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The Polycomb group (PcG) proteins regulate stem cell differentiation via the repression of gene transcription, and their deregulation has been widely implicated in cancer development. The PcG protein Enhancer of Zeste Homolog 2 (EZH2) works as a catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) by methylating lysine 27 on histone H3 (H3K27me3), a hallmark of PRC2-mediated gene repression. In skeletal muscle progenitors, EZH2 prevents an unscheduled differentiation by repressing muscle-specific gene expression and is downregulated during the course of differentiation. In rhabdomyosarcoma (RMS), a pediatric soft-tissue sarcoma thought to arise from myogenic precursors, EZH2 is abnormally expressed and its downregulation in vitro leads to muscle-like differentiation of RMS cells of the embryonal variant. However, the role of EZH2 in the clinically aggressive subgroup of alveolar RMS, characterized by the expression of PAX3-FOXO1 oncoprotein, remains unknown. We show here that EZH2 depletion in these cells leads to programmed cell death. Transcriptional derepression of F-box protein 32 (FBXO32) (Atrogin1/MAFbx), a gene associated with muscle homeostasis, was evidenced in PAX3-FOXO1 RMS cells silenced for EZH2. This phenomenon was associated with reduced EZH2 occupancy and H3K27me3 levels at the FBXO32 promoter. Simultaneous knockdown of FBXO32 and EZH2 in PAX3-FOXO1 RMS cells impaired the pro-apoptotic response, whereas the overexpression of FBXO32 facilitated programmed cell death in EZH2-depleted cells. Pharmacological inhibition of EZH2 by either 3-Deazaneplanocin A or a catalytic EZH2 inhibitor mirrored the phenotypic and molecular effects of EZH2 knockdown in vitro and prevented tumor growth in vivo. Collectively, these results indicate that EZH2 is a key factor in the proliferation and survival of PAX3-FOXO1 alveolar RMS cells working, at least in part, by repressing FBXO32. They also suggest that the reducing activity of EZH2 could represent a novel adjuvant strategy to eradicate high-risk PAX3-FOXO1 alveolar RMS.

A first characterization of newly realized micro periodic structures including metallic nanoparticles is reported. The original mixture, generally utilized for the realization of polymer-liquid-crystal-polymer-slices gratings (POLICRYPS), has been enriched with a small amount of silver nanoparticles. The obtained structure shows a spectral response that strongly depends on the polarization of the probing light. These first structures are oriented to the fabrication of devices with metamaterial properties.

In a previous paper,1 we proposed an optofluidic modulator based on peristaltic flow. A microchannel made of polydimethylsiloxane is filled with nematic liquid crystal molecules that align homeotropically in the steady state. Once we apply a periodic peristaltic flow through mechanical deformation of the channel, liquid crystal molecules tend to realign with the gradient velocity field and thus change their optical properties. In this paper, we focus on the channel deformation with the finite elements program Comsol®, and we highlight the limitations in frequency of such optofluidic components.

International audience; Rhabdomyosarcoma (RMS) is a paediatric soft-tissue sarcoma arising from skeletal muscle precursors coexpressing markers of proliferation and differentiation. Inducers of myogenic differentiation suppress RMS tumourigenic phenotype. The Notch target gene HES1 is upregulated in RMS and prevents tumour cell differentiation in a Notch-dependent manner. However, Notch receptors regulating this phenomenon are unknown. In agreement with data in RMS primary tumours, we show here that the Notch3 receptor is overexpressed in RMS cell lines versus normal myoblasts. Notch3-targeted downregulation in RMS cells induces hyper-phosphorylation of p38 and Akt essential for myogenesis, resulting in the differentiation of tumour cells into multinucleated myotubes expressing Myosin Heavy Chain. These phenomena are associated to a marked decrease in HES1 expression, an increase in p21(Cip1) level and the accumulation of RMS cells in the G1 phase. HES1-forced overexpression in RMS cells reverses, at least in part, the pro-differentiative effects of Notch3 downregulation. Notch3 depletion also reduces the tumourigenic potential of RMS cells both in vitro and in vivo. These results indicate that downregulation of Notch3 is sufficient to force RMS cells into completing a correct full myogenic program providing evidence that it contributes, partially through HES1 sustained expression, to their malignant phenotype. Moreover, they suggest Notch3 as a novel potential target in human RMS. Cell Death and Differentiation (2012) 19, 871-881; doi:10.1038/cdd.2011.171; published online 25 November 2011

Experimental characterization of a switchable wedge-shaped holographic grating involved as a tunable phase retarder is reported. The structure is made of polymer slices alternated to films of well aligned Liquid Crystals (POLICRYPS). The sample shows a birefringence that depends on the anisotropy of the composite liquid crystalline material and on the geometrical cell parameters. The phase retardation introduced by the structure on the impinging probe light can be finely tuned by varying the amplitude of the externally applied electric field or by spatially shifting the probed area on the sample. The quarter wave plate condition for a He-Ne laser probe has been obtained confirming the possible application of the structure as an achromatic phase retarder.

