Early CR Research Articles

Cognitive remediation improves memory and psychosocial functioning in first-episode psychiatric out-patients

Cognitive remediation (CR) is an effective treatment for several psychiatric disorders. To date, there have been no published studies examining solely first-episode psychiatric cohorts, despite the merits demonstrated by early intervention CR studies. The current study aimed to assess the effectiveness of CR in patients with a first-episode of either major depression or psychosis. Method Fifty-five patients (mean age=22.8 years, s.d.=4.3) were randomly assigned to either CR (n=28) or treatment as usual (TAU; n=27). CR involved once-weekly 2-h sessions for a total of 10 weeks. Patients were comprehensively assessed before and after treatment. Thirty-six patients completed the study, and analyses were conducted using an intent-to-treat (ITT) approach with all available data. In comparison to TAU, CR was associated with improved immediate learning and memory controlling for diagnosis and baseline differences. Similarly, CR patients demonstrated greater improvements than TAU patients in psychosocial functioning irrespective of diagnosis. Delayed learning and memory improvements mediated the effect of treatment on psychosocial functioning at a marginal level. CR improves memory and psychosocial outcome in first-episode psychiatric out-patients for both depression and psychosis. Memory potentially mediated the functional gains observed. Future studies need to build on the current findings in larger samples using blinded allocation and should incorporate longitudinal follow-up and assessment of potential moderators (e.g. social cognition, self-efficacy) to examine sustainability and the precise mechanisms of CR effects respectively.

FDG-PET/CT Early After 90Y-Ibritumomab Tiuxetan Therapy Predicts Outcome in Relapsed or Refractory Indolent B-Cell Lymphoma

AbstractAbstract 3648 Background:Radioimmunotherapy (RIT) with 90Y-ibritumomab tiuxetan has been used for the treatment of relapsed or refractory indolent B-cell lymphoma. Early prediction of response to the therapy may offer the potential to identify patients who will benefit this therapy. We evaluated the efficacy of fluorine 18 fluorodeoxyglucose (FDG) combined positron emission tomographic-computed tomographic (FDG-PET/CT) imaging for assessment of therapy and predicting outcome in 90Y-ibritumomab tiuxetan radioimmunotherapy. Methods:Radioimmunotherapy with 90Y-ibritumomab tiuxetan was preformed in 52 patients with relapsed or refractory indolent B cell lymphoma (follicular lymphoma, 45; mucosa-associated lymphoid tissue lymphoma, 5; lymphoplasmacytic lymphoma, 2) at Hyogo College of Medicine Hospital from June 2009 through August 2012. FDG-PET/CT scanning was performed at two weeks and the later after 90Y-ibritumomab tiuxetan therapy. Results:In FDG-PET at 2 weeks after 90Y-ibritumomab therapy, 26 (50%) showed complete response (defined as early CR), 20 (38%) showed partial response (PR-2W) and 6 (12%) showed non response (NR-2W). Further follow-up revealed 10 later CR (8 CR out of 20 PR-2W and 2 CR out of 6 NR-2W), showing 69 %(36) of overall CR rate. Relapse was occurred in 4(17%) of 26 early CR and in 6 (60%) of 10 later CR, indicating significantly low relapse late in early CR (P= 0.0074, by Chi-square test). Patients with early CR (CR in 2 weeks after the RIT) showed significantly better progression free survival than those with later CR (P=0.0046, by Logrank test). In contrast, analysis at six weeks after the RIT showed 36 CR patients (10 of which eventually relapse), but failed to discriminate patients who had high risk of relapse. Conclusion:Our results suggest that CR assessed by FDG-PET/CT at 2 weeks after 90Y-ibritumomab tiuxetan therapy discriminates good responder to the RIT and predicts better progression free survival in relapsed or refractory indolent B cell lymphoma. Disclosures:No relevant conflicts of interest to declare.

