ALBERT

Description: During the last years, a number of telescopes have been dedicated to the followup of the GRBs. But after the Swift launch, the average observed intensity of the GRBs showed to be lower than thought before. Our experience with the robotic 60 cm REM telescope confirmed this evidence, with a large number oflostGRBs. Then, we proposed to study the feasibility of a 4 m fast pointing class telescope, equipped with a multichannel imagers, from Visible to Near Infrared. In this paper, we present the main result of the feasibility study we performed so far.

Description: Data collection in wireless sensor networks (WSNs) can become extremely expensive in terms of power consumption if all measurements have to be fetched. However, since multiple applications do not require data from all nodes but to compute a function over a smaller data set, much of the available data on the network can be considered irrelevant and not worthy of spending energy. In this context, in-network filtering schemes can be used to forward only relevant data towards a sink node for processing purposes. In this work, we propose and evaluate two schemes that can drive this filtering process. Both of them are based on the integration of metaheuristics and learning algorithms inspired by nature. In particular, we consider the computation of the maximum function as case study for these schemes. We investigate the trade-off between communications costs, which are directly associated with power consumption, and error costs due to fetching not all relevant data. We show by simulation that communication costs can be significantly reduced with respect to traditional schemes while keeping the computation error bounded.

Description: The combination of fludarabine, cyclophosphamide and rituximab (FCR) is still currently regarded as the standard regimen for treatment of physically fit patients with chronic lymphocytic leukemia (CLL). This therapy can be associated with significant toxicity, and patient adherence to the protocol may often be difficult outside of clinical trials. This retrospective study aimed to evaluate the efficacy and safety of FCR therapy in the real life setting, with particular focus on the influence of dose reduction on treatment outcome. A total of 132 CLL patients (≤70 years of age) treated with FCR as frontline therapy from 10 medical centers, were reviewed. The majority of patients were males (73.5%, n=97) and younger than 60 years (78%, n=103). Eleven patients had Binet stage A (8.3%), 72 (54.5%) were stage B and 49 (37.1%) had Binet stage C. Results of FISH analysis were available for 99 patients, with high risk cytogenetics of del(11q) in 21 patients (21.2%) and del(17p) in 9 cases (9.1%). The majority (56.5%, n=74) received rituximab at a dose of 500mg/m2 and the rest 375mg/m2. Almost half of the patients (49.2%, n=65) were given a reduced dose of chemotherapy (

Description: Background: Severe thrombocytopenia is an uncommon event in lower risk MDS patients, but it may significantly influence the prognosis. In fact, when it occurs, major bleeding may be a life-threatening complication. No licensed pharmacologic approach is nowadays available yet for these patients. Eltrombopag seems to be a very interesting product, but its efficacy and safeness are still to be better demonstrated. Romiplostim could be suitable too, but, at present, its safety is uncertain in MDS patients. Also danazol, an attenuated androgen, seems to have some ability to increase the platelet count in this context. Patients and methods: We retrospectively reviewed 17 thrombocytopenic patients affected by MDS, treated with danazol and observed for at least 6 months. Three patients of these had a therapy-related MDS. At the starting time of danazol therapy, the IPSS was “low” or “intermediate-1” in 16 cases; “intermediate-2” in 1 case. The IPSS-R was “very low”, “low” or “intermediate” in 16 cases; “very high” in 1 case. In 14 patients the platelet count was lower than 25x109/L, in the other 3 lower than 40x109/L, but with spontaneous bleeding. The initial dose was 600 mg/day for all the patients. The IWG criteria of response (Cheson 2006) were adopted. The outcomes were observed after 3 and 6 months from the beginning of therapy. Only