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Key Points First report of an FLT3-targeted therapy added to nonintensive chemotherapy that has improved survival in older FLT3-ITD patients with AML.Quizartinib is well tolerated, improves response and survival in older FLT3-ITD AML patients and merits consideration in future therapies. Now amended as text above., Visual Abstract, Survival for older patients with acute myeloid leukemia (AML) unsuitable for intensive chemotherapy is unsatisfactory. Standard nonintensive therapies have low response rates and only extend life by a few months. Quizartinib is an oral Fms-like tyrosine kinase 3 (FLT3) inhibitor with reported activity in wild-type patients. As part of the AML LI trial, we undertook a randomized evaluation of low-dose ara-C (LDAC) with or without quizartinib in patients not fit for intensive chemotherapy. Overall, survival was not improved (202 patients), but in the 27 FLT3-ITD patients, the addition of quizartinib to LDAC improved response (P = .05) with complete remission/complete remission with incomplete haematological recovery for quizartinib + LDAC in 5/13 (38%) vs 0/14 (0%) in patients receiving LDAC alone. Overall survival (OS) in these FLT3-ITD+ patients was also significantly improved at 2 years for quizartinib + LDAC (hazard ratio 0.36; 95% confidence intervals: 0.16, 0.85, P = .04). Median OS was 13.7 months compared with 4.2 months with LDAC alone. This is the first report of an FLT3-targeted therapy added to standard nonintensive chemotherapy that has improved survival in this population. Quizartinib merits consideration for future triplet-based treatment approaches. This trial was registered at www.clinicaltrials.gov as ISRCTN #ISRCTN40571019 and EUDRACT @2011-000749-19.

Despite the approval of 8 new drugs for acute myeloid leukemia (AML) since 2017, the disease remains challenging, given the significant toxicity associated with available treatments and relatively low cure rates, especially in older adults. Although advantageous for patients, self-congratulatory rejoicing about the new agents would be extremely premature. Questions abound about the need for a specific versus less specific FLT3 inhibitor (eg, midostautin) in the upfront setting and whether a single agent (gilteritnib), albeit better than chemotherapy, is sufficient for relapsed disease. Is the new liposomal formulation of daunorubicin/cytarabine better than ‘3 + 7’ only in secondary AML? Should only those newly diagnosed patients with core binding factor AML routinely receive gemtuzumab ozogamicin? The isocitrate dehydrogenase inhibitors were approved based on non-randomized data; thus, one wonders whether single-agent isocitrate dehydrogenase inhibitor therapy is appropriate for relapsed patients. Glasdegib, an orally available hedgehog inhibitor, is approved in conjunction with low-dose cytarabine in unfit patients but is rarely used in favor of a combination of hypomethylating agents or low-dose cytarabine with venetoclax, which are hopeful newly approved combinations for the older and/or unfit previously untreated. Perhaps venetoclax-based combinations should be more widely used, but the data is currently lacking. Thus, a temperate approach, more clinical research, and a critical analysis of the available data remain important in this “optimistic” new era of AML therapeutics.

Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10−8; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10−10; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA)., Genome wide association studies in cancer are used to understand the heritable genetic contribution to disease risk. Here, the authors perform a genome wide association study in European patients with acute myeloid leukemia and identify loci associated with risk of developing the disease.

BackgroundAcute myeloid leukaemia (AML) is a heterogeneous disease where outcome is substantially influenced by age. Over the last 30-40 years, significant improvements have been made in survival for younger patients (those under 60). However, with the median age of the disease at diagnosis at 65 years, outcome in older patients has improved much less. Additionally, many elderly patients are not considered suitable for intensive chemotherapy and the current standard treatment is considered unsatisfactory. MethodsLI1 will evaluate several relevant therapeutic questions in AML patients over 60 years of age for whom intensive chemotherapy is not considered suitable. Patients are invited to enter a randomized comparison of standard therapy (LD Ara-C) versus a novel treatment. A number of different treatment options are available at any one time, but there is no comparison between novel agents. If, at initial review, a novel agent is deemed unlikely to demonstrate the required improvement, it may be removed from the protocol and replaced with another novel agent, via protocol amendment. Agents are initially entered into a phase II comparison against standard of care - where an agent is considered promising at interim review (based on remission rates), the randomisation may be extended to a fully powered phase III comparison based on survival. Agents which may prolong survival or improve remission rates will also be required to demonstrate equivalence or better of quality of life in patients – therefore, quality of life assessments are undertaken throughout, in each arm. DiscussionEven when less intensive treatment options are delivered, the outcomes are not satisfactory. The NCRI AML working group has a strong network, required for delivery of this trial program. The UK network is augmented by international collaborative groups, most notably from New Zealand and Denmark. The use of the Pick-a-Winner design improves efficiency and speed of review of the available novel agents with the aim of benefitting the increasing number of patients in this age group.Trial registration: ISCRTN40571019, EUDRACT2011-000479-19 (12th May 2011)

Since the comprehensive recommendations for the management of acute promyelocytic leukemia (APL) reported in 2009, several studies have provided important insights, particularly regarding the role of arsenic trioxide (ATO) in frontline therapy. Ten years later, a European LeukemiaNet expert panel has reviewed the recent advances in the management of APL in both frontline and relapse settings in order to develop updated evidence- and expert opinion–based recommendations on the management of this disease. Together with providing current indications on genetic diagnosis, modern risk-adapted frontline therapy, and salvage treatment, the review contains specific recommendations for the identification and management of the most important complications such as the bleeding disorder APL differentiation syndrome, QT prolongation, and other all-trans retinoic acid– and ATO-related toxicities, as well as recommendations for molecular assessment of the response to treatment. Finally, the approach to special situations is also discussed, including management of APL in children, elderly patients, and pregnant women. The most important challenges remaining in APL include early death, which still occurs before and during induction therapy, and optimizing treatment in patients with high-risk disease.

An all-acceptor napthalenediimide-bithiazole-based co-polymer, P(NDI2OD-BiTz), was synthesized and characterized for application in thin-film transistors. Density functional theory calculations point to an optimal perpendicular dihedral angle of 90° between acceptor units along isolated polymer chains; yet optimized transistors yield electron mobility of 0.11 cm2/(V s) with the use of a zwitterionic naphthalene diimide interlayer. Grazing incidence X-ray diffraction measurements of annealed films reveal that P(NDI2OD-BiTz) adopts a highly ordered edge-on orientation, exactly opposite to similar bithiophene analogs. This report highlights an NDI and thiazole all-acceptor polymer and demonstrates high electron mobility despite its nonplanar backbone conformation.

