ALBERT

Description: In this letter, we report radiation stability of graphene under extreme condition of high energy density generated by 150 MeV Au ion irradiation. The experiment reveals that graphene is radiation resistant for irradiation at 10 14  ions/cm 2 of 150 MeV Au ions. It is significant to note that annealing effects are observed at lower fluences whereas defect production occurs at higher fluences but significant crystallinity is retained. Our results demonstrate applicability of graphene based devices in radiation environment and space applications.

Description: Abstract 4519 Background: Despite advances in our understanding of clinical, genetic, and molecular aspects of multiple myeloma (MM) coupled with availability of more effective therapies, it remains an incurable disease. Combining cytoreduction from high-dose (chemo- or chemoradio-) therapy with adoptive immunotherapy forms the basis of an autologous-allogeneic (auto-allo) hematopoietic cell transplantation (HCT) strategy. However, when an auto-allo HCT approach is compared to tandem autologous (auto-auto) HCT, conflicting results have been reported. Accordingly, we performed a systematic review of published studies comparing auto-auto HCT with auto-allo HCT in patients with newly diagnosed MM. Methods: A systematic search of MEDLINE thru Nov 5, 2011, and pertinent conference proceedings, was conducted. Included studies allocated newly diagnosed MM patients to auto-allo HCT if an HLA-matched sibling donor was available versus auto-auto if sibling donor was not available (biologic randomization). Independent, dual data extraction was performed. Pooling of data from similar outcomes was done using the random-effects model. Results: Our search identified 152 publications, of which five (manuscript=four, abstract=one) met inclusion criteria. The five included trials enrolled 1538 patients (auto-allo=565, auto-auto=973). At least a very good partial response was assessed in one study (522 patients) and did not differ among the treatment arms [risk ratio (RR) (95% CI) = 0.97 (0.87–1.09), p=0.66]; but complete remission, assessed in five studies (1130 patients), was higher in the auto-allo HCT arm [RR(95% CI) =1.65 (1.25–2.19), p=0.0005]. Event-free survival did not differ among auto-allo HCT group versus auto-auto HCT group on per-protocol analysis [hazard ratio (HR) (95% CI) = 0.78 (0.58–1.05)), p=0.11] of three trials (409 patients), or ITT analysis [HR(95% CI) = 0.83 (0.60–1.15), p=0.26] in three trials (1229 patients). Overall survival (OS) did not differ among these treatment arms whether analyzed on per-protocol [HR(95% CI) = 0.88 (0.33–2.35), p=0.79] in two trials (214 patients), or by ITT [HR(95% CI) = 0.80 (0.48–1.32), p=0.39] analysis in three trials (1229 patients). Non-relapse mortality (NRM) was worse with auto-allo HCT [RR(95%CI) = 3.55 (2.17–5.80), p

Description: Background: The identification of occult micrometastatic disease is potentially important in management of breast cancer (BC) patients. Therefore, detection of cytokeratin 19 (CK-19) and others molecular markers using reverse transcriptase polymerase chain reaction (RT-PCR)-based techniques to detect micrometastases could have significant implications in prevention, early detection and treatment of breast cancer. Objective: To assess the diagnostic specificity and sensitivity of detection of CK-19 in the peripheral blood (PB) of BC patients as well as to assess its relation to prognostic factors and implication on survival. Methods: We conducted a systematic review/meta-analysis of all studies that analyzed CK-19 in the PB of BC patients. We searched MEDLINE, LILACS and Cochrane Database of Systematic Reviews (last search June 2004). Studies that had at least 10 BC patients and controls and evaluated the presence of CK-19 in PB using RT-PCR were included in this review. Diagnostic sensitivity was defined as the percentage of detection of CK-19 in patients with histological proven diagnosis of breast cancer. The specificity was defined as the percentage of negative tests for CK-19 in the control group (healthy individuals or non breast cancer patients). Results: Out of 1842 relevant studies that were identified, 26 met our inclusion criteria, enrolling 2398 patients (1176 treatment and 1222 controls). Results showed that PCR had an overall diagnostic sensitivity of 0.39 (95% CI: 0.36–0.42) and diagnostic specificity of 0.83 (95% CI: 0.76–0.87) regardless of the breast cancer stage. Six studies researched the association between CK-19 and well established prognostic factors (i.e. positive axillary lymph nodes, hormonal receptors, tumor size); however data were not available for quantitative synthesis. Survival was poorly reported making impossible to generate any conclusion about the implication of detection of CK-19 on prognosis. When studies were critically appraised, we also identified many methodological weaknesses in the design, conduct and the analysis of these studies (e.g. use of multiple control arms, use of non-consecutive patients, different timing of sample collection, inclusion of all stages of breast cancer and differential work-up in the study & control groups) hence resulting in biased findings due to selection, verification, detection and spectrum bias. Conclusion: The existing body of evidence regarding the assessment and prognostic value of CK-19 using RT-PCR techniques is poor and needs ample improvement before the initiation of its clinical application.