Characterization of Common Fusion Oncogenes As Prognostic Molecular Identities in Adult Acute Lymphoblastic Leukemia Identifies the Need for Genetic Testing At Presentation, Molecular Prognostication and Differential Treatment

AbstractAbstract 5115 Introduction:Acute lymphoblastic leukemia (ALL) is a heterogeneous lymphoid disorder with many genetic abnormalities of which fusion oncogenes (FGs) are very common with a known role in leukemogenesis (Harrison & Foroni, 2002). Although prognostic significance of FGs is well characterized in pediatric ALL, the role of FGs in adult ALL is not well established (Moorman et al., 2007). Methods:We studied the frequency and association of five most common FGs namely BCR-ABL, MLL-AF4, ETV6-RUNX11, E2A-PBX1 and SIL-TAL1 with disease biology and treatment outcome in adult ALL. FGs were studied at diagnosis in 104 adult ALL patients using RT-PCR (Van-Dongen et al, 1999) and Interphase FISH. Results:FGs were found in 78. 8% (82/104) subjects (Table 1). Overall survival (OS) and relapse free survival (RFS) were 26. 17 and 11. 147 months, respectively (Figures 1–2). Patients with MLL-AF4 (12. 19%) showed an elevated total leukocyte count (TLC), prominent organomegaly, frequent central nervous system (CNS) involvement, and a poor clinical outcome (OS=8. 8 months). SIL-TAL1 (35. 36%) was associated with lymphadenopathy, frequent organomegaly, low platelets count and poor survival. Patients with BCR-ABL (20. 3%) had high TLC (p-value <0. 001), splenomegaly (p-value <0. 001), low platelets count (p-value <0. 001), poor outcome (OS=9. 3 & RFS=6. 3 months) and 10% less chances of CR as compared to BCR-ABL negative cases. ETV6-RUNX1 (4. 8 %) was mostly associated with low TLC, less common organomegaly, high CR rates and higher OS (30. 2 months), but their long term survival negatively affected by late relapses. Patients with TCF3-PBX1 (16. 3%) were associated with younger age (10/17, 59%), lower TLC (14/17, 82%), platelet count higher than 50×109/l (12/17, 71%), less common hepatomegaly (2/17, 12%), less common splenomegaly (3/17, 18%), early CR (11/17, 65%) but high relapse rate (13/17, 76. 1%) and shorter OS (11. 6 months). Conclusions & Discussion:High relapse rates and shorter OS despite favorable prognosis manifested by clinical features and high early CR rates in TCF3-PBX1 highlights the need for their identification at presentation and intensified treatment protocols to manage high relapse rate (Foa et al., 2003). Association of SIL-TAL1 with lymphadenopathy can help in better identification of this adult ALL subgroup at low resource centers. We found much higher frequency of TCF3-PBX1 and lower frequency of ETV6-RUNX1 than previously reported (Van Dongen et al, 1999). Although MLL-AF4 positive ALL is rarely observed in adult ALL, its frequency was 9. 7% in our adult ALL patients, which added to overall poor outcome of adult ALL in our population. Characterization of TCF3-PBX1 as poor prognostic molecular entity in our adult ALL population, low frequency of favorably prognostic ETV6-RUNX1, high frequency of poor prognostic MLL-AF4 and TCF3-PBX1 reflects ethnic and geographic differences in the biology and treatment of adult ALL (Burmeister et al., 2010). Therefore, it identifies the need for molecular testing in routine clinical settings at diagnosis and its implication in molecular prognostication and differential treatment. It also indicates the need for in-depth molecular analysis using advanced techniques and their implication in understanding the leukemogenesis and clinical management of adult ALL.Table 1:Comparison of the clinical characteristic of different FGs in ALL adult patientsClinical featuresBCR-ABL N=21 NO (%)ETV6-RUNX1 N=5 NO (%)MLL-AF4 N=10 NO (%)SIL-TAL1 N=29 NO (%)TCF3-PBX1 N=17 NO (%)Gene not detectedMale15 (71)4 (80)7 (70)24 (83)15 (88)17Female6 (29)1 (20)3 (30)5 (17)2 (12)5Age16y-29 y4 (19)3 (60)6 (60)19 (65)10 (59)1730y-59y13 (62)2 (40)3 (30)9 (31)6 (35)4≥60y4 (19)01 (10)1 (3)1 (6)1WBC<30,00011 (52)4 (80)7 (30)16 (55)10 (58.8)20>30,00010 (48)1 (20)3 (70)13 (45)7 (41.1)1HepatomegalyNo11 (52)2 (40)5 (50)24 (83)15 (88)22yes10 (48)3 (60)5 (50)5 (17)2 (12)0SplenomegalyNo5 (24)5 (100)5 (50)21 (72)14 (82)20Yes16 (76)05 (50)8 (28)3 (18)2LymphadenopathyNo3 (14)4 (80)5 (50)21 (21)2 (12)8yes18 (86)1 (20)5 (50)8 (28)15 (88)14Platelets<50,00020 (95)1 (20)9 (90)6 (21)5 (29)2>50,0001 (5)4 (80)1 (10)23 (79)12 (71)20ImmunophenotypingT-ALL00024 (83)00B-ALL3 (14)2 (40)2 (20)09 (53)2Unknown19 (90)3 (60)8 (80)5 (17)8 (47)20CR<4 weeks4 (19)4 (80)6 (60)20 (69)11 (65)15>4 weeks14 (66)1 (20)2 (20)1 (3)3 (18)3No remission3 (14)02 (20)8 (28)3 (18)4 [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