Background: Many patients with Acute Myeloid Leukemia (AML) diagnosed after 60 years of age are not considered suitable for intensive remission induction chemotherapy, either due to co-morbidities or frailty associated with advanced age. Despite treatment with either a hypomethylating agent or low-dose cytarabine arabinoside (LDAC), survival is usually poor, with 1-year survival after LDAC of 24-37% in NCRI AML16 and historical arms of LI-1. Combination therapy with additional agents represents an attractive option, and has the potential to improve patient outcomes without substantially increasing toxicity. Lenalidomide (Revlimid TM) is an immunomodulatory drug, used to treat myeloma, and some cases of myelodysplastic syndrome, and has potent antineoplastic, anti-angiogenic, anti-inflammatory and pro-erythropoietic properties. Early-phase trials of lenalidomide in AML have demonstrated clinical activity with acceptable toxicity. Aim: To assess the efficacy and tolerability of LDAC+lenalidomide versus LDAC alone in patients aged 60+ unsuitable for intensive therapy. The aim was to double 2-year survival from 11% to 22% (HR 0.69). Methods: LI-1 was an international multicentre, multi-arm, randomised phase II trial developed to study the efficacy and tolerability of novel non-intensive therapies in AML using a "pick a winner" design. LDAC was given at 20mg BD SC on days 1-10 of each course. Lenalidomide was administered orally once daily in a flat 10mg dose for 21 days, where day 1 is day 1 of LDAC with courses occurring at 5-week intervals for courses 1-4. Patients considered to be benefitting after 4 courses, i.e. in remission or stable disease, could continue to receive treatment until disease progression, either with LDAC+lenalidomide at 6-week intervals, or lenalidomide only at 4-week intervals if patient had experienced significant toxicity. Toxicities were recorded using CTCAEv3. Primary objectives included overall survival (OS), complete remission (CR + CRi) achievement, reasons for failure, duration of response (CR/CRi), relapse rates and deaths in first CR. Secondary objectives included toxicity, supportive care requirements, and Quality of Life assessments (measured using EORTC QLQ-30, EQ5D and HADS tools). Results: Between Jan-17 and Jun-19, 202 patients from Denmark (8%), New Zealand (16%) and the UK (76%) were randomised. Median age was 78 years (range 62-89). Overall, 58% were male; 76% de novo AML, 20% secondary AML, and 4% high risk MDS; 1% favourable, 66% intermediate, 19% adverse and 14% unknown cytogenetics; WHO performance status 0 for 15%, 1 for 58%, 2 for 22% and 3 for 5%. Median of 2 courses (range 0-24; mean 3.28) was delivered in LDAC arm and 1 course in LDAC+lenalidomide arm (range 0-25; mean 3.48). Overall response (CR/CRi) was achieved in 40/202 patients (20%), (LDAC+lenalidomide 25%, LDAC 14%, OR 0.45 (0.22, 0.93), P=0.031). 30-day mortality was not significantly increased (19% in both arms); and 2-year OS showed no significant difference (14% vs 11.5%, HR 0.94 (0.69, 1.29, P=0.719). Median OS was 3.5 vs 4.6 months; HR 0.96 (0.71, 1.30), P=0.80. 1-year OS for patients that didn't enter CR/CRi was 6.8% for LDAC+lenalidomide vs 16.9% for LDAC (P=0.028). Cause of death for the majority of patients was resistant/recurrent disease: 45(53%) vs 47(58%). Most adverse events (AEs) were grade 1/2 in both arms. During cycle 1, there were 78 vs 51 grade 3/4 AEs in the LDAC+lenalidomide and LDAC arms, respectively (P=0.02). This included 5 thrombotic events in the LDAC+lenalidomide arm (4 grade 3 and 1 grade 4) and none in the LDAC arm. In course 1, supportive care requirements were higher in terms of both days of antibiotics (7 vs 3; p=0.001) and hospitalisation days (11 vs 6.5; p=0.005) for the LDAC+lenalidomide arm. There was no difference in transfusion requirements. Conclusions: Despite improving the CR/CRi rate, the combination of lenalidomide+LDAC did not improve OS, relapse-free survival or time in remission in elderly patients with AML. The addition of lenalidomide to LDAC resulted in increased toxicity, including episodes of thrombosis, as well as increased supportive care requirements. Alternative strategies to improve survival for elderly patients with AML remain a significant clinical need. Acknowledgements: We are grateful to Blood Cancer UK for funding the trial and Celgene for providing drug and additional support for this IIS. Fig 1: OS All patients Figure 1 Figure 1. Disclosures Copland: Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria, Speakers Bureau; Cyclacel Ltd: Research Funding. Russell: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Jazz: Research Funding, Speakers Bureau. OffLabel Disclosure: Off label use of lenalidomide in combination with low dose cytarabine will be discussed in the setting of elderly unfit AML.