descriptive statistical analysis was used. Results: At the beginning of therapy, the average platelet count of the 17 patients was 22.6 x109/L (S.D. 8.8, range 6-38). After 3 months, the therapy with danazol was ongoing in 16 patients (in 1 case the drug was discontinued due to renal failure). Platelet improvement, according to IWG criteria, was observed in 8 cases (47%). The average platelet count was 45.3x109/L (S.D. 32.9, range 4-133). The only one “high risk” patient did not show response. After 6 months danazol was still ongoing in 11 patients (in 5 cases the drug was stopped for inefficacy). The response according to IWG criteria was evident in 9 patients (52% of the initial 17 patients). The average platelet count was 66x109/L (S.D. 63.9, range 11-218). Adverse events recorded were as follows: increase in transaminases in 3 cases (in 2 of these the dose was reduced to 400 mg/day); severe but reversible renal failure in 1 case (the drug was stopped); moderate increasing of serum creatinine in 1 case (the drug was reduced to 400 mg/day); reversible cutaneous rush (the drug was reduced to 400mg/day); amenorrhea in 1 case (the only fertile woman in the series); weight loss and loss of appetite in 1 case, weight gain in 1 case. Conclusions This series confirms the efficacy of danazol to improve platelet count in approximately half of patients with severe thrombocytopenia due to “low-risk” MDS. In all patients with increased platelet count, the response was clinically significant. The response may not be immediate. Actually, there was an improvement of platelet count even after three months of therapy. The toxicity profile of this drug is low. The mechanism of action of danazol in MDS patients remains unclear. Waiting for more information on the efficacy and safety of eltrombopag from the clinical trials in progress, danazol may be a good therapeutic option for these patients. Disclosures Off Label Use: Danazol in MDS patients with severe trhombocytopenia.

Description: Background CMV infection represents one of the main cause of morbility and mortality after stem cell transplantation. Type III interferons (IFNs), including IFNl1 (IL29), IFNl2 (IL28A) and IFNll3 (IL28B), are thought to display potent antiviral and immunemodulatory properties in vivo, which may overlap partially with those exerted by type I IFNs. Type I and Type III IFNsl both generate an antiviral state by triggering the JAK-STAT pathway, ultimately upregulating the expression of interferon-stimulated genes. Rs12979860 single nucleotide polymorphism (SNP) in IL28B gene region is well known to influence the spontaneous and treatment-induced clearance in HCV infection. Data on the relevance of such a SNP in other viral infections is still debated even, Bravo et al. recently documented a protective effect of the T allele against CMV infection in the Allogenic stem cell transplantation (Allo-SCT) (Journal of Medical Virology 2014.86:838). Aim of the study: the current study was aimed at investigating whether the IL28B polymorphism rs12979860 may effect on the incidence rate of clinically-relevant active CMV infection in the Autologous stem cell transplantation setting. Patients and methods: From October 2014 45 patients were included in the study because underwent a autologous stem cell transplantation for hematological diseases. The median age of the patients was 56 years (16-66 years). Patients were distributed according to Hematologic disease as following: 73% of the patients had Multiple Myeloma, 20% non Hodgkin Lymphoma, 5% Hodgkin Lymphoma e 2% Acute Myeloid Leukemia. The rs12979860 IL28B SNP (C/T) genotype was determined by Melthing analysis on DNA derived from peripheral blood samples. CMV DNAemia was determined by quantitative Real-Time PCR with a limit detection of 50 copies/mL (Artus, Qiagen). Patients were monitored for CMV DNAemia weekly for the three months after stem cell transplantation. RESULTS: CC genotype was detected in 51% of patients, CT genotype in 35.5% and TT genotype only in 13.5% of patients according to the lowest frequency of TT genotype harboring in general population. A clinically-active CMV infection was documented respectively in 66,6%, 17,4% and 12,5% of patients carrying TT, CT and CC genotype. A trend towards