We report the toxicity of high-dose chemotherapy (HDC) based on etoposide, thiotepa and CY (ETC) in children with poor-prognosis Ewing's sarcoma family tumors (ESFTs). A total of 26 patients with high-risk ESFT (metastasis or axis localization or tumor volume200 ml or necrosis95%) were reviewed. The conditioning was based on etoposide (600 mg/m(2)), thiotepa (750 mg/m(2)) and CY (120 mg/kg) followed by autologous BM or PBSC rescue. The conditioning regimen was well tolerated, without any toxic deaths. The median time from transplant to a neutrophil count of0.5 x 10(9)/l was 10 days (range 6-27) and 22.5 days (range 9-114) for a plt count of50 x 10(9)/l. Oral mucositis was recorded in 20 patients, grade 1/2 in 19 and grade 3 in the last patient. Diarrhea grade 1/2 was recorded in four patients and grade 1/2 liver toxicity in four patients. Sepsis was documented in four cases and skin toxicity in three. Lung and tubular toxicity, respectively, were reported in one patient each. We conclude that the ETC regimen presented a limited and manageable toxicity. Further studies would confirm the role of ETC in high-risk ESFT.

Purpose We report the off-label study aimed at investigating the use of temozolomide (TMZ) as single agent in relapsed or resistant pediatric solid tumors. The drug was administered at the dose of 215 mg/m2/day × 5 days or 180 mg/m2/day × 5 days in patients with prior craniospinal irradiation (CSI) or autologous bone marrow transplantation (ABMT). Patients and Methods Fifty two patients, median age 127.6 months, with resistant or relapsed solid tumors were enrolled. Tumor types were: neuroblastoma (NB; n = 17), medulloblastoma (MB; 8), brain stem glioma (BSG; 8), extraosseous Ewing's sarcoma/peripheral neuroectodermal tumor (EOES; 4), Ewing's sarcoma (ES; 4), anaplastic astrocytoma (AA; 3), rhabdomyosarcoma (RMS; 2), ependymoma (EP; 2), cerebral primitive neuroectodermal tumor (cPNET; 2), hepatocarcinoma (HC; 1), and osteosarcoma (OS; 1). All patients were pre-treated. Two outpatient courses were administered, with a median of 4.8 courses/pt. Results Objective response-rate (CR + PR + MR) in our series was 13.4% (1.9% CR, 3.8% PR, and 7.7% MR), SD occurred in 38.4% of patients and 48% had PD. The median survival was 7.8 months (range 1–37) and median time to progression was 3.4 months (range 1–20); these data were significantly correlated with histology and previous nitrosureas administration in multivariate analysis. Haematological toxicity grade 3–4 (mainly thrombocytopenia) was observed in 21.4% of administered courses, nausea was reported in 3.1% and respiratory distress in 0.7%. Conclusion Oral TMZ was well tolerated in children with resistant or relapsed solid tumors and showed activity in NB and CNS tumours refractory to standard chemotherapy. © 2005 Wiley-Liss, Inc.

In this paper we report a detailed characterization of a new structure (POLICRYPS) in which liquid crystal films are completely separated by polymer slices. This structure behaves as a Bragg diffraction grating and exhibits efficiencies that can become as high as 96–98%. The temperature dependence of the diffraction efficiency can be explained in terms of a Kogelnik-like model. A numerical simulation has been implemented which makes use only of real values of physical quantities and accounts for the experimental results with good accuracy. An applied electric field is able to switch off the grating, with a characteristic switching time which is lower than 1 ms. Threshold values of the field vary in the range 3–5 V/μm for gratings with a 1.39 µm fringe spacing.