Background: Among patients with Acute Myeloid Leukaemia (AML) over the age of 60, a considerable number are not considered suitable for intensive remission-induction chemotherapy. Survival in these patients is poor, whether they are treated using hypomethylating agents or low-dose ara-C (LDAC). The possibility of combination therapy with additional agents represents an attractive option. Arginine metabolism plays a key role in AML pathogenesis (Mussai et al. Blood 2013); BCT-100 is a pegylated recombinant human arginase that leads to a rapid depletion in extracellular and intracellular arginine concentrations resulting in G0/G1 arrest, and subsequent death by necrosis. BCT-100 demonstrates significant activity as single-agent against AML cell lines, AML xenografts and primary AML blasts from newly diagnosed or relapsed patients (Mussai et al. Blood 2015). Importantly BCT-100 is synergistic in combination with cytarabine. Aims: To assess the efficacy of LDAC+BCT100 versus LDAC alone in patients aged 60+ unsuitable for intensive therapy, in a "pick a winner" design. This design allows several treatments to be assessed simultaneously in a randomised fashion, with the aim of doubling 2-year survival from 11% to 22% (HR 0.69), with interim assessments after 50 and 100 patients per arm are recruited. Methods: LDAC was given at 20mg BD SC on days 1-10 of each course. Patients randomised to the combination received LDAC as above with BCT-100 1600U/kg on Days 1, 8, 15 and 22 as a 1-hour intravenous infusion. Courses occurred at 4-6 week intervals. Toxicities were recorded using CTCAE version 3. Pharmacokinetic and biomarker samples were assessed in BCT-100 patients. Results here are based upon median follow-up of 3.8 months (range: 0.1 - 20.6 months) Results: Between September 2018 and December 2020, 83 patients were randomised. The trial was prematurely closed due to the COVID pandemic and did not reach the pre-planned first evaluation. Median age was 76.7 years (range 62-88). Overall, 65% were male; 70% de novo AML, 23% secondary AML, and 6% high risk MDS; 2% favourable, 59% intermediate, 23% adverse and 15% unknown/unreported cytogenetics. Median of 2 courses was delivered in either arm (mean 2 LDAC, 2 LDAC+BCT, range for both: 1-12). BCT-100 leads to a depletion of arginine from baseline in the majority of patients. Overall response (CR/CRi) was achieved in 12/81 patients (15%), (LDAC+BCT-100 15%, LDAC 15%, R 1.03 (0.30, 3.51),P=0.963). Thirty-day mortality was not significantly increased (18% vs 11%, HR 1.71 (0.50, 5.84), P=0.393; and 1-year survival showed no evidence of a difference (31% vs 30%, HR 1.28 (0.72, 2.25). Median overall survival time was 3.8 vs 6.4months; overall survival HR 1.11 (0.64, 1.90), P=0.715. The most common cause of death was resistant/recurrent disease: 12(46%) vs 16(59%). BCT-100 was not associated with any haematological toxicity; although rare grade 3/4 cardiac and hepatic events were reported, these were not significantly increased with BCT-100. Summary: The addition of BCT-100 to LDAC did not improve response rate or survival. BCT-100 was well tolerated with an acceptable toxicity profile. Further clinical evaluation of BCT-100 induced arginase depletion continues in a variety of malignancies. Acknowledgements: We are grateful to Blood Cancer UK for funding the trial and Bio-Cancer Treatment International for providing drug and additional support for this Investigator Initiated Study. Figure 1. OS All patients Figure 1 Figure 1. Disclosures Knapper: Jazz: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Astellas: Ended employment in the past 24 months, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. McMullin: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: clinical trial support, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan: Research Funding, Speakers Bureau. Copland: Incyte: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Cyclacel Ltd: Research Funding; Astellas: Honoraria, Speakers Bureau; Jazz: Honoraria, Speakers Bureau. Russell: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Jazz: Research Funding, Speakers Bureau.

Background: Therapeutic resistance and treatment tolerance vary greatly in patients with AML, likely due to the advanced age and genetic diversity in pharmacokinetics of those affected. Undoubtedly, tools to accurately predict outcomes of individual therapies for patients could inform decision-making and improve response rates. To this end, several scoring systems have been developed aimed at identifying patients at high risk of poor outcome after intensive chemotherapy. Similar tools for use after non-intensive therapies are currently not available. As such therapies are increasingly effective and more widely utilized we sought to develop tools to predict early death and survival for patients treated with non-intensive therapies. Patients and Methods: We developed prediction models for all-cause death by day 28, 42, 56, and 100 from enrollment using data from 796 patients enrolled on MRC/NCRI trial LI-1, which we then validated in a cohort of 540 patients treated on SWOG trials S0432, S0703, and S1612. Treatments included: Low dose Ara-C (LDAC) alone, sapacitabine alone and LDAC in combination with vosaroxin, tosedostat or ganetespib (MRC/NCRI); Azacytidine (AZA) alone, tipifarnib alone, and AZA in combination with mylotarg, midostaurin, and nivolumab (SWOG). The following covariates were available in the MRC/NCRI and SWOG cohorts to build multivariable logistic regression models (quantitative unless specified otherwise): age, performance status (PS; 0-1 vs. 2-4), secondary AML (vs. de novo AML or high-risk myelodysplastic syndrome), white blood cell and platelet counts, and percentage of bone marrow blasts - all assessed at enrollment. The regression coefficients from the model fit in the MRC/NCRI cohort were used to derive a score and applied to each patient in the SWOG cohort. The models' prognostic accuracies were assessed using the area under the receiver operating characteristic curve (AUC). For the MRC/NCRI cohort, additional covariates were available: cytogenetic risk (per Grimwade 2011), FLT3-ITD, and NPM1 mutation and patient-reported outcomes using the QLQ-C30 instrument. Logistic regression models with these covariates were fit and optimism-corrected AUC estimated to assess prognostic performance for early death. Results: Both patient cohorts were largely composed of older individuals (median age of 75 [range: 60-91] for MRC/NCRI and 77 [60-94] for SWOG, respectively. A substantial subset in each had a PS of 2-4 (MRC/NCRI: 20%; SWOG: 37%) and/or secondary AML (MRC/NCRI: 26%; SWOG: 41%). Overall, the ability to predict early death either by day 28, 42, 56, or 100 was limited in the MRC/NCRI cohort. Subscales of the QLQ-C30 had univariate AUC=0.67, the highest among all covariates evaluated. Multivariable models with just clinical covariates had optimism-corrected AUCs ranging from 0.63-0.65; adding cytogenetic risk and FLT3-ITD and NPM1 mutation status led optimism-corrected AUCs ranging from 0.64-0.66; addition of two QLQ-C30 subscales (fatigue and appetite loss) led to optimism-corrected AUCs ranging from 0.66-0.69. The SWOG cohort did not collect QLQ-C30 or mutational data on all patients and only the clinical multivariable models could be evaluated. The models had a similar performance in the SWOG cohort with AUCs ranging from 0.65-0.68. Conclusion: Our ability to predict early death in older patients treated with lower intensity AML therapies is limited with routinely available clinical variables. Inclusion of cytogenetic risk, FLT3-ITD, and NPM1 mutation status minimally improved the prognostic accuracy as did some of the QLQ-C30 subscales. Our data highlight the difficulties in predicting outcomes with non-intensive AML therapy with routinely available baseline clinical information. Improving the clinical utility of these models may require more complete characterization of patient comorbidities (including frailty index, cognitive function, renal and hepatic function, comorbidity scores) or additional PRO measures since some QLQ-C30 subscales had the strongest univariate signals. Support: NIH/NCI grants CA180888 and CA180819; Blood Cancer UK grant 13041 and Cardiff University. Figure 1 Figure 1. Disclosures Assouline: Novartis: Honoraria, Research Funding; Amgen: Current equity holder in publicly-traded company, Research Funding; Gilead: Speakers Bureau; Johnson&Johnson: Current equity holder in publicly-traded company; Jewish General Hospital, Montreal, Quebec: Current Employment; Eli Lilly: Research Funding; Roche/Genentech: Research Funding; Takeda: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Erba: AbbVie Inc; Agios Pharmaceuticals Inc; Astellas; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Daiichi Sankyo Inc; Genentech, a member of the Roche Group; GlycoMimetics Inc; Incyte Corporation; Jazz Pharmaceuticals Inc; Kura Oncology; Nov: Other: Advisory Committee; AbbVie Inc: Other: Independent review committee; AbbVie Inc; Agios Pharmaceuticals Inc; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Incyte Corporation; Jazz Pharmaceuticals Inc; Novartis: Speakers Bureau; AbbVie Inc; Agios Pharmaceuticals Inc; ALX Oncology; Amgen Inc; Daiichi Sankyo Inc; FORMA Therapeutics; Forty Seven Inc; Gilead Sciences Inc; GlycoMimetics Inc; ImmunoGen Inc; Jazz Pharmaceuticals Inc; MacroGenics Inc; Novartis; PTC Therapeutics: Research Funding. Walter: Jazz: Research Funding; Pfizer: Consultancy, Research Funding; Selvita: Research Funding; Amphivena: Consultancy, Other: ownership interests; Agios: Consultancy; Astellas: Consultancy; BMS: Consultancy; Genentech: Consultancy; Janssen: Consultancy; Kite: Consultancy; Macrogenics: Consultancy, Research Funding; Immunogen: Research Funding; Celgene: Consultancy, Research Funding; Aptevo: Consultancy, Research Funding; Amgen: Research Funding. Othus: Daiichi Sankyo: Consultancy; Celgene: Other: Data safety monitoring board; Merck: Consultancy; Biosight: Consultancy; Glycomimetics: Other: Data safety monitoring board.