On- versus Off-Pump Coronary Artery Bypass Grafting: No Difference in Early Postoperative Kidney Function Based on TNF-α or C-Reactive Protein

Background/Aims: There are controversial data about renal function following off-pump coronary artery bypass grafting (CABG). The present study aimed to evaluate renal function changes 24 h after on- and off-pump CABG, as well as renal function correlated with high-sensitivity C-reactive protein (hs-CRP) and tumor necrosis factor-α (TNF-α). Methods: Ninety patients with coronary artery disease referred to our center for CABG from July 2006 to November 2007 were enrolled in the study. Patients were equally and randomly divided in two groups, on- and off-pump. Serum levels of creatinine (Cr), blood urea nitrogen, creatinine clearance (CrCl), hs-CRP, and TNF-α were determined immediately before and 24 h after surgery. Results: Cr and CrCl changes after surgery were not significantly different between the two groups; however, blood urea nitrogen levels after surgery were significantly higher in the on-pump group (p = 0.035). No statistically significant difference was noted between the two groups in terms of changes in levels of hs-CRP and TNF-α (p = 0.350 and 0.805, respectively). The changes in CrCl levels had no significant correlation with hs-CRP and TNF-α. Conclusions: The early Cr and CrCl levels after surgery are not significantly different in on- and off-pump groups. The early renal function after on- or off-pump CABG is not correlated with the levels of inflammatory markers including hs-CRP and TNF-α.

Sirolimus as renal and immunological rescue agent in pediatric liver transplant recipients

CNI have improved the outcome of LT. However, their inherent potential to nephrotoxic and sometimes-inadequate immunosuppressive effect has lead to the usage of newer drugs like SRL. Aim of this study was to review children who received SRL. Thirty-seven (20 women) children post-LT, median age 10.4 yr (0.8-17.4) with a minimum follow-up of six months comprised the study group. Indications for SRL were biopsy-proven resistant acute allograft rejection (n = 12), early CR (n = 12), and CNI-induced nephropathy with MMF intolerance (n = 11). In two patients, the indication was the recurrence of BSEP disease in the allograft. In patients with acute rejection, AST normalized in 10/12 patients. In patients with CR, AST normalized in 6/12 patients. Those with renal impairment showed improvement in their creatinine levels from a mean baseline of 99-56.7 μm (p = 0.03) and their mean cystatin C was 1.02 after SRL. Side effects leading to discontinuation of SRL were seen in three patients. SRL was effective in rescuing patients with acute and chronic allograft rejection and improving renal function in CNI-induced nephropathy group.