Children affected by advanced neuroblastoma have a discouraging prognosis, but intensive induction chemotherapy may increase the complete response rate. The combination of ifosfamide, carboplatin and etoposide (ICE) was used for the first time as front-line regimen in patients with stage 4 neuroblastoma over the age of 1 y. Similarly, second-line treatment for children with relapsed neuroblastoma, particularly after high-dose chemotherapy, has been unsatisfactory. The combination of topotecan and cyclophosphamide was studied in resistant or relapsed solid tumors. Furthermore, there is a need for effective palliative treatment in patients failing therapy. Temozolomide, a new dacarbazine analog with optimal oral bioavailability, is being used in an ongoing phase II study as an alternative to oral etoposide. Seventeen patients with stage 4 neuroblastoma have entered the ICE study; 15/16 (94%) major responses after induction were observed and 6/16 (37%) evaluable patients are disease free after a median of 51 mo. Twenty-one patients with relapsed/refractory disease (of whom 13 neuroblastomas) entered the topotecan/cyclophosphamide study: 7/21 (33%) patients responded. Forty-one patients entered the temozolomide study (of whom 16 had neuroblastomas): stable disease and symptom relief were obtained in 15/30 (50%) evaluable patients. Intensive induction with ICE resulted in a faster response with high response rate; a larger study with longer follow-up is needed to confirm a survival advantage. Second-line treatment was effective in obtaining remissions, some of them long lasting. Third-line treatment did not elicit measurable responses in neuroblastoma, but achieved prolonged freedom from disease progression and excellent palliation in several patients.

The use of a nonstandard photocuring technique can produce noticeably improved results: POLICRYPS optimally verifies this condition. Originally being invented as a tunable diffractive structure, POLICRYPS has rapidly attracted much attention for its excellent morphology and related peculiar features. Low light scattering, low switching voltages and short switching times qualify POLICRYPS as a suitable platform for the realization of several applications.

We present a model for the photoinduced formation of composite materials by means of an inhomogeneous curing pattern. The model assumes that redistribution of molecules is due to mass diffusion and incorporates a realistic kinetic description of polymerization processes. Numerical simulations predict two different kinds of structure that have already been experimentally observed when this procedure was used to produce switchable diffraction gratings in polymer-based liquid-crystalline composite materials. We demonstrate how two parameters, related to diffusion and curing intensity, govern the phenomenon and determine the structure that will be formed after the curing process has been completed.

A one-year prospective, multicentre surveillance study on aetiology, main clinical features and outcome of bloodstream infections in children with cancer was conducted in 18 paediatric haematology centres belonging to the Italian Association for Paediatric Haematology and Oncology. A total of 191 bloodstream infections were reported during the study period. Of them, 123 (64%) occurred in neutropenic and 68 (36%) in non-neutropenic patients. Gram-positive cocci caused 45% (85/191) of the episodes, gram-negative rods 41% (78/191), and fungi 9% (18/191). The remaining 5% (10/191) of the episodes were poly-microbial infections. A total of 204 pathogens were isolated (46% gram-positive cocci; 44% gram-negative rods; and 10% fungi). The aetiologic distribution was similar among neutropenic and non-neutropenic patients. A correlation between the infection and the presence of an indwelling central venous catheter was found in 20% (23/114) of the episodes among neutropenic patients and in 55% (23/62) among non-neutropenic patients. Gram-negative micro-organisms were isolated in an unusually high proportion of catheter-related infections (48%). The overall mortality rate from any cause within 30 days from the first positive blood culture was 11%, and was higher among patients who were neutropenic at the onset of the infection than among those who were not neutropenic (15 versus 4%, P = 0.03). In addition, the mortality was significantly higher in recipients of bone marrow transplantation than in patients with acute leukaemia or solid tumour (21, 11 and 6%, respectively) and was also higher in fungaemias and poly-microbial infections (22 and 30%) than in single gram-positive and gram-negative bacteraemias (11 and 6%).

Several studies are consistent with the hypothesis that available iron may have some role in promoting tumor cell growth with different biological mechanisms. For this reason, several studies have been carried out to demonstrate the antitumor activity of deferoxamine (DFO), an iron chelator with a high affinity for ferritin-bound iron. In particular, the effects of DFO have been studied in patients with neuroblastoma, where ferritin is in part tumor derived and high concentrations correlate with poor outcome. To date, in vitro and in vivo studies demonstrating the antitumor effects of DFO are very promising, but further investigations are required to establish an exact role for DFO in the treatment of cancer.

Based upon phase I and II studies of deferoxamine alone and in combination with cytotoxic agents cyclophosphamide, etoposide, carboplatin, and thiotepa (D-CECaT), we initiated a single arm multicentre trial in 1992 for advanced neuroblastoma. 57 of 65 patients who entered the trial were evaluable. Following 4 courses of the DCECaT, almost all the patients underwent surgery. Toxicity was moderate and mainly reversible myelosuppression. The post-surgically defined responses in stage 3 high risk, stage 4 moderate risk and stage 4 high risk patients included 24 complete responses, 26 partial responses, and 3 minor responses, and 4 patients had progressive disease. These patients are being followed to determine the impact of this programme on their overall survival.