a higher incidence of clinically-active CMV infection was noted in the TT population with respect to CT and CC population (TT vs CC: P= 0.03 and TT vs CT: P=0.02). The duration and peak of CMV-DNAemia levels tended to be higher in patients carrying the TT genotype then in ones with CC or CT genotype, although statistical significance was not reached. A positive correlation was observed between day 7 post ASCT CMV-DNAemia and the monocytes and neutrophils count. By the contrast, a negative correlation was found between day 21 post ASCT CMV-DNAemia levels and the monocytes count on 35th and 45th days after ASCT. Conclusions In conclusion, our data suggest that patients with TT genotype have higher incidence of clinically-active CMV infection in Auto-SCT setting. Even though these results should be confirmed by a larger sample size, the lowest prevalence of TT genotype in general population and higher (66.6%) clinically-active CMV infection in TT genotype patients strongly support our data. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Multiple myeloma (MM) is a neoplasm of B lymphoid line that is characterized by clonal proliferation of malignant plasma cells in the bone marrow, producing monoclonal paraprotein (M) in blood and/or serum. Interleukin-6 (IL-6) is one of the key molecules related to growth, survival and proliferation of MM cells. Tocilizumab (TCZ) is a humanized monoclonal antibody directed against IL-6 receptor (IL-6R). When radiolabeled and used for tumor imaging, intact IgG exhibits high liver uptake. Antibody fragments (Fab´s) are quickly eliminated from blood and normal tissues (except kidneys), achieving high tumor-to-blood and tumor-to-normal tissue ratios with renal clearance. The aim of our work was to develop a 99mTc radiolabeled TCZ Fab´s fragment and to perform its chemical and biological evaluation in order to be used as a potential MM imaging agent for staging and restaging. Methods: Antibody fragmentation was carried out with papain and, once purified, Fab´s(TCZ) fragments were identified and derivatized with NHS-HYNIC-Tfa as bifunctional coupling agent. MALDITOF/TOF was used to confirm all procedures. A mixture of Tricine/SnCl2.2H2O was added to Fab´s(TCZ)-Tfa-HYNIC and radiolabeled with 99mTcO4-. Radiochemical purity and in-vitro stability in saline, serum and different concentration of L-cysteine up to 4 h were analyzed by ITLC and HPLC. In-vitro binding assays were performed using U266 and MM1S cell lines up to 120 min. Biodistribution and SPECT/CT images were evaluated on healthy Balb/c mice and MM1S tumor-bearing Balb/c nude mice at 0.5, 2 and 4 h. Results: Radiolabeling of HYNIC-Tfa-Fab´s(TCZ) was carried out in a fast, reproducible, easy, stable way showing high radiochemical purity and high specific activity. In vitro binding assays confirm that after its derivatization and radiolabeleing, Tfa-HYNIC-Fab`s(TCZ) does not interfere with the epitope recognition. In vivo biodistribution studies on healthy Balb/c mice and MM1S tumor-bearing Balb/c mice showed that 99mTc-HYNIC-Fab´s (TCZ) has significant renal uptake with neglectable uptake in other organs, indicating renal clearance. Tumor uptake was 12.84±1.80 %ID/g followed by 8.94±0.61 %ID/g and 3.05±1.49 %ID/g at 2 and 4 h, respectively. U266 tumor-to-muscle ratios were 5.79, 8.61 and 2.71 at 0.5, 2 and 4 h, respectively.Tumor uptake for MM1S tumor-bearing Balb/c nude mice was 10.05±1.32 %ID/g, 8.59±2.36 %ID/g and 3.88±0.68 %ID/g at 0.5, 2 and 4 h, respectively. MM1S tumor-to-muscle ratios were 6.32, 4.61 and 3.08 at 0.5, 2 and 4 h, respectively. Biodistribution data of 99mTc-HYNIC-Fab´s(TCZ) on U266 tumor-bearing Balb/c nude mice showed good tumor uptake and retention 0.5 h after its injection SPECT/CT images on healthy Balb/c mice and MM1S tumor-bearing Bal/c nude mice of 99mTc-HYNIC-Fab´s(TCZ) showed renal uptake and a discrete tumor uptake at 4 h p.i (Figure 1). Conclusions: Labeling Fab´s(TCZ) with 99mTc using HYNIC was performed in an easy, fast, stable and reproducible way preserving its biological activity. Biodistribution and SPECT/CT imaging assays allowed us to observe and evaluate its potential role as a diagnostic molecular imaging agent for MM. Disclosures No relevant conflicts of interest to declare.