Triple-Decker-Sandwich versus Rice-Ball Structures for Tris(benzene)dimetal Derivatives of the First-Row Transition Metals

Compounds of the type M(2)Bz(3) (Bz = benzene, C(6)H(6)) have been of interest since the related triple-decker mesitylenechromium sandwich (1,3,5-Me(3)C(6)H(3))(3)Cr(2) has been synthesized and characterized structurally by X-ray crystallography. Theoretical studies predict the lowest-energy M(2)Bz(3) structures of the early transition metals Ti, V, and Cr to be the triple-decker sandwiches trans-Bz(2)M(2)(η(6),η(6)-μ-C(6)H(6)) having quintet, triplet, and singlet spin states, respectively. In these structures, the central benzene ring functions as a hexahapto ligand to each metal atom. The singlet rice-ball cis-Bz(2)M(2)(μ-C(6)H(6)) structures with a 2.64-Å Mn═Mn double bond or a 2.81-Å Fe-Fe single bond are preferred for the central transition metals Mn and Fe. Singlet triple-decker-sandwich structures trans-Bz(2)M(2)(μ-C(6)H(6)) return as the lowest-energy structures for the late transition metals Co and Ni but with the central benzene ring only partially bonded to each metal atom. Thus, the lowest-energy cobalt derivative has a trans-Bz(2)Co(2)(η(3),η(3)-μ-C(6)H(6)) structure in which the central benzene ring acts as a trihapto ligand to each metal atom. Similarly, the lowest-energy nickel derivative has a trans-Bz(2)Ni(2)(η(2),η(2)-μ-C(6)H(6)) structure in which the central benzene ring acts as a dihapto ligand to each metal atom, leaving an uncomplexed C═C double bond. The metal-metal bond orders in the singlet "rice-ball" structures cis-Bz(2)M(2)(μ-C(6)H(6)) (M = Mn, Fe) and the hapticities of the central benzene rings in the singlet late-transition-metal triple-decker-sandwich structures trans-Bz(2)M(2)(μ-C(6)H(6)) (M = Co, Ni) are governed by the desirability for the metal atoms to attain the favored 18-electron configuration.

Cyclophosphamide, Thalidomide and Dexamethasone (CTD) Versus Melphalan Plus Dexamethasone (MD) for Newly-Diagnosed Systemic AL Amyloidosis – Results From the UK Amyloidosis Treatment Trial.