BACKGROUND: Glutathione S-transferase (GST) enzymes are involved in detoxifying chemotherapy agents and clearing reactive oxygen species formed by radiation. In this study, we explored the relationship between the host GSTP1-105 polymorphism (rs1695), tumor GSTpi protein expression, and clinical outcomes in pediatric medulloblastoma. We hypothesized that the GSTP1-105 G-allele and increased tumor GSTpi expression would be associated with lower progression-free survival and fewer adverse events. METHODS: The study included 106 medulloblastoma/primitive neuroectodermal tumor (PNET) patients seen at Texas Children’s Cancer Center. Genotyping was performed using an Illumina HumanOmni1-Quad BeadChip and tumor GSTpi expression was assessed using immunohistochemistry. We used the Kaplan-Meier method for survival analyses and multivariable logistic regression for toxicity comparisons. RESULTS: Patients with a GSTP1-105 AG/GG genotype or who had received a higher dose of craniospinal radiation (median 36 Gy) had a greater risk of requiring hearing aids than their respective counterparts (OR 4.0, 95%CI 1.2 - 13.6, and OR 3.1, 95%CI 1.1 - 8.8, respectively). Additionally, there was a statistically significant interaction between the two variables. Compared with the lowest risk group (GSTP1-105 AA-lower dose radiation) patients with a GSTP1-105 AG/GG genotype who received a higher dose radiation were 8.4 times more likely to require hearing aids (95%CI 1.4 - 49.9, p-trend ¼ 0.005). When adjusted for age, gender, and amifostine use, the association remained. CONCLUSIONS: The GSTP1-105 G-allele is associated with permanent ototoxicity in pediatric medulloblastoma/PNET and strongly interacts with radiation dose. A possible mechanism for this finding is that the GSTP1-105 G-allele leads to reduced GSTpi free radical detoxification in the setting of multimodality therapy including cisplatin and radiation. Patients with this allele should be considered for clinical trials employing radiation dose modifications and more targeted cytoprotectant strategies than are currently being used with amifostine.

Gold nanoparticles have been dissolved in a cholesteric liquid crystal and then infiltrated in a micro-periodic polymeric structure. This has been realized by combining a holographic step and a microfluidic etching process. The spectral behavior of the nano-composite soft-structure has been investigated in the UV-Vis range for two different polarization directions of an impinging probe light and in presence of external perturbations (electric field, temperature variation). Obtained results show a highly tunable plasmonic response of the material.

Fabrication of samples showing plasmonic properties is a fundamental step towards the realization of devices that can exhibit peculiar electromagnetic properties. In this work we illustrate some fabrication techniques that can reveal useful for the realization of this kind of samples. For what concerns materials, we used polydimethylsiloxane (PDMS) combined with Au nanoparticles (NPs). A first experimental characterization of the obtained structures has been reported.

R. Caputo1, L. De Sio1, A. Veltri1, A. V. Sukhov2, N. V. Tabiryan3 and C. P. Umeton1 1LICRYL (Liquid Crystals Laboratory, IPCF-CNR), Center of Excellence (CEMIF.CAL) and Department of Physics, University of Calabria, Arcavacata di Rende, 87036 Cosenza, 2Institute for Problems in Mechanics, Russian Academy of Science, Moscow 119526, 3Beam Engineering for Advanced Measurements Company, Winter Park, Florida 32789, 1Italy 2Russia 3USA

We report on the fabrication and characterization of a micro periodic structure realized in soft-composite materials containing metallic nanoparticles. The particles are used to infiltrate a passive polymer template realized by combining a holographic curing setup and a microfluidic etching process. In other experiments, small amounts of nanoparticles are dissolved in the original mixture utilized for the realization of polymer-liquid-crystal-polymer-slices gratings (POLICRYPS); this enables to fabricate POLICRYPS-like structures showing novel electromagnetic properties. Obtained structures are characterized in term of impinging probe polarization in the UV/visible range. Correlation between the optical response and external perturbations (electric field, temperature) is also reported. These first attempts are oriented to the fabrication of devices with tunable metamaterial properties.

By replacing common buffers with anisotropic liquids in microfluidics, an enhanced range of optofluidic functionalities is enabled. Such an anisotropic liquid is nematic liquid crystals (NLC), which exhibits optical properties that can be tuned by optical, electrical or mechanical fields, such as flow. We demonstrate an optofluidic modulator based on direct flow of nematic liquid crystals in microfluidic channels. We discuss this optofluidic paradigm both under steady state conditions, and under flow. Rapid pulsatile flows are detrimental towards more compact and ultra-fast devices. These were enabled via peristaltic pumps, demonstrating liquid crystal modulators operating above the limit of 3 kHz. We discuss the latter results, but also assess the feasibility of performing ultra-fast optics and additional functionalities for on- and off-chip imaging.