The clinical benefit of adding FMS-like tyrosine kinase-3 (FLT3)-directed small molecule therapy to standard first-line treatment of acute myeloid leukemia (AML) has not yet been established. As part of the UK AML15 and AML17 trials, patients with previously untreated AML and confirmed FLT3-activating mutations, mostly younger than 60 years, were randomly assigned either to receive oral lestaurtinib (CEP701) or not after each of 4 cycles of induction and consolidation chemotherapy. Lestaurtinib was commenced 2 days after completing chemotherapy and administered in cycles of up to 28 days. The trials ran consecutively. Primary endpoints were overall survival in AML15 and relapse-free survival in AML17; outcome data were meta-analyzed. Five hundred patients were randomly assigned between lestaurtinib and control: 74% had FLT3-internal tandem duplication mutations, 23% FLT3-tyrosine kinase domain point mutations, and 2% both types. No significant differences were seen in either 5-year overall survival (lestaurtinib 46% vs control 45%; hazard ratio, 0.90; 95% CI 0.70-1.15; P = .3) or 5-year relapse-free survival (40% vs 36%; hazard ratio, 0.88; 95% CI 0.69-1.12; P = .3). Exploratory subgroup analysis suggested survival benefit with lestaurtinib in patients receiving concomitant azole antifungal prophylaxis and gemtuzumab ozogamicin with the first course of chemotherapy. Correlative studies included analysis of in vivo FLT3 inhibition by plasma inhibitory activity assay and indicated improved overall survival and significantly reduced rates of relapse in lestaurtinib-treated patients who achieved sustained greater than 85% FLT3 inhibition. In conclusion, combining lestaurtinib with intensive chemotherapy proved feasible in younger patients with newly diagnosed FLT3-mutated AML, but yielded no overall clinical benefit. The improved clinical outcomes seen in patients achieving sustained FLT3 inhibition encourage continued evaluation of FLT3-directed therapy alongside front-line AML treatment. The UK AML15 and AML17 trials are registered at www.isrctn.com/ISRCTN17161961 and www.isrctn.com/ISRCTN55675535 respectively.

We demonstrate conductive templating interlayers of graphene ink, integrating the electronic and chemical properties of graphene in a solution-based process relevant for scalable manufacturing. Thin films of graphene ink are coated onto ITO, following thermal annealing, to form a percolating network used as interlayer. We employ a benchmark n-type semiconductor, C60, to study the interface of the active layer/interlayer. On bare ITO, C60 molecules form films of homogeneously distributed grains; with a graphene interlayer, a preferential orientation of C60 molecules is observed in the individual graphene plates. This leads to crystal growth favoring enhanced charge transport. We fabricate devices to characterize the electron injection and the effect of graphene on the device performance. We observe a significant increase in the current density with the interlayer. Current densities as high as ∼1 mA/cm2 and ∼70 mA/cm2 are realized for C60 deposited with the substrate at 25 °C and 150 °C, respectively.

D2C7-(scdsFv)-PE38KDEL (D2C7-IT) is a novel immunotoxin that reacts with wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFRvIII proteins overexpressed in glioblastomas. This study assessed the toxicity of intracerebral administration of D2C7-IT to support an initial Food and Drug Administration Investigational New Drug application. After the optimization of the formulation and administration, two cohorts (an acute and chronic cohort necropsied on study days 5 and 34) of Sprague-Dawley (SD) rats (four groups of 5 males and 5 females) were infused with the D2C7-IT formulation at total doses of 0, 0.05, 0.1, 0.4 µg (the acute cohort) and 0, 0.05, 0.1, 0.35 µg (the chronic cohort) for approximately 72 hours by intracerebral convection-enhanced delivery using osmotic pumps. Mortality was observed in the 0.40 µg (5/10 rats) and 0.35 µg (4/10 rats) high-dose groups of each cohort. Body weight loss and abnormal behavior were only revealed in the rats treated with high doses of D2C7-IT. No dose-related effects were observed in clinical laboratory tests in either cohort. A gross pathologic examination of systemic tissues from the high-dose and control groups in both cohorts exhibited no dose-related or drug-related pathologic findings. Brain histopathology revealed the frequent occurrence of dose-related encephalomalacia, edema, and demyelination in the high-dose groups of both cohorts. In this study, the maximum tolerated dose of D2C7-IT was determined to be between 0.10 and 0.35 µg, and the no observed adverse effect level was 0.05 µg in SD rats. Both parameters were utilized to design the Phase I/II D2C7-IT clinical trial.