Abstract 2869Poster Board II-845 Introduction:Risk adapted CTD, oral MD and high dose melphalan with autologous stem cell transplantation (SCT) (in selected cases) have emerged as important frontline treatments in AL amyloidosis. We report the interim results of a randomised prospective pilot study designed to estimate response rates and test feasibility of two randomisations using these treatments for patients with newly-diagnosed systemic AL amyloidosis. The final analysis is due in October 2009 and final full study results will be presented at the meeting. Patients and methods:The trial recruited for 14 months from January 2008 in the UK. Twenty four patients each were planned to enter a high intensity (SCT versus CTD) or a low intensity randomization (MD versus CTD) respectively, depending on suitability for SCT. Eligibility for the high-intensity arm was deliberately stringent in order to minimize risk of transplant-related mortality. Primary endpoints were haematologic response by free light chain assay (measured at each cycle with landmark assessments at 3 and 7 months), safety and recruitment rate. A myeloma quality of life (QOL) questionnaire was piloted in the absence of a disease-specific questionnaire for AL amyloidosis at baseline and 7 months post randomisation. Results:The high intensity arm was closed early due to lack of recruitment, mostly from clinical ineligibility and no further results from this arm are reported. The low intensity arm successfully recruited the required 24 patients (12 in each group). Median (range) age at randomization was 66 (42-85) years and stratification was by ECOG performance status which ranged from 0 to 3 (21%, 33%, 33% and 13% of patients respectively). 24 (100%) and 16 (67%) patients have response assessments (or are not evaluable) at 3 months and 7 months respectively at the time of submission. One patient in each arm died and one patient in the MD arm withdrew prior to the 3 month assessment. Overall haematological response rate at 3 months (at least a PR) was similar between the two arms; 9 (75.0% (95% Confidence Interval 43% to 95%)) in the CTD arm versus 8 (66.7% (95% CI 35% to 90%)) in the MD arm. At 3 months, CR was achieved in 7 (58.3% (95% CI 28% to 85%)) CTD and 3 (25.0% (95% CI 6% to 57%)) MD patients. Final response data at 7 months will be presented at the meeting. Median (range) time to achieve at least a PR from commencement of chemotherapy was 88 (34-218) and 95 (74-133) days in the CTD and MD groups respectively. To date, 17 of the 24 patients have reached their maximal clonal response (10 CTD, 7 MD patients), two patients died before achieving maximal response and one patient is not evaluable as they withdrew prior to the first response assessment. 4 patients could still achieve maximal response once 7 month follow up is completed. Of those currently evaluable for a maximal response, 8 (80%) CTD patients had CR versus 3 (43%) MD patients and 1 (1%) CTD patient had PR compared with 4 (57%) MD patients. There were no treatment-related deaths in either arm. Seventeen of 24 (71%) patients experienced grade ≥ 3 toxicities during chemotherapy (10 CTD patients (83%) versus 7 MD patients (58%)) though only 9 were classified as trial medication related SAEs (serious adverse events) which appeared to be similar in each arm - 5 CTD versus 4 MD. Lethargy (n=6), worsening congestive heart failure/fluid overload (n=5), infections (n=7) and pain (n=4) were the most common grade 3/4 toxicities, again with no noticeable differences between the treatment groups. The EORTC QLQ-MY20 myeloma QOL questionnaire appeared valid for use in AL amyloidosis patients and showed comparable QOL among both groups. Conclusions:Randomisation to SCT versus combination chemotherapy is not feasible using the current criteria in the UK. These interim results suggest that CTD may compare favourably with MD with possible higher early CR rates with CTD. There is a general perception that CTD has greater toxicity than MD but in this study there was no evidence of increased SAEs in either group and the QOL was comparable. Further comparison of CTD and MD is warranted in a large phase III randomized trial, but in order to be feasible would require international collaboration. Disclosures:Off Label Use: Off label use of thalidomide.

NPM1 but not FLT3-ITD mutations predict early blast cell clearance and CR rate in patients with normal karyotype AML (NK-AML) or high-risk myelodysplastic syndrome (MDS)

NPM1 but not FLT3-ITD mutations predict early blast cell clearance and CR rate in patients with normal karyotype AML (NK-AML) or high-risk myelodysplastic syndrome (MDS)

The Baseline PET SUV Correlates Better with Clinical Outcome Than the Post-Therapy PET Scan in Previously Untreated Patients with Histologically Aggressive Non-Hodgkin Lymphoma (NHL)