Nematogens rotate by the application of external fields, thereby enabling optical modulation. This principle has had a profound impact on our daily lives through the plethora of liquid-crystal displays in use around us(1,2). However, the wider use of nematic liquid crystals, particularly in microdisplays(3) and information processing, has been hampered by their slow response times. In nematogens, rotational and translational molecular motions are coupled(4), so flow is inevitably linked with optical modulation(5,6). This linkage motivated us to fuse microfluidics with anisotropic liquids and introduce an optofluidic(7,8) modulator that exhibits a submillisecond (250 mu s) symmetric response and can operate at frequencies up to 1 kHz. The modulator is based on peristaltic nematogen microflows(9) realized in polydimethylsiloxane microfluidics. The latter simultaneously permits peristalsis by means of elastomeric deformation, nematogen alignment and rapid prototyping through cast-moulding. Together with large-scale, vertical integration and piezoelectric nanotechnologies, this optofluidic paradigm can enable high-density and three-dimensional architectures of fast modulators.

We present an optical interrogation system based on a holographic soft-matter filter. It provides a wavelength-dependent transmittance, with a linear relation between Bragg wavelength shift and variation in the filter output intensity. This is the demonstration of a simple and inexpensive technology to implement a, low cost, monitoring system based on a fiber Bragg grating sensor.

In this paper we present two practical technological approaches to demonstrate that liquid crystals and composite materials can be employed to make low cost integrated optic devices with the specifications of fibre optic systems. In a first approach active properties are conferred to passive glass waveguides, by means of LC-based composite holographic grating cladding: this grating presents a specific morphology called POLICRYPS (POlymer LIquid CRYstal Polymer Slices). It can be electrically addressed, so that a tunable integrated optical filter has been achieved. In this paper we present the electro-optical characterization. In a second approach SiO2/Si V-grooves are filled with composite materials to produce a high performance integrated optical filter with the same POLICRYPS morphology. A first passive prototype of such optical filter is presented hereafter. Both prototypes have been characterized in terms of spectral response.

Thirteen patients with Stage III (3 patients) or Stage IV (10 patients) neuroblastoma were treated with a new iron chelation-cytotoxic therapy regimen. Deferoxamine given for five consecutive days followed by 3 days of cyclophosphamide, etoposide, carboplatin, and thiotepa (D-CECaT) caused moderate to severe myelotoxicity. In 39 courses there were four episodes of sepsis; platelet and packed red blood cell transfusions were required in 72% and 82% of courses, respectively. Mild nausea and vomiting occurred in 52% of courses. Objective responses after two courses were observed in 12 of 13 patients. Three of four partial responses were achieved in previously treated relapsed patients, and seven of eight complete responses (four of which were surgically documented) were achieved in previously untreated patients. This cytoreduction regimen appears to be an improvement over other initial induction regimens and may be worth testing in larger populations.

Background: Metastatic spread in retinoblastoma is a rare occurrence in developed countries but still associated with a poor prognosis. Patients and methods: Medical records of all metastatic retinoblastoma diagnosed during a 20-year period were retrospectively reviewed. Results: Six patients out of 104 presented a metastatic disease with an incidence at diagnosis of 2%. Three had a metastatic disease at diagnosis, one patient a trilateral retinoblastoma and two a metastatic spread after enucleation. All but one were sporadic retinoblastoma. Central nervous system (CNS) involvement was reported in five patients, while one patient had an intraorbital lesion, and bone and bone marrow spread. Different treatment strategies were administered based on local treatment plus chemotherapy and radiotherapy with or without high-dose chemotherapy. An ifosfamide/carboplatin/etoposide regimen was administered in three patients resulting in a partial response. Out of six patients, four died, and two patients are alive at 60 and 63 months from diagnosis. Both children with a long follow-up were treated with high-dose chemotherapy. All but one of the patients with CNS involvement died; the survivor was a patient with pineal involvement. Conclusion: This retrospective review confirms a curable strategy based on local treatment and conventional plus high-dose chemotherapy. Patients with CNS involvement remain incurable.

We report on the electrically controlled optical phase modulator behavior of light sculptured periodic structures made of polymer slices alternated to films of well aligned Liquid Crystals (POLICRYPS). Arbitrarily polarized light normally incident on the structure experiences a birefringence that depends on the anisotropy of the composite liquid crystalline material and on the geometrical cell parameters. The sample behaves as a retardation plate in good agreement with the Jones matrices formalism. Birefringence tuning is obtained by applying a suitable voltage, while a negligible birefringence variation is detected by increasing the incidence power. This makes POLICRYPS structures suitable as switchable phase retarders for high power laser beams. (C) 2008 Optical Society of America.