Therapy-related acute promyelocytic leukemia (t-APL) is relatively rare, with limited data on outcome after treatment with arsenic trioxide (ATO) compared to standard intensive chemotherapy (CTX). We evaluated 103 adult t-APL patients undergoing treatment with all-trans retinoic acid (ATRA) alone (n = 7) or in combination with ATO (n = 24), CTX (n = 53), or both (n = 19). Complete remissions were achieved after induction therapy in 57% with ATRA, 100% with ATO/ATRA, 78% with CTX/ATRA, and 95% with CTX/ATO/ATRA. Early death rates were 43% for ATRA, 0% for ATO/ATRA, 12% for CTX/ATRA and 5% for CTX/ATO/ATRA. Three patients relapsed, two developed therapy-related acute myeloid leukemia and 13 died in remission including seven patients with recurrence of the prior malignancy. Median follow-up for survival was 3.7 years. None of the patients treated with ATRA alone survived beyond one year. Event-free survival was significantly higher after ATO-based therapy (95%, 95% CI, 82–99%) as compared to CTX/ATRA (78%, 95% CI, 64–87%; P= 0.042), if deaths due to recurrence of the prior malignancy were censored. The estimated 2-year overall survival in intensively treated patients was 88% (95% CI, 80–93%) without difference according to treatment (P= 0.47). ATO when added to ATRA or CTX/ATRA is feasible and leads to better outcomes as compared to CTX/ATRA in t-APL.

The Food and Drug Administration Amendments Act of 2007 (FDAAA 2007, US Public Law 110-98) mandated registration and reporting of results for applicable clinical trials (ACTs). Meeting these registration and results reporting requirements has proven to be a challenge for the academic research community. Duke Medicine has made compliance with registration and results reporting a high priority. In order to create uniformity across a large institution, a written policy was created describing requirements for clinical trials disclosure. Furthermore, a centralized resource group was formed with three full time staff members. The group not only ensures compliance with FDAAA 2007, it also acts as a resource for study teams providing hands-on support, reporting, training and ongoing education. Intensive resourcing for results reporting has been crucial for success. Due to implementation of the institutional policy and creation of centralized resources, compliance with FDAAA 2007 has increased dramatically at Duke Medicine for both registration and results reporting. A consistent centralized approach has enabled success in the face of changing agency rules and new legislation.

Background Oral immunotherapy (OIT) is an investigational therapeutic approach for the treatment of food allergies. Characterization of the drug product used in oral immunotherapy trials for peanut allergy has not been reported. Objective To quantify relative amounts of the major peanut allergens and microbial load present in peanut flour used in OIT trials and assess whether these parameters change over a 12-month period. We also anticipate that this report will serve as a guide for investigators seeking to conduct OIT trials under Food and Drug Administration–approved Investigational New Drug applications. Methods Densitometric scanning of Ara h 1 and Ara h 2 resolved on SDS-PAGE gels was used to assess allergen content in peanut flour extracts. Microbial testing was conducted on peanut flour under US Pharmacopeia guidelines for the presence of Escherichia coli , salmonella, yeast, mold, and total aerobic bacteria. In addition, aflatoxin was quantified in peanut flour. Reported results were obtained from 4 unique lots of peanut flour. Results Relative amounts of the major peanut allergens were similar between different lots of peanut flour and remained stable over a 12-month period. E coli and salmonella were absent from all lots of flour. Yeast, mold, total aerobic bacteria, and aflatoxin were within established US Pharmacopeia guidelines on all lots tested and remained within the criteria over a 12-month period. Conclusions Peanut flour used as a drug product contains the major peanut allergens and has low levels of potentially harmful microbes. Both these parameters remain stable over a 12-month period.

We report on an experimental measurement of the phase shifts associated with the AC Stark effect. The optically induced light shift was measured using a Ramsey fringe technique and we have made detailed studies of the potential sources of coherence loss that can occur for an atomic sample manipulated by light. We investigated the loss of coherence due to the light shifts induced by using a non-uniform laser beam and the effects of scattered light. These measurements have implications for experiments which use optical techniques for manipulating atomic wavepackets in atom optics and atom interferometry.

Prior to human clinical trials, nonclinical safety and toxicology studies are required to demonstrate that a new product appears safe for human testing; these nonclinical studies are governed by good laboratory practice (GLP) regulations. As academic health centers (AHCs) embrace the charge to increase the translation of basic science research into clinical discoveries, researchers at these institutions increasingly will be conducting GLP-regulated nonclinical studies. Because the consequences for noncompliance are severe and many AHC researchers are unfamiliar with Food and Drug Administration (FDA) regulations, the authors describe the regulatory requirements for conducting GLP research, including the strict documentation requirements, the necessary personnel training, the importance of study monitoring, and the critical role that compliance oversight plays in the process. They then explain the process that AHCs interested in conducting GLP studies should take prior to the start of their research program, including conducting a needs assessment and a gap analysis and selecting a model for GLP compliance. Finally, the authors identify and analyze several critical barriers to developing and implementing a GLP-compliant infrastructure at an AHC. Despite these challenges, the capacity to perform such research will help AHCs to build and maintain competitive research programs and to facilitate the successful translation of faculty-initiated research from nonclinical studies to first-in-human clinical trials.

The acute myeloid leukaemia (AML)14 trial addressed four therapeutic questions in patients predominantly aged over 60 years with AML and High Risk Myelodysplastic Syndrome: (i) Daunorubicin 50 mg/m2 vs. 35 mg/m2; (ii) Cytarabine 200 mg/m2 vs. 400 mg/m2 in two courses of DA induction; (iii) for part of the trial, patients allocated Daunorubicin 35 mg/m2 were also randomized to receive, or not, the multidrug resistance modulator PSC-833 in a 1:1:1 randomization; and (iv) a total of three versus four courses of treatment. A total of 1273 patients were recruited. The response rate was 62% (complete remission 54%, complete remission without platelet/neutrophil recovery 8%); 5-year survival was 12%. No benefits were observed in either dose escalation randomization, or from a fourth course of treatment. There was a trend for inferior response in the PSC-833 arm due to deaths in induction. Multivariable analysis identified cytogenetics, presenting white blood count, age and secondary disease as the main predictors of outcome. Although patients with high Pgp expression and function had worse response and survival, this was not an independent prognostic factor, and was not modified by PSC-833. In conclusion, these four interventions have not improved outcomes in older patients. New agents need to be explored and novel trial designs are required to maximise prospects of achieving timely progress.

As therapy for hematologic malignancy evolves, new regimens and novel agents that target specific cellular processes allow a more optimistic prognosis for many patients. Bortezomib and tipifarnib are two new, targeted treatments for hematologic malignancies. Bortezomib, a proteasome inhibitor, has shown impressive efficacy in patients with relapsed multiple myeloma and as initial treatment, including before autologous stem cell transplantation. It has been studied as monotherapy and in combination with standard treatments such as dexamethasone, and with newer agents such as the immunomodulators thalidomide and lenalidomide; response is encouraging, even in patients who have relapsed after previously receiving components of a regimen as single agents. Bortezomib is generally well tolerated, including in combination with novel and conventional agents. Tipifarnib is a specific inhibitor of farnesyltransferase. Clinical trials in patients with high-risk acute leukemias and myelodysplastic syndromes have demonstrated good efficacy with tipifarnib. Continued investigation with these new, targeted treatments will further define their use as treatment options in patients with hematologic cancer.