The FDG-PET/CT scan has become a standard tool in management of NHL. Failure to achieve an early metabolic CR (mCR) has been previously associated with a poor outcome and is considered as an adverse prognostic feature. Most studies which have supported this finding have used standard CHOP+/−R therapy or included a small or histologically heterogeneous population. As more effective therapies are introduced, some proven prognostic factors will lose relevance. We designed a prospective study to answer the following questions: 1- is the PET scan still capable of predicting outcome with the newer dose dense CHOP−R? 2) Is a very early PET, one week after the first chemotherapy (W1 PET) as good or better as the traditional 3rd course PET scan (C3 PET)? We have entered 55 pts, of which 40 were frontline previously untreated histologically aggressive NHL (35 DLCL, 5 FLCL) and 15 previously treated recurrent NHL (9 DLCL, 3 transformed DLCL, 2 PTCL, 1 high grade NOS). Treatment consisted of CHOP-R in all pts (dose dense in 38/40). A baseline PET was performed and followed by a W1 PET and a C3 PET. Median follow up is 20 mos. IPI was ≥2 in 20/55 (37%). The failure free survival (FFS) at 24 months was 85% for previously untreated pts and 35% for previously treated. For previously untreated pts, median baseline SUVmax= 20.5 (5.6–66.6) and one week after the first course (W1 PET), median SUVmax dropped to 2.6 and by C3 PET the median was 0. We examined the correlation between baseline PET, W1 PET and C3 PET with clinical outcome in previously untreated pts and found that the best correlation was with the baseline PET (figure). [Display omitted] Table 1 shows that the W1 PET as well as the C3 PET failed to correlate with outcome in previously untreated pts. Those who achieved mCR (defined as SUV<4) on the W1 PET or C3 PET didn't have a significantly superior FFS than those who didn't reach mCR. Other cut-off points including SUV<3 and <2 gave similar results. IPI, although showing a trend for correlation with FFS in previously untreated pts, was not significantly associated with outcome: IPI <3 had FFS= 87% vs. ≥3 = 82%, P=0.62. For the 15 cases with recurrent aggressive NHL, the FFS was 100% for those whose W1 PET SUV<4 versus 13% for those with SUV≥4 (P=.013). For those with baseline SUV ≥12 it was 52% vs 0% for SUV <12. For previously treated pts with IPI <3 the 2 yr FFS= 50% vs 0% for those with IPI≥3.Conclusions- for previously untreated pts: a- Striking improvements in PET are seen as early as 1 week after chemotherapy and improved further by C3 PET, but their correlation with the clinical outcome was poor and only the baseline PET SUV correlated well with outcome. b-Those with an SUV below the typical range for DLCL (i.e. <12) were the only ones who relapsed. c- IPI was not significantly associated with outcome. For previously treated pts both the baseline and the W1 PET were predictive of outcome. IPI also correlated with outcome. A possible explanation for these unexpected findings in the frontline group is that traditional prognostic factors might have changed with the introduction of the more effective dose dense CHOP-R regimen. Our FFS of 85% is better than expected for the traditional 21 day CHOP-R. This erosion of traditional prognostic factors might also be reflected by the lack of correlation between the traditional IPI and clinical outcome. For previously treated pts where the impact of treatment is not as prominent, the post treatment PET and IPI still hold as prognostic factors. These findings might not necessarily apply to other histologies or to other treatments.Table 1:W1PET SUVmaxN%FFS 24 mos.P value<4.02483%≥4.01690%0.68C3PET SUV max<4.03583%≥4.03100%0.59

Prognostic Significance of CD20 Expression in Adult B-Cell Precursor Acute Lymphoblastic Leukemia.

Introduction: CD20 expression is classically considered to be associated with inferior survival in adults with B-cell precursor acute lymphoblastic leukemia (ALL) but this notion is not strongly sustained in the literature. A recent pediatric study performed at St Jude's Children's Research Hospital reports that CD20 expression does not appear to be associated with inferior outcome in a cohort of 359 patients treated with contemporary regimens. This question is of importance notably since favorable experience has been reported for the use of rituximab, a chimeric monoclonal antibody to CD20, in combination with chemotherapy in mature B-cell lymphoma and leukemia, and possibly also in adult B-cell precursor ALL.Method: To determine the prognostic impact of CD20 expression in adult patients with B-cell precursor ALL and therefore the potential utility of rituximab in this subset of patients, we studied 143 patients treated in the GRAALL-2003 trial, designed to offer a dose-intensive pediatric-like approach in adults with Ph-negative ALL until 55 years of age.Results: CD20 positivity, defined as expression of CD20 in more than 20% of leukemia blasts, was observed in 49 patients (34%). There was no association between CD20 expression and patient age, white blood cell count at diagnosis, E2A-PBX, or ploidy. None of 21 patients with MLL-AF4 expressed CD20 (p<0.001). Even if CD20 expression tended to be associated with corticoresistance (24% in CD20+ cases vs. 14% in others, p=0.16), it was not associated with chemoresistance, overall early response (cortico- and/or chemoresistant ALL), CR rate, or post-induction MRD >10-3, as assessed by clonal Ig rearrangements quantification. However, the cumulative incidence of relapse at 30 months was significantly higher in CD20+ cases (39% [95% CI, 25 to 55] vs. 20% [95% CI, 13 to 31], p=0.02). Interestingly, a negative impact of corticoresistance and high white blood cell count at diagnosis on the cumulative incidence of relapse was only observed in this population of CD20+ patients (p=0.05 and p<0.001, respectively), but not in CD20neg patients (p=0.85 and 0.67). These data suggest either an intrinsic resistance of CD20+ leukemic cells or a lack of impact on these cells of the dose intensification (reinforcement of the induction course with a sequential bolus administration of cyclophosphamide) applied to corticoresistant patients. Disease-free survivals at 30 months were of 57% [95% CI, 40 to 70] and 64% [95% CI, 52 to 74] in CD20+ and CD20neg groups, respectively (p=0.36).Conclusion: In contrast to pediatric ALL, CD20 expression appears to be associated with inferior outcome in adult ALL with a significantly higher cumulative incidence of relapse in this group of patients. This reinforces the interest of evaluating the effect of rituximab combined to chemotherapy in adult ALL.