We report simulations of a theoretical model describing the formation of holographic diffraction gratings in multicomponent materials. The concentration of the chemical species in the initial mixture plays a fundamental role in determining the final features of the realized sample; our investigation is devoted to determine the best initial mixture realizing good holographic gratings. Along with the model, that is valid for any initial the multicomponent mixture, we report a complete characterization of the numerical solution of the model for two well known cases: H-PDLC and POLICRYPS grating. Obtained results are in good agreement with experimental observation, showing that our model represent a necessary reference for fabrication and the characterization of holographic diffraction gratings in multicomponent materials.

Experimental findings on a novel, compact, low cost tuneable and switchable guided wave optical filter using a composite holographic Bragg grating as the perturbation element of the guided optical field is summarized. The optical transmittance of the filter is measured by an optical spectrum analyzer. The tuning of the filter reflection response is also obtained.

In this paper we report the investigation of a beam coupling effect that occurs during the formation (by UV curing) of POLICRYPS diffraction gratings. Along with observations, we present a complete theoretical model which accounts for the main experimental features of the effect. Numerical solutions confirm the observed absence of any energy transfer process for unit ratio of the impinging beam intensities. When this ratio is not unit, the transfer is instead present and tends to equalize the beam intensities during the curing process; the capability of performing this equalization is strongly related to the grating diffraction efficiency. Furthermore, in this case, numerical simulations enable also to visualize the final (distorted) morphology of the fabricated structure.

We present a case report of a child who developed acute lymphoblastic leukemia, neurofibromatosis, optic glioma, and xanthogranulomatosis. This complex is unusual, not previously described, and appears to be a coincidence of different diseases. The importance of this case is that it may offer a clue to the genetic base of neurofibrosis syndromes including leukemic associations.

Aims and Background The necessity of an antiemetic prophylaxis in patients treated with chemotherapy of low emetogenic potential, such as 5-fluorouracil ± folinic acid fractionated over several consecutive days, is controversial. The aim of the study was to evaluate the therapeutic behavior of oncologists on this issue. Methods All consecutive in and out patients who started chemotherapy in 33 Italian oncological departments from June 24 to July 6, 1996, were studied. The antiemetic prescription pattern and its effectiveness, in patients submitted to 5-fluorouracil ± folinic acid were evaluated. Results Of the 1956 patients submitted to cancer chemotherapy, 259 patients received 5-fluorouracil ± folinic acid. Of these, 186 patients were treated for 5 consecutive days, 47 for 4 days, 20 for 3 days and 6 for 2 days. A total of 219 (84.5%) received an antiemetic prophylaxis: 43.4% a 5-HT3 antagonist ± steroids, 37.5% an antidopaminergic drug, 10.9% a steroid ± antidopaminergic drug, and 8.2% other drugs. Only 40 patients (15.5%) did not receive an antiemetic prophylaxis. Overall complete protection from vomiting/nausea was 225/259 (86.9%)/163/259 (62.9%). The complete protection from vomiting/nausea during the 5 days in the 186 patients was not significantly different among patients receiving or not an antiemetic prophylaxis (88.1%/64.9% vs 88.9%/55.6%). At unifactorial analysis, the previous experience of vomiting/nausea caused by chemotherapy was found to be a significant prognostic factor. In fact, overall complete protection from vomiting/nausea was significantly inferior in patients who had previous experience of vomiting/nausea (65.1%/35.0%) with respect to those who did not (91.2%/75.4%, P < 0.001/> 0.001, respectively). Conclusions. The study showed that in clinical practice patients submitted to 5-fluorouracil ± folinic acid obtained a similar high protection from vomiting and nausea regardless of whether or not antiemetic prophylaxis was given. It would be therefore reasonable not to treat patients undergoing such chemotherapy, whereas patients with previous experience of vomiting/nausea caused by chemotherapy should be given an antiemetic prophylaxis.

The Italian Association for Paediatric Haematology and Oncology prepared a guideline document aimed at unifying and rationalising as much as possible the management of febrile neutropenia in children with cancer, because of the potential impact of these procedures on hospital costs and on the development of antibiotic resistance. Before starting anti-infective therapy, at least 2 blood cultures, a throat swab, urine-culture, and cultures from any suspected infected site, should be performed. Routine chest X-rays at onset of febrile neutropenia are probably not necessary, in absence of respiratory signs. At the present time, the safer option probably remains the combination of a beta-lactam and an aminoglycoside, and treating febrile neutropenia outside of hospital should be considered an investigational approach. The choice of the most appropriated regimen for each institution should be based also on the local bacteriological statistics and patterns of bacterial resistance. Antibiotic toxicity and cost should be other important factors. Every subsequent addition or substitution of antibiotics should be based on objective signs of clinical deterioration. The only accepted empirical modification is empirical antifungal therapy, while the empirical addition of a glycopeptide antibiotic cannot be recommended.