An overview is provided of the papers presented at the Discussion Meeting on ‘Laser-driven particle accelerators: new sources of energetic particles and radiation’ which was held at the Royal Society on 6 and 7 June 2005. A discussion of the future prospects of the field, held during the last session of the meeting, is summarized and the conclusions of this presented.

Modifying induction therapy in acute myeloid leukemia (AML) may improve the remission rate and reduce the risk of relapse, thereby improving survival. Escalation of the daunorubicin dose to 90 mg/m 2 has shown benefit for some patient subgroups when compared with a dose of 45 mg/m 2, and has been recommended as a standard of care. However, 60 mg/m 2 is widely used and has never been directly compared with 90 mg/m 2. As part of the UK National Cancer Research Institute (NCRI) AML17 trial, 1206 adults with untreated AML or high-risk myelodysplastic syndrome, mostly younger than 60 years of age, were randomized to a first-induction course of chemotherapy, which delivered either 90 mg/m 2 or 60 mg/m 2 on days 1, 3, and 5 combined with cytosine arabinoside. All patients then received a second course that included daunorubicin 50 mg/m 2 on days 1, 3, and 5. There was no overall difference in complete remission rate (73% vs 75%; odds ratio, 1.07 [0.83-1.39]; P = .6) or in any recognized subgroup. The 60-day mortality was increased in the 90 mg/m 2 arm (10% vs 5% (hazard ratio [HR] 1.98 [1.30-3.02]; P = .001), which resulted in no difference in overall 2-year survival (59% vs 60%; HR, 1.16 [0.95-1.43]; P = .15). In an exploratory subgroup analysis, there was no subgroup that showed significant benefit, although there was a significant interaction by FLT3 ITD mutation. This trial is registered at http://www.isrctn.com as #ISRCTN55675535.

Hypnosis improves irritable bowel syndrome (IBS), but the mechanism is unknown. Possible physiological and psychological mechanisms were investigated in two studies. Patients with severe irritable bowel syndrome received seven biweekly hypnosis sessions and used hypnosis audiotapes at home. Rectal pain thresholds and smooth muscle tone were measured with a barostat before and after treatment in 18 patients (study I), and treatment changes in heart rate, blood pressure, skin conductance, finger temperature, and forehead electromyographic activity were assessed in 24 patients (study II). Somatization, anxiety, and depression were also measured. All central IBS symptoms improved substantially from treatment in both studies. Rectal pain thresholds, rectal smooth muscle tone, and autonomic functioning (except sweat gland reactivity) were unaffected by hypnosis treatment. However, somatization and psychological distress showed large decreases. In conclusion, hypnosis improves IBS symptoms through reductions in psychological distress and somatization. Improvements were unrelated to changes in the physiological parameters measured.

The development of new treatments for older patients with acute myeloid leukemia is an active area, but has met with limited success. Vosaroxin, a quinolone-derived intercalating agent has several properties that could prove beneficial. Initial clinical studies showed it to be well-tolerated in older patients with relapsed/refractory disease. In vitro data suggested synergy with cytarabine (Ara-C). To evaluate vosaroxin, we performed 2 randomized comparisons within the “Pick a Winner” program. A total of 104 patients were randomized to vosaroxin vs low-dose Ara-C (LDAC) and 104 to vosaroxin + LDAC vs LDAC. When comparing vosaroxin with LDAC, neither response rate (complete recovery [CR]/complete recovery with incomplete count recovery [CRi], 26% vs 30%; odds ratio [OR], 1.16 (0.49-2.72); P = .7) nor 12-month survival (12% vs 31%; hazard ratio [HR], 1.94 [1.26-3.00]; P = .003) showed benefit for vosaroxin. Likewise, in the vosaroxin + LDAC vs LDAC comparison, neither response rate (CR/CRi, 38% vs 34%; OR, 0.83 [0.37-1.84]; P = .6) nor survival (33% vs 37%; HR, 1.30 [0.81-2.07]; P = .3) was improved. A major reason for this lack of benefit was excess early mortality in the vosaroxin + LDAC arm, most obviously in the second month following randomization. At its first interim analysis, the Data Monitoring and Ethics Committee recommended closure of the vosaroxin-containing trial arms because a clinically relevant benefit was unlikely.

We have realized a quantum accelerator mode using a system consisting of ultracold cesium atoms falling through a pulsed standing wave of off resonant light. We present a picture of this system based on diffraction and show that the effect arises from the application of blazed matter wave diffraction gratings. The implications of our results for quantum chaos and the prospect of constructing a large angular separation matter wave beam splitter are discussed.

We describe in detail our caesium atom interferometer which uses a combination of microwaves and momentum-changing adiabatic transfer pulses. This combination allows us to achieve spatial separation between the arms of the interferometer. We account for the observed visibility of the resulting interference fringes and find that the effects which contribute the most are optical pumping and magnetic fields.

We present experimental results showing that a dark state with finite lifetime, a grey state, becomes darker the more the atom is exposed to on-resonant light. We discuss this phenomenon theoretically in the context of the complex eigenenergies and show that it can be understood qualitatively in terms of the quantum Zeno effect. The predicted dependence of the lifetime on the composition of the grey state and on the light intensity is experimentally confirmed with caesium atoms. This has implications for velocity-selective coherent population trapping and adiabatic transfer.