Effect of Spin State on the Dihydrogen Binding Strength to Transition Metal Centers in Metal-Organic Frameworks

In several recent experimental studies, it has been found that exposed transition metal (TM) sites in metal-organic frameworks (MOFs) yield the largest binding to H2 by about 10 kJ/mol. However, this binding is significantly smaller than what has been observed in the so-called Kubas molecules, also with exposed metal sites. Our ab initio calculations quantitatively account for the experimental findings and further show that the splitting and occupation of the spin orbitals in the MOF systems are the reasons for their unexpected small binding energies. We predict that the binding energy to H2 in the MOF systems can be tuned between 10 and 50 kJ/mol by using early TM elements, namely, Sc, Ti, V, Cr, and Mn.

Theory of x-ray absorption spectroscopy in solids: Mixing of the core states by the aspherical effective potential

Theoretical investigation of x-ray core-level spectroscopy requires calculation of electronic core states in the static effective potential. Thereby the aspherical part of the potential is usually neglected. The effect of this aspherical part on the mixing of the $2{p}_{1∕2}$ and $2{p}_{3∕2}$ states of the early transition metal Cr in $\mathrm{Cr}{\mathrm{O}}_{2}$ is determined by ab initio density-functional electron theory in the $\mathrm{LDA}+\mathrm{U}$ version, and its influence on the x-ray circular dichroism spectra at the ${L}_{2}$ and ${L}_{3}$ edges is investigated. It turns out that the influence is rather small, which justifies neglecting it in theoretical investigations of x-ray core-level spectroscopy.

NPM-1, but Not FLT3-ITD Mutations Predict Early Blast Cell Clearance and CR Rate in Patients with Normal Karyotype AML or High-Risk Myelodysplastic Syndrome (MDS).

Background: Mutations in the NPM1 gene represent the most frequent alterations in patients with AML and are associated with a favourable clinical outcome.Patients and Methods: We analyzed 803 patients that were treated in the AMLCG2000 study. Patients with de novo or secondary AML or high-risk myelodysplastic syndrome (MDS) were randomly assigned upfront for induction therapy containing one course with standard dose and one course with high-dose cytarabine, or two courses with high-dose cytarabine, and in the same step received postremission prolonged maintenance or busulfan/cyclophosphamide chemotherapy with autologous stem-cell transplantation. At diagnosis mutations in the NPM1 and FLT3 gene were analyzed by routine molecular techniques.Results: The median age of all patients was 60 years and the median observation time 23 months. Results of the mutations status of FLT3 (FLT3-ITD) and NPM1 were available in 761/803 (94,8 %) and 690/803 (85,9 %) patients, respectively. NPM1 and FLT3-ITD mutation were found in 352 (51,1%) and 199 (28,9%), respectively. On the basis of these two molecular markers, patients were grouped in 4 subgroups: 1. NPM1+/FLT3−, N=214 (31%), 2. NPM1+/FLT3+, N=138 (20%