A two-month-old infant developed a vascular tumor of the right flank which upon biopsy proved to be a spindle cell hemangioendothelioma. The increased capillary bed characterizing the neoplasm caused a severe thrombocytopenia together with a consumption coagulopathy (Kasabach-Merritt syndrome). The patient, who was dependent on platelet transfusions, improved quickly after interferon alpha-2a was given at the dosage of 3,000,000 U/m2, with resolution of the Kasabach-Merritt syndrome after three weeks and a 75% decrease of the tumor volume within three months of treatment.

The role of intensive pre- and postoperative chemotherapy in unresectable nonmetastatic neuroblastoma is still controversial. A preoperative regimen that included deferoxamine, cyclophosphamide, etoposide, carboplatin and thiotepa (D-CECaT) was evaluated in 10 children over one year of age at diagnosis, and this was followed by surgery and postoperative chemotherapy. After four courses of D-CECaT, the response rate was 9/10 with 3 complete responses, 6 partial responses and 1 minor response. Severe but transitory myelosuppression was the major toxic effect. Complete remission by combined D-CECaT chemotherapy and surgery was obtained in 9/10 patients, while 1 case achieved complete remission only with postoperative chemotherapy. All children are disease-free with a median follow-up of 30.5 months (range: 1+ to 50+). This intensive treatment was effective in both standard- and high-risk unresectable NB. However, whether a less intensive approach and fewer courses can also give similar results in standard-risk cases warrants further study.

Based upon phase I and II studies of deferoxamine alone and in combination with cytotoxic agents cyclophosphamide, etoposide, carboplatin, and thiotepa (D-CECaT), we initiated a single arm multicentre trial in 1992 for advanced neuroblastoma. 57 of 65 patients who entered the trial were evaluable. Following 4 courses of the D-CECaT, almost all the patients underwent surgery. Toxicity was moderate and mainly reversible myelosuppression. The post-surgically defined responses in stage 3 high risk, stage 4 moderate risk and stage 4 high risk patients included 24 complete responses, 26 partial responses, and 3 minor responses, and 4 patients had progressive disease. These patients are being followed to determine the impact of this programme on their overall survival.

10068 Background: Rhabdomyosarcoma is a pediatric soft tissue sarcoma that originates from skeletal muscle progenitors that proliferate indefinitely. Notch signaling inhibits myogenesis and has bee...

A method for collecting peripheral blood mononuclear cells following mobilizing chemotherapy in pediatric patients is described. The critical elements of the method included temporary heparinization of the patient to reduce citrate overload, and limiting extracorporeal circulation to 15% of the patient's blood volume using packed red blood cells and albumin. A median of 0.9 x 10(8) mononuclear cells/kg per collection were harvested in 40 collections from eight patients with only one episode of fever and chills. Peripheral blood stem cells were reinfused into six of these patients with refractory/recurrent pediatric tumors after intensive chemotherapy. Bone marrow reconstitution followed with a mean of 30 days (19-38) for absolute neutrophils and 48 days (32-275+) for platelets. Previous chemotherapy did not appear to affect peripheral blood stem cell efficacy in reconstituting chemotherapy-ablated bone marrow.

POLICRYPS (an acronym of polymer liquid crystal polymer slices) is a nano/microcomposite structure made of slices of almost pure polymer alternated with films of well aligned nematic liquid crystal (NLC). The structure is obtained by irradiating a homogeneous syrup of NLC, monomer and curing agent molecules with an interference pattern of UV/visible light under suitable experimental and geometrical conditions; the spatial periodicity can be easily varied from an almost nanometric (200 nm) to a micrometric (15 mu m) scale. Where the effect on an impinging reading light beam is concerned, the POLICRYPS can be utilized either in a transmission or a reflection configuration (depending on the geometry and substrate used) with negligible scattering losses, while the effect of spatial modulation of the refractive index (from polymer to NLC values) can be switched on and off by applying an external electric field of the order of few V mu m(-1). In this paper, we start by reviewing the general features of the POLICRYPS structure, that is the 'recipe' to fabricate it, along with a chemical-diffusive model that indicates the right physical and chemical conditions to make samples exhibiting good morphological, optical and electro-optical properties. We then show some possible utilizations of POLICRYPS with a light beam impinging almost perpendicularly to the structure: a switchable diffraction grating and a switchable optical phase modulator. Furthermore, we put into evidence that POLICRYPS channels can become an array of mirrorless optical micro-resonators for lasing effects. Finally, we report about utilization of POLICRYPS with a light beam impinging parallel to the structure and perpendicular to the channels, demonstrating that, in this case, the structure becomes a tuneable Bragg filter. Performances exhibited in all above applications put the POLICRYPS structure at the top level of the state of art of application oriented research in optics of liquid crystalline composite materials.