The relative efficacy and toxicity of the chemotherapeutic agents thioguanine (6TG) and etoposide (VP16) were assessed by a randomized comparison of the DAT (daunorubicin, cytarabine, thioguanine) versus ADE (daunorubicin, cytarabine, etoposide) regimens in the Medical Research Council's 10th acute myeloid leukaemia trial (MRC AML 10), which was open to patient entry from May 1988 to April 1995. In this, the largest reported trial of AML therapy to date, 1,857 eligible patients, mostly less than 56 years old, were randomized: 929 (including 143 children under 15 years old) were allocated to DAT and 928 (143 children) to ADE. The two groups were well matched for presentation features. The complete remission (CR) rate was 81% with DAT and 83% with ADE (P = .3). The percentages of remitters achieving remission after 1, 2, or more than 2 courses were 70%, 22%, and 8% for DAT and 74%, 21%, and 5% for ADE. The percentages failing to achieve a CR due to resistant disease were 11% with DAT versus 9% with ADE (P = .07). There was a slightly higher death rate in CR during consolidation chemotherapy with ADE (9%) than with DAT (6%) (P = .06). Patients receiving DAT took slightly but significantly longer to recover from neutropenia and thrombocytopenia but the median number of days in hospital were similar in each group. ADE patients experienced slightly more severe nonhematologic toxicity. There was also no significant difference between the groups in the longer-term measures of efficacy: disease-free survival at 6 years from CR was 42% (±4) for DAT and 43% (±4) for ADE (P = .8); relapse rate at 6 years was 50% (±4) for DAT and 49% (±5) for ADE (P = .6); survival at 6 years was 40% (±4) for both DAT and ADE (P = .9). Subgroup analysis failed to show any benefit for etoposide in patients with monocytic or myelomonocytic disease, or in any other diagnostic subgroup. In conclusion, DAT and ADE both achieve high remission rates and good long-term survival, and are equally effective chemotherapy regimens for the treatment of AML patients aged up to 55 years.

Purpose: This study highlights Warning Letter (WL) findings issued to sponsor-investigators (S-Is) by the Food and Drug Administration (FDA). Methods: The online index of WLs issued from October 1, 2007 through September 30, 2012 was reviewed [1]. Through a manual screening process, letters were evaluated if specifically issued to ‘clinical investigators’, ‘sponsors’ or ‘sponsor-investigators’. A particular focus was given to S-Is at Academic Health Centres (AHCs). Each letter was scored for the presence of violations in 40 general regulatory categories. Results: A review of FDA WLs issued over a five-year period (FDA Fiscal Years 2008-2012) revealed that WLs to S-Is represent half of the WLs issued to all sponsors (16 of 32 letters). A review of these letters indicates that S-Is are not aware of, or simply do not meet, their regulatory responsibilities as either investigators or sponsors. In comparing total sponsor letters to those of S-Is, the most cited violation was the same: a lack of monitoring. A review of publicly available inspection data indicates that these 16 letters merely represent the tip of the iceberg. Conclusion: This review of the WL database reveals the potential for serious regulatory violations among S-Is at AHCs. Recent translational funding initiatives may serve to increase the number of S-Is, especially among Academic Health Centres (AHCs) [2]; thus, AHCs must become aware of this S-I role and work to support investigators who assume both roles in the course of their research.

The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health convened the Cell Therapy for Lung Disease Working Group on November 13–14, 2012, to review and formulate recommendations for future research directions. The workshop brought together investigators studying basic mechanisms and the roles of cell therapy in preclinical models of lung injury and pulmonary vascular disease, with clinical trial experts in cell therapy for cardiovascular diseases and experts from the NHLBI Production Assistance for Cell Therapy program. The purpose of the workshop was to discuss the current status of basic investigations in lung cell therapy, to identify some of the scientific gaps in current knowledge regarding the potential roles and mechanisms of cell therapy in the treatment of lung diseases, and to develop recommendations to the NHLBI and the research community on scientific priorities and practical steps that would lead to first-in-human trials of lung cell therapy.

The aims of this study were to determine the impact of irritable bowel syndrome on quality of life using a well-standardized measure, the SF-36, and to determine whether apparent impairments may be due to neuroticism. Undergraduate students with irritable bowel syndrome who had consulted a physician (41 females, 42 males), students with irritable bowel who had not consulted a physician (91 females, 74 males), and asymptomatic controls (52 females, 70 males) completed questionnaires on quality of life, neuroticism, and psychological distress. Patients showed greater impairment in quality of life than nonconsulters, who in turn showed greater impairment than controls. Neuroticism and psychological distress were correlated with all quality-of-life measures. However, when neuroticism and psychological distress were statistically partialed out, irritable bowel syndrome still had a significant negative impact. The SF-36 may be a useful outcome measure in treatment studies, but investigators will need to correct for confounding influences of neuroticism.

Reported is the spectral shifting observed when a ≈ 1 ps, 1 μm laser pulse is focussed into a cell containing argon at pressures from 0–10 bar. Focal intensities of 1–5×10 15 W cm -2 would be expected in vacuum for the ‖/8 focussing used. Instead evidence is found in the spectra of a significant decrease in the focal intensity reached when higher gas pressures are used. For the first time the spatial distribution of the shifted spectra is investigated. Spectral shifts are found to increase off-axis in the transmitted beam profile. The distributions show many peaks and minima and contain much extra detail. A two-dimensional numerical propagation model shows good general agreement with the experimental results.

Summary The kinetics of haematological recovery were retrospectively analysed in 53 patients with acute myeloid leukaemia in first remission after myeloablative chemoradiotherapy followed by autologous bone marrow transplantation. The median time to achieve a neutrophil count of 1 × 109/1 was 46d (22–196 d) and median time to achieve unsupported platelet counts of 20 × 109/1 and 50 × 109/1 was 70 d (24–310 d) and 126 d (29–497 d) respectively. Multivariate analysis revealed two factors that were significantly associated with delayed neutrophil and platelet recovery: (1) use of high dose fractionated TBI and mononuclear cell cryopreservation, and (2) low platelet count at the time of bone marrow harvest. There was no correlation with: number of courses of chemotherapy, remission to ABMT interval, CMV status, indices of autograft quality or the development of elevated platelet associated immunoglobulin. Delayed haematological recovery did not predict for relapse or death. Delayed platelet recovery did, however, present significant problems with increased blood and platelet requirements and lengthening of hospital stay.

Purpose Investigator-initiated research involving investigational drugs and devices is key to improving health. However, this requires the investigator to serve as a "sponsor-investigator," which can be complex and overwhelming. The Investigational New Drug/Investigational Device Exemption (IND/IDE) Taskforce of the Clinical and Translational Science Award (CTSA) consortium carried out a survey to examine how academic health centers (AHCs) assist sponsor-investigators with regulatory responsibilities. Method The 24 CTSA centers existing in 2008 were surveyed regarding regulatory oversight and support for sponsor-investigators. Responses were analyzed by descriptive statistics. The evaluation of survey responses yielded three models of institutional support/oversight. Results Nineteen centers and one affiliate responded. Eleven (55%) reported having an IND/IDE support office, increased from five (25%) prior to their CTSA award. The volume of investigator-initiated IND/IDE research was highly variable (measured by numbers of investigators, IND/IDE applications, and studies). Oversight, if done, was provided by either the IND/IDE office or elsewhere in the institution. Most IND/IDE offices assisted with IND/IDE submissions and preparation for external audits. Half reported advanced training for sponsor-investigators. Almost all reported a goal to increase IND/IDE research. Important issues include the need for robust training of investigator/staff, appropriate determination of IND-exempt research, and sufficient support for preparing IND/IDE applications. Conclusions Investigator-initiated research involving IND/IDEs is essential, but complex. AHCs should examine how they support sponsor-investigators in meeting the complex requirements. A model of either expert consultation/support or full service will minimize risks to participants and institutions, and regulatory noncompliance.