Description: Introduction. Multiple Myeloma (MM) is a heterogeneous, incurable disease. Several prognostic scores have been developed to estimate response to treatment, progression free survival (PFS) and overall survival (OS). The International Staging System defines 3 stages with distinct prognostic significance, using serum beta 2 microglobulin (b2M) and serum albumin. However, due to a higher power of risk discrimination, current guidelines recommend to stratify patients according to cytogenetics (CG) and treat high-risk patients with Bortezomib (BZ)-based therapies. In Uruguay, BZ is financed and regulated by a National Funding Board and is approved for high-risk MM or renal impairment at diagnosis or at relapse. As a consequence, the patients included in this study are a selected high risk MM subgroup. Even though proteasome inhibitors have improved outcomes for many high-risk MM patients, some still present short response duration and poor survival. Identifying simple factors that can predict response to BZ would be useful in order to better select the most appropriate therapeutic choice. Patients and Methods. We conducted a retrospective study to evaluate MM response to BZ-based therapy according to b2M, serum creatinin (Cr) and CG. Forty-seven MM patients [median age 59 years (38-77), females 25 (53%)] from two public centers treated with BZ-based combinations were included. According to local regulatory policies, only patients with renal failure and/or high risk CG features received BZ as first line therapy (n=31). Other 16 individuals received BZ combinations for relapsed/refractory disease. Patients received a median of 5 cycles of BZ (3-6). Nineteen individuals (40%) received high dose melphalan and autologous stem cell transplantation after BZ-based induction. At diagnosis, 28 (59%) had an ISS 3, 24 (51%) patients had serum Cr higher than 2 mg/dL and 14 (30%) exhibited high risk CG. Responses to BZ therapy were evaluated according with International Myeloma Working Group criteria as complete response (CR), very good partial response (VGPR), partial response (PR), stable disease (SD) and progressive disease (PD). Responses were analyzed depending on b2M level, serum Cr and CG. Comparison between groups was made by chi-square test. PFS and OS were calculated by the Kaplan-Meier method. Survival was compared between groups by log-rank test. Results. No differences in responses to BZ-based therapies were found when comparing patients with low (lower than 5,5 mg/L) versus high b2M levels (CR/VGPR 44,4 vs 44% respectively, p=0.97), low versus high serum Cr (CR/VGPR 34 vs 55% respectively, p=0.18) and standard versus high risk CG (CR/VGPR 46,7 vs 38,5% respectively, p=0.62). Patients with renal failure (serum Cr 2 mg/dL or higher at diagnosis, n=23) had a median of 53% (0 - 88%) reduction in Cr levels after receiving at least three cycles of BZ therapy. Eleven of them (47,8%) had normal renal function after completing BZ treatment. From 9 patients requiring dyalisis at diagnosis, 4 were out of dyalisis after BZ treatment. No significant differences in PFS and OS were observed when patients with low versus high b2M levels and standard versus high risk CG were compared. Patients with low Cr levels at diagnosis show a significantly better OS compared with those with Cr higher than 2 mg/dL (median OS not reached versus 42 months respectively, p=0.004), with no differences in PFS. Conclusion. In a selected high risk MM patients group treated with BZ-based therapies, similar response rates were obtained in individuals with high or low b2M levels, Cr levels, and standard or high risk CG. Although individuals with renal failure at diagnosis exhibit similar quality of responses than standard patients, long term OS of this group is still impaired and further improvements in therapy are needed. Note: GB and ER have contributed in equal parts to this work. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 4081 Introduction: Multiple myeloma (MM) accounts for 10% of hematological malignancies and 1% of cancer. It represents the second most common hematologic malignancy. The disease is characterised by plasma cell infiltration of the bone marrow, osteolytic bone lesions and the presence of a monoclonal paraprotein in the serum or urine. Interleukin-6 (IL-6) is a key molecule in the pathogenesis of MM. Its secretion occurs from the tumoral plasma cell as well as from the microenvironment. This results in myeloma cell proliferation. Tocilizumab, a humanized anti IL-6 receptor monoclonal antibody that blocks IL-6 cell-to-cell signaling, is currently being studied in MM. Most MM patients experience bone lesions. In spite of the new imaging techniques, the distinction between malignant and benign lesions remains sometimes difficult in clinical practice. The development of a more specific imaging agent may improve the accuracy of this diagnosis. Objective: Development of 99mTcHYNIC-Tocilizumab conjugate. Chemical and biological evaluation as a potential imaging agent in multiple myeloma. Methodology: 10 mg Tocilizumab (Roche) were added to 20 mg HYNIC in NaHCO3 1M, incubated for 30 min at room temperature and purified by means of PD10 column. 1 ml fractions were measured at 280nm. Conjugation of HYNIC-Tocilizumab was evaluated by mass spectrometry MALDITOF and acrylamide gel electrophoresis. 20 uL Tricine/stannous chloride in a 1:1 mass relation were added to 1 mg HYNIC-Tocilizumab in 100 uL of 0.9% NaCl. 2 mL of a solution containing 370 MBq 99mTcO4- was added. Radiochemical purity was controlled by three chromatographic systems: ITLC/NaCl 0.9%, Whatman 1MM/MEK, ITLC in BSA/EtOH-NH3-H2O (2:1:5) as stationary and mobile phase, respectively. Binding to IL-6 receptor in U266 myeloma cells was evaluated in vitro at 15, 30, 60 and 120 min. Tocilizumab was derivatized with FTIC and purified by PD10 column. Laser scanning confocal microscopy was done with an excitation/emission wavelength of 488/530 nm. Fluorescent images were obtained. Biodistribution studies were performed at 24 h in CD1 normal mice (n=3). Each mice was injected with 37 MBq of 99mTcHYNIC-Tocilizumab and sacrificed 24 hs after injection. Organs of interest were collected. Results: Mass spectroscopy MALDITOF (MH+Tocilizumab 147626 Da, M+HYNIC-Tocilizumab 148375 Da) confirmed derivatization of the antibody. This represents 5 molecules of HYNIC per molecule of the antibody. Poliacrylamide gel electrophoresis confirmed that the antibody retained its integrity after derivatization. Radiochemical purity was 88±3 %. In vitro cell binding assays confirmed the binding ability of the radiolabeled antibody to IL-6 receptor. Specificity of binding was supported by competition experiments using unlabelled antibody. Confocal microscopy proved the ability of the fluorescent antibody to recognize the IL-6 receptor in U266 myeloma cells. Biodistribution at 24 h showed blood (8.0±2.0) %act/g, liver (11±1.5) %act/g, kidney (4.0±1.0)%act/g and spleen (6±1.4) %act/g uptake with hepatic and renal elimination. Animal models of MM are being evaluated using xenografted MM cells. Conclusion: 99mTcHYNIC-Tocilizumab labeling was performed. The labeled antibody retained adequate biochemical and biological properties, which included maintenance of specific binding to IL-6 receptor. These findings indicate that this radiolabeled antibody could be used as an imaging agent in multiple myeloma. Acknowledgments: OIEA, Laboratorios Roche, Dr Gustavo Arroyo. Disclosures: No relevant conflicts of interest to declare.

