressive lymphoma patients. Moreover the possibility of a sufficient collection of CD34+ PBSC (cell dose > 2,5 x106/Kg) in a single procedure was tested. Methods. Between July 2004 and July 2005 twenty two pretreated patients with aggressive lymphoma (8 Hodgkin’s lymphoma, 11 diffuse large B cell lymphoma, 3 anaplastic lymphoma) received salvage chemotherapy with cisplatin-based regimens: (R)-DHAP, dexametasone, cisplatin, cytarabine, or (R)-IPAD idarubicin, dexametasone, cisplatin, cytarabine, with or without Rituximab. A 6 mg single dose of pegfilgrastim was given from day +1 or +2 after chemotherapy completion. Duration of grade 4 neutropenia, adverse events, time to neutrophil and CD34+ cell recovery were recorded. Stem cell collection was started when the absolute number of CD34+ was not less than 20/μL. Leukapheresis was daily performed until the minimum target cell dose of 2.5 x 10 6 CD34+ cells /kg was reached. Results. Following the administration of either (R)-DHAP or (R)-IPAD regimens, 21/ 22 pts (95%) were able to harvest a median of 14,2 x 10 6/Kg CD34+ cell (range 2,4– 45,8), after a median of 9 days from stimulation (range 8–12). A single apheresis procedure was sufficient to obtain a median of 14,8 x 10 6/kg CD34+ cell (range 5,2–45,8) in 18/21 pts (86%) Grade 4 neutropenia was present in all pts with a median duration of 3 days (range 1–7). Pegfilgrastim determined mild bone pain as only adverse event. Seven patients underwent autologous bone marrow transplantation and all of them showed a rapid and sustained engraftment after high-dose chemotherapy. Conclusions. In aggressive lymphoma patients a single dose of pegfilgrastim following chemotherapy completion was safe and highly effective in enhancing the mobilization of CD34+ PBSC. Stem cell collection was performed in a single procedure in most of patients (86%) obtaining a stem cell harvest of a median of 14,8 x 106/Kg CD34+ cells. In 7 autologous bone marrow transplanted patients these results determined early engraftment and sustained hematological reconstitution.

Minimal residual disease (MRD) following sequential administration of CHOP and rituximab was studied in previously untreated patients with follicular lymphoma. At diagnosis, the presence of Bcl-2/IgH-positive cells in the peripheral blood (PB) and/or bone marrow (BM) was demonstrated in all patients (n = 128) by polymerase chain reaction (PCR) analysis. Patients who achieved a clinical response following CHOP but remained PCR-positive were eligible for rituximab (375 mg/m2 intravenously, weekly for 4 weeks). After CHOP, 57% achieved a complete response (CR), 37% a partial response (PR), and 6% were nonresponders (NR). At this stage, patients proving PCR-negative (n = 41) or failing to achieve a clinical response (n = 8) were excluded from rituximab treatment. Seventy-seven patients received rituximab and entered a scheduled MRD follow-up program. At the first molecular follow-up (+12 weeks), 59% had converted to PCR negativity in the BM and PB, with a further increase documented at the second control (+28 weeks) with 74% PCR negative. At the last molecular follow-up (+44 weeks), 63% of the patients remained PCR negative. At 3 years, the estimated overall survival of all patients is 95% (95% confidence interval [CI], 86-98). For patients achieving PCR-negative status following CHOP and therefore excluded from rituximab treatment, freedom from recurrence (FFR) was 52% (95% CI, 28-71). For patients treated with rituximab, a durable PCR-negative status was associated with a better clinical outcome since FFR was 57% (95% CI, 23-81) compared with 20% (95% CI, 4-46) in patients who never achieved or lost the molecular negativity ( P

Summary. Options for relapsed/refractory indolent lymphoma include chemotherapy, immunotherapy and high-dose therapy with autologous support. The best combination of these approaches, however, is not defined. We treated 10 patients with relapsed/refractory follicular (n = 7) or mantle cell lymphoma (n = 3) using chemotherapy, immunotherapy, high-dose therapy and autotransplant in a sequence of four phases, each designed to play a specific role in tumour eradication. After the debulking with VACOP-B (doxorubicin, cyclophosphamide, etoposide, vincristine, prednisone, bleomycin) (phase 1), 9/10 patients responded but none achieved a molecular response. After the immuno-chemotherapy phase, which combined Rituximab with vincristine and cyclophosphamide, seven patients were in complete response (CR) and three in good partial response (PR), and all those with a molecular marker of disease showed a disappearance of the signal from marrow and blood. Phase 3, which coupled high-dose cytarabine with Rituximab, was effective in mobilizing an adequate number of progenitor cells that were polymerase chain reaction negative in all informative cases. Phase 4 consisted of high-dose therapy with autologous support followed by two doses of Rituximab. Autograft was performed in nine patients. The haematopoietic recovery was as expected. This sequence of chemotherapy, immuno-chemotherapy, stem cell mobilization with in vivo purging and autotransplant, organized in four blocks of treatment, was simple to administer and devoid of toxic effects. It permits rapid attainment of clinical and molecular response and enables the harvest of lymphoma-free peripheral blood progenitor cells even in heavily pretreated patients with relapsed or refractory disease.

Clinical criteria for the diagnosis of Prader-Willi Syndrome (PWS) were established by consensus in 1993 (Holm et al.). Specific molecular testing is now available and the purpose of diagnostic criteria has shifted to identify individuals to test, thus avoiding the expense of unnecessary analysis. The aim of this study was to find clinical indicators to select patients with suspected PWS for laboratory testing. We analyzed the prevalence of clinical signs and symptoms in 147 genetically diagnosed Italian patients with PWS (67 males and 80 females), aged from 9 months to 34.6 years (13.6 +/- 8.3 years), using the consensus diagnostic criteria, and according to age, sex and type of genetic abnormality. The prevalence of several clinical features changed significantly with age, but very few with sex. According to genetic subtypes (deletion vs UPD), only hypopigmentation and acromicria were more frequent in patients with deletion. Some criteria considered as minor or supportive by Holm et al. have higher prevalence than some major criteria. In conclusion, in order to identify patients with suspected PWS to submit to laboratory testing, we recommend a classification of clinical criteria according to age, giving more attention to those so-called minor or supportive criteria.