Description: Background: The current approach for treating anemia in multiple myeloma (MM) patients entails prescribing recombinant erythropoetin (EPO) only if chemotherapy fails initially to raise hemoglobin (Hb) levels. However, this practice is not based on synthesis of the totality of evidence obtained from data of all trials testing EPO exclusively in myeloma patients. Objective: To conduct a systematic review/ meta-analysis (SR/MA) regarding the use of EPO in MM patients. Methods: We conducted a SR of all randomized controlled trials (RCTs) that studied the effect of EPO exclusively in MM patients. We searched all major electronic databases (MEDLINE, LILACS, EMBASE and the Cochrane Controlled Trials Register) as well as performing hand searches of relevant meeting proceedings (ASH, ASCO, EHA), and ongoing NCI trials. We included RCTs that had at least 10 patients in each arm and had compared the use of EPO against a control group. We also identified trials that compared different doses of EPO. We excluded trials that enrolled patients treated with high-dose myeloablative chemotherapy followed by stem cell transplantation or hemodialysis. Results: We identified more than 500 relevant studies; 6 trials met our eligibility criteria and were included in the analysis. Five trials (4 published as full text manuscripts and 1 as the abstract) compared epoetin alpha against a control [placebo (2 trials) or no therapy with or without specification of red cells transfusion trigger level (3 trials)] in anemic MM patients. One trial compared 2 different schedules of epoetin alpha. No trial tested the effect of darbopoeitin. All 5 trials that studied EPO against controls used initial doses of 150 IU 3x/week SC with the possibility of increasing to 300 IU if necessary. In the majority of trials the patients had been receiving chemotherapy at the time EPO was administered. The number of patients included in each trial ranged from 24 to 145. All trials concluded that EPO was superior to a placebo or no treatment in terms of Hb increase. Two trials also concluded that EPO improves quality of life. Our meta-analysis showed that hematological response was favored in the group receiving EPO [relative risk (RR) 7.75; 95% CI 4.19 to 14.35, 4 trials, n = 272]. Mean Hb level improvement with EPO was also significant [weighted mean difference (WMD) 2.29; 95% CI2.00 to -2.58, 3 trials, n = 235]. In terms of adverse events, hypertension was more often found in the EPO arm [RR 5.80; 95% CI 1.30-25.90, 4 trials, n = 290]. Survival and data related to tumor response were not available in all trials. Critical appraisal indicated that available evidence was modest in quantity (5 trials, n= 385 total patients enrolled) and poorly reported in all important methodological domains. Conclusion: Available body of evidence suggests that EPO improves hematological outcomes in patients with myeloma. However, the quality of current evidence is insufficient, data on most important patients’ outcomes are lacking (e.g. survival etc.), thus preventing us from making definitive recommendations regarding the role of EPO in managing anemia in the myeloma setting. A definitive RCT to resolve the role of EPO in myeloma is indicated.