21001 Background: Evaluate the impact of a topotecan-based induction regimen in high-risk (HR) neuroblastoma. Methods: Patients with HR and/or MYCN-amplified neuroblastoma received 2 courses of top...

20009 Background: Gefitinib (G) has shown potent inhibitory activity on neuroblastoma (NB) cell proliferation in in vitro models. Experimental data have also reported that the addition of G to cytotoxic drugs can increase in vitro and in vivo antitumor activity in several tumor models, but if this will translate in significant clinical benefits, with respect to survival, is still unclear. We evaluated the feasibility of administering an oral regimen including G combined with topotecan (TPT) and cyclophosphamide (CPA) in heavily pretreated pts with relapsed/resistant metastatic NB. Methods: Patients received oral CPA (50 mg/m2/day) followed by TPT (0.8 mg/m2/day) plus G (at the fixed dose of 250 mg/day) for 14 consecutive days in an outpatient setting. Courses were repeated every 28 days until progression, and response was evaluated every second course. Expression of EGFR mRNA in primary tumors was assessed by real-time RT-PCR. Results: Six pts (1M/5F), median age 5.4 years (range 4.1–8.2), were enrolled between October 2004 and October 2006. All pts were relapsed after high-dose chemotherapy and hemopoietic rescue with PBSCs. At the time of inclusion, 3 pts were in PR after 8 courses of second-line therapy, whilst 2 pts had achieved SD after 1 and 8 courses of second-line therapy, resp; 1 pt had PD right after PBSC rescue. Significant levels of EGFR mRNA were detected in 4/6 tumors. A median of 7.5 courses (range 1–24) per pt were administered. In 4 pts, the dose of TPT and CPA was reduced by 25% after the first course. After a median follow-up of 12 months (range 1–26), 1 pt is DOD at 15 months since the inclusion and 5 pts are alive, 1 in VGPR (26+ months) and 5 with SD (26+, 1+, 4+, 9+ and 18+ months). Median PFS is 7.5 months (range 1–26). Neutropenia grade 4 was observed in 4/6 pts; rash grade 2 in 2 pts, and hepatic (LFT increase) grade 3 toxicity in 1. Conclusions: The regimen was feasible and well tolerated in this series of heavily pretreated pts. PFS is encouraging, but deserves further evaluation and longer follow-up. Additional molecular studies are ongoing aimed at identifying the subset of NB pts most likely to benefit from the synergy between G and cytotoxic drugs observed in preclinical models. No significant financial relationships to disclose.

8522 Background: We report the preliminary results of an off-label study investigating the activity of temozolomide (TMZ) in relapsed or resistant neuroblastoma (NB) at dosage of 215 mg/m2/day x 5 ...

8536 Background: Treatment options for advanced neuroblastoma are still limited, but new agents have recently shown promising activity. A pilot study with front-line topotecan was started in April ...

The endocrine profile of patients with breast cancer has been the object of extensive studies during the past several years. Abnormal secretion of a variety of hormones has been described on different occasions in patients with breast cancer (Gambrell, 1982; Henderson et al., 1982; Kirschner et al., 1982; Kwa and Wang, 1977; Ohgo et al., 1976), and has been considered a possible risk factor. However, conclusive evidence has not yet been presented to show that the cancer patients are significantly different in endogenous hormone profiles from their healthy counterparts. The main purpose of the present study was to critically reevaluate this controversial issue and possibly identify hormonal changes in a large population of patients with operable breast cancer not present in a comparable population of normal healthy women.

SummarySixteen patients with mild and moderate hemophilia were given Desmopressin (DDAVP) subcutaneously in the absence of any actual bleeding. The response to the drug – in terms of factor VIII coagulant activity rise – became apparent 15 min after the injection, reaching the maximal response after one hour (x̄ 3.2 times the baseline levels; SD 1.21). This response was not different from that elicited using the intravenous route in 18 hemophiliacs of comparable severity after the same time interval. No local or general side-effects were recorded after the subcutaneous administration of DDAVP. We therefore conclude that the subcutaneous route adds further evidence to the reliability of this alternative treatment in mild factor VIII deficiencies, thus making home treatment with this vasopressin analogue possible.