Description: Background: The Israel National Cancer Registry (INCR) is a population based, national passive tumor registry established in 1960. Reporting by hospitals, laboratories, and other providers has been mandatory in Israel since 1982 and most cancer cases are registered on the basis of pathology reports and hospital records. In some hematopoietic malignancies where the diagnosis was not based on tissue pathology and patients initially received no inpatient treatment, cases may not have been reported to the registry, or reporting to the INCR may have been delayed, resulting in an underestimation of the true burden of disease. One diagnosis for which there is particular concern in this regard is CLL/SLL and here we used active surveillance to estimate the true incidence of CLL/SLL in Israel. Here we present the interim results Methods: We attempted to estimate the incidence of CLL in Israel more accurately,recognizing the fact that the exact incidence may never be known. The Israel Chronic Lymphocytic Leukemia Study Group, working with the Israel Center for Disease Control of the Ministry of Health, actively documented new cases of CLL/SLL in Israel for calendar years 2011 and 2012. All flow cytometry laboratories in Israel provided lists of patients with B cell clones. Israeli hematologists diagnosing CLL were asked to verify which of the B cell clones indicated a diagnosis of CLL, SLL, PLL or MBL and to fill out an internet-based reporting form. Diagnoses based on flow cytometry were verified by medical record review. Cases identified through active surveillance were pooled with cases known to INCR in order to estimate the true annual incidence of CLL/SLL and assess the completeness of the INCR data. Results: We identified 432 and 396 CLL/SLL cases for 2011 and 2012, respectively of whom 57.4% were males. The average age was 68.8. The corresponding age-adjusted[1]incidence rates per 100,000 (ASR) were 4.26 for 2011 and 3.79 for 2012. In comparison, the INCR registered 295 new CLL cases in 2011 (ASR=2.78) and 232 in 2012 (ASR=2.19), 54.5% of them males. The average age at diagnosis was 69.9. These data indicate a gap between true and reported incidence (1.48 and 1.60/100,000 in 2011 and 2012, respectively). However, it should be noted that the INCR will be fully updated for 2012 only by the beginning of 2015. Of active surveillance cases, 157 (2011) and 152 (2012) were registered in the INCR. Most cases missing in the INCR were diagnosed based on flow cytometry, peripheral blood samples and FISH (85.9% in 2011, 89.8% in 2012) without histo-pathological confirmation. Of the CLL/SLL cases existing in the INCR dataset for 2011-12 but not detected by active surveillance (138 in 2011; 80 in 2012), most (76.8% in 2011, 63.8% in 2012) had been diagnosed earlier and the remainder were coded as diagnoses other than CLL/SLL. Omitting these cases from the INCR dataset substantially increased the observed gaps in the true and the registered annual incidence of CLL/SLL (from 1.48 to 2.80 per 100,000 in 2011 and from 1.60 to 2.37 per 100,000 in 2012). Conclusions: The true incidence of CLL is unknown, but it is clear that there is under reporting to cancer registries. Completeness of CLL/SLL data requires accurate reporting of cases by hematologists and other care providers in the community. In Israel, this issue has been addressed by publishing updated guidelines for mandatory reporting stressing the requirement for reporting of hematologic malignancies. [1] Age-adjustment made on the basis of the world standard population Disclosures Ruchlemer: Roche: Research Funding.

Description: Background. In the last decade major advances have been made in the management of AL amyloidosis, such as the use of free light chains (FLC) and cardiac biomarkers in diagnosis, risk assessment, and evaluation of response, and the introduction of novel agents in the therapeutic armamentarium. However, available studies on the natural history of this disease are based on data collected before this era, and large comparative studies on novel agents are still lacking. We report the outcome of the 984 consecutive patients diagnosed between 2004 and 2014 at the Pavia Amyloidosis Research and Treatment Center (ARCT). Methods. Baseline evaluation and therapeutic strategy were protocolized. Patients were prospectively followed for response and survival. Response was assessed by intent to treat. Results. Overall, the heart was involved in 76% (Mayo stage III 39%), the kidney in 66% (stage III 15%), the liver in 14%, the soft tissues in 17%, and the peripheral nervous system (PNS) in 12%. Isolated involvement of the heart or kidney was observed in 17% and 14% of cases, respectively, while the liver or PNS were the only organs involved in