Description: Abstract 236 Background: There is little consensus on which maintenance therapy clinicians should choose for their patients. Since 1999, the three novel agents of bortezomib, lenalidomide, and thalidomide have been approved for use among patients with MM. These agents have been increasingly used as maintenance therapy. To date, only two randomized controlled trials of maintenance therapy have examined the efficacy of these novel agents head-to-head. Here, we conduct a network meta-analysis of bortezomib, lenalidomide, and thalidomide to determine which of these novel agents could potentially increase overall survival (OS) and progression-free survival (PFS). Methods: A comprehensive literature search of MEDLINE (PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and meetings abstracts from American Society of Hematology, American Society of Clinical Oncology, European Society for Medical Oncology and European Hematology Association was undertaken to identify all phase III randomized controlled trials (RCTs) of maintenance therapy published until July 2012. We applied the Bayesian mixed treatment comparison (MTC) method under the random-effects model. The indirect comparisons were constructed from trials that have one treatment in common. For each included RCT, we calculated the hazard ratio (HR) and its corresponding standard error and used this to calculate the indirect estimates of HR and corresponding credible intervals (CrI). We also ranked the treatments according to the probability of best treatment and calculated the surface underneath the cumulative ranking curve (SUCRA). All analyses were conducted in WinBUGS 1.4.3 and Stata 11.2. Results: The network, number of trials for each comparison, and number of patients enrolled is shown in Figure 1. The network for OS was based on 12 RCTs enrolling 5542 patients and the network for PFS was constructed from 13 RCTs and 5784 patients. The MTC networks were consistent for both OS and PFS. For both OS and PFS, two comparisons were produced (Figure 2). For OS, the analysis showed that none of the treatments were superior. For PFS, lenalidomide was superior to thalidomide (HR = 0.58, 95% CrI [0.37, 0.94]). The estimates of SUCRA and rank probabilities (Figure 3) suggested that for OS bortezomib was best followed by lenalidomide and thalidomide. For PFS, lenalidomide was best followed by bortezomib and thalidomide. Conclusion: Using the MTC method, we found no evidence that any of the novel agents are superior to one another in terms of OS. Lenalidomide was the only novel agent which was superior to another active therapy (thalidomide). While these results provide preliminary evidence to which novel agent may be more beneficial as maintenance therapy, definitive conclusions cannot be reached until large, well designed RCTs evaluating these therapies head-to-head are conducted. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 3511 Background: While multi-agent induction chemotherapy produces impressive complete remission rates, long term survival remains elusive for most patients with adult acute lymphoblastic leukemia (ALL). Consolidation chemotherapy, autologous hematopoietic cell transplantation (HCT), and allogeneic HCT represent potential treatment alternatives for post-remission therapy, but there is genuine uncertainty regarding the optimal approach. Objectives: To synthesize evidence from all existing randomized controlled trials with a donor vs. no donor comparison in adults with ALL in first complete remission. Our objectives were to determine whether or not there is a survival advantage with allogeneic HCT for ALL in CR1, and also to discern the benefit of this therapy according to disease risk subgroups. Search methods: A broad search of the Medline and Embase electronic databases was performed along with hand search of literature cited in relevant primary articles, search of abstracts from American Society of Hematology and American Society of Clinical Oncology meetings, as well as consultation with content experts in the field. Selection criteria: Include trials were those consisting of adults with ALL in CR1, and prospective randomized controlled trial (RCT) design with ‘genetic randomization' (i.e. based on availability of matched sibling donor vs. not). Data collection and analysis: Data from relevant trials was abstracted and reviewed by two investigators independently. We extracted data on benefits (OS, PFS) and harms (treatment related mortality, relapse) of compared treatments. Time-to-event data (OS, PFS) were reported as hazard ratios (HR) and dichotomous data (relapse and NRM) were reported as risk ratios (RR). The summary results from each study were pooled under a random effects model. Heterogeneity was assessed both by visual inspection of the forest plots for each outcome, as well as by formal statistical testing for heterogeneity using the chi square and I2 test. Subgroup analyses were performed for disease risk categories. Sensitivity analyses were performed according to domains of methodological quality. Results: A total of 14 relevant trials were identified, consisting of a total of 3215 patients. There was a statistically significant overall survival advantage in favor of the donor vs. no donor group HR of 0.79 (95% CI 0.7 – 0.90; p = 0.0003). The following was observed according to disease risk: standard risk ALL (HR of 0.62 (95% CI 0.46 – 0.84), p = 