A one-dimensional model, including pulse propagation and detailed ionization dynamics, is developed in order to calculate the spectrum of an intense femtosecond laser pulse transmitted through an atmospheric-density noble gas. The spectrum is broadened and blueshifted due to self-phase-modulation resulting from a combination of optical-field-induced ionization and collisional ionization. Different features in the spectrum can be used to indicate the relative importance of the two ionization mechanisms. The calculations are in good agreement with the recent experimental results of Wood, Siders, and Downer [Phys. Rev. Lett. 67, 3523 (1991)], but indicate that a significant degree of defocusing occurs as a result of plasma generation. The simulations could possibly be used as a test of various theoretical models for optical-field-induced ionization.

This paper develops a multiple contingency selection procedure that can identify the single contingencies that cause thermal stress on the same branch or branches and, thereby, produce critical multiple contingences. This multiple contingency selection procedure is required if enumerative transmission reliability is to be successfully applied since all critical single and multiple contingences can be identified without excessive computation or false alarm or misclassification problems. The multiple contingency selection is accomplished by determining a list of contingencies for each branch that have: apparent power flows that exceed {alpha} {times} 100% of the thermal limit and apparent power flow changes that exceed {beta} {times} 100% of the thermal limit. A branch contingency measure is used to rank these single contingencies. Combination of the single contingencies taken from any branch's list of contingencies would produce multiple critical contingences with thermal overloads on that branch assuming superposition holds. The BOUNSM computer program that provides the information for the enumerative transmission reliability program also provides the information required to perform a transfer capability study. A monitored branch measure, which is the sum of the branch contingency measures for a particular branch, would identify the branches, paths, and interfaces that are most insecure for anmore » anticipated transfer and must be specified to run a transfer capability study. The combination of branch's list of contingencies for each of these branches, paths, and interfaces would be the list of contingencies that needs to be specified to perform a transfer capability study.« less

The wave equation for laser light incident on a static, steep-gradient plasma has been solved numerically, with the inclusion of an intensity-dependent electron-ion collision rate, and incorporating spatial dispersion and wave-breaking effects. At moderate intensities (\ensuremath{\sim}${10}^{14}$ W/${\mathrm{cm}}^{2}$), the nonlinearity has little effect on the calculated reflectivity, but at higher intensities the reflectivity is greater than that predicted by a linear model. The discrepancy is small for a steplike plasma (with a density gradient scale length L\ensuremath{\sim}0.01${\ensuremath{\lambda}}_{0}$), but increases for longer scale lengths (L\ensuremath{\sim}${\ensuremath{\lambda}}_{0}$). In the case of p-polarized light, the angular dependence of reflectivity is sharpened at higher intensities, and resonance effects play an important role even for very short scale lengths.

The optimum chemotherapy schedule for reinduction of patients with high-risk acute myeloid leukemia (relapsed, resistant/refractory, or adverse genetic disease) is uncertain. The MRC AML (Medical Research Council Acute Myeloid Leukemia) Working Group designed a trial comparing fludarabine and high-dose cytosine (FLA) with standard chemotherapy comprising cytosine arabinoside, daunorubicin, and etoposide (ADE). Patients were also randomly assigned to receive filgrastim (G-CSF) from day 0 until neutrophil count was greater than 0.5 × 109/L (or for a maximum of 28 days) and all-trans retinoic acid (ATRA) for 90 days. Between 1998 and 2003, 405 patients were entered: 250 were randomly assigned between FLA and ADE; 356 to G-CSF versus no G-CSF; 362 to ATRA versus no ATRA. The complete remission rate was 61% with 4-year disease-free survival of 29%. There were no significant differences in the CR rate, deaths in CR, relapse rate, or DFS between ADE and FLA, although survival at 4 years was worse with FLA (16% versus 27%, P = .05). Neither the addition of ATRA nor G-CSF demonstrated any differences in the CR rate, relapse rate, DFS, or overall survival between the groups. In conclusion these findings indicate that FLA may be inferior to standard chemotherapy in high-risk AML and that the outcome is not improved with the addition of either G-CSF or ATRA.

It is now possible to describe the response of single electron systems to laser fields around one atomic unit. In such intense fields an atom or ion may generate a comb of harmonics that extends far into the XUV. Many experimental and theoretical groups are now studying this process and assessing the relative merits of different species and laser wavelengths for the efficient production of harmonics. This is a very complex matter indeed involving microscopic—single electron multiphoton response as well as macroscopic propagation of intense light in an ionising medium—issues.

The prognostic significance of FLT3 mutations in acute promyelocytic leukemia (APL) is not firmly established and is of particular interest given the opportunities for targeted therapies using FLT3 inhibitors. We studied 203 patients with PML-RARA–positive APL; 43% of the patients had an FLT3 mutation (65 internal tandem duplications [ITDs], 19 D835/I836, 4 ITD+D835/I836). Both mutations were associated with higher white blood cell (WBC) count at presentation; 75% of the patients with WBC counts of 10 × 109/L or greater had mutant FLT3. FLT3/ITDs were correlated with M3v subtype (P < .001), bcr3 PML breakpoint (P < .001), and expression of reciprocal RARA-PML transcripts (P = .01). Microarray analysis revealed differences in expression profiles among patients with FLT3/ITD, D835/I836, and wild-type FLT3. Patients with mutant FLT3 had a higher rate of induction death (19% vs 9%; P = .04, but no significant difference in relapse risk (28% vs 23%; P = .5) or overall survival (59% vs 67%; P = .2) at 5 years. In in vitro differentiation assays using primary APL blasts (n = 6), the FLT3 inhibitor CEP-701 had a greater effect on cell survival/proliferation in FLT3/ITD+ cells, but this inhibition was reduced in the presence of ATRA. Furthermore, in the presence of CEP-701, ATRA-induced differentiation was reduced in FLT3/ITD+ cells. These data carry implications for the use of FLT3 inhibitors as frontline therapy for APL.