0.002); high risk ALL (HR of 0.8 (95% CI 0.63 – 1.01), p = 0.06). There was also a statistically significant improvement in disease-free survival in the donor vs. no donor group HR of 0.78 (95% CI 0.66 – 0.92), p = 0.003. Those in the donor group realized a statistically significant reduction in primary disease relapse, RR 0.54 (95% CI 0.4 – 0.73), p 〈 0.0001, but at the cost of statistically significant increase in non-relapse mortality, RR 2.8 (95% CI 1.66 – 4.73; p = 0.001). There were no significant subgroup differences or heterogeneity demonstrated in sensitivity analyses according to methodological quality domains. Conclusion: The results of this systematic review and meta-analysis support matched sibling donor allogeneic hematopoietic cell transplantation as the optimal post-remission therapy in adults age greater than or equal to 15. This therapy offers superior overall survival, disease-free survival, significantly reduces the risk of disease relapse, but does impose an increased risk of non-relapse mortality. These data importantly are based on adult ALL treated with largely total body irradiation-based myeloablative conditioning, and, therefore, can not be generalized to pediatric ALL, alternative donors including HLA mismatched or unrelated donors, or reduced toxicity or non-myeloablative conditioning regimens. Forrest plot of overall survival according to donor vs. no-donor status. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 2055 Background: Erythropoiesis stimulating agents (ESAs) are commonly used to treat chemotherapy-induced anemia (CIA) in cancer patients. However, numerous clinical trials indicate that about half of the patients fail to show an increase in hemoglobin (Hb) levels or a reduction in red blood cell (RBC) transfusions following treatment. This may be attributed to functional iron deficiency (FID) experienced by these patients. Iron is often used to supplement ESAs to correct the FID. However, no systematic review has been conducted that tackles the role of iron supplementation. This is the first systematic review and meta-analysis that addresses the efficacy and safety of iron supplementation to ESAs in the management of CIA. Methods: Literature search of PubMed, Cochrane databases and meetings abstracts from American Society of Clinical Oncology, American Society of Hematology and European Hematology Association was undertaken to identify phase III RCTs published until June 2010. No limits were used in the search. We extracted data on hematopoietic response rate, time to hematopoietic response, RBC transfusions, mean change in Hb level, quality of life (QOL), overall survival (OS), and grade III-IV treatment related harms. We conducted subgroup analyses based on type and route of administration of iron. Time to event data, dichotomous data, and ratio level data were pooled as hazard ratios, risk ratios (RR), and mean difference (MD), respectively, under the random effects model. Results: Seven RCTs (5 full papers and 2 meeting abstracts) were included enrolling 1,777 patients. For the outcome of hematopoietic response, there was a beneficial effect of iron supplementation to ESAs compared with ESAs alone (RR= 0.65, 95% CI: 0.53 – 0.79). However, for this outcome, RCTs which used intravenous iron favored ESAs and iron (RR= 0.57, 95% CI: 0.44 – 0.74), whereas no differences were found in RCTs using oral iron (RR= 0.81, 95% CI: 0.64 – 1.03) (test of interaction: p= 0.02). No differences were found in the median time to hematopoietic response between patients receiving ESAs and iron versus those receiving ESAs alone. Significantly fewer patients treated with ESAs and iron required RBC transfusions compared to the number treated with ESAs alone (RR= 0.67, 95% CI: 0.52 – 0.86) (Table 1). There were no differences in RBC transfusions based on the route of iron administration. Although mean change in Hb level data was reported in 71% of studies (5/7), data were extractable for meta-analysis from only 43% of RCTs (3/7). The mean change in Hb level was significantly greater in patients receiving ESAs and iron (MD = 0.77, 95%CI: 0.27–1.28) compared with ESAs alone. QOL was reported in three studies, but due to variation in the scales used (FACT-F and LASA) we were unable to provide a pooled estimate. In trial by Bastit et al., no differences in the QOL were found between patients treated with ESA and iron versus those treated with ESAs alone. In the trial by Auerbach et al., patients receiving ESAs and iron had statistically significant better QOL than those receiving ESAs alone. None of the included RCTs reported OS estimates. No differences were found related to risk of grade III-IV thromboembolic events between patients receiving ESAs and iron versus patients receiving ESAs alone (RR= 1.09, 95% CI: 0.55 – 2.18, p= 0.807, 3 RCTs, 614 patients). Type of iron used (gluconate vs. dextran vs. sucrose vs. sulphate) had no impact on any outcome. Conclusion: Compared with ESA alone/placebo, iron supplementation to ESAs significantly increases hematopoietic response rates and reduces number of RBC transfusions in patients with CIA. Intravenous iron appears to be superior to oral iron in achieving hematopoietic response. Both treatments are well tolerated with no significant differences in adverse events. Note: RR=Risk Ratio; CI=Confidence Interval; NNT=Number Needed to Treat Disclosures: No relevant conflicts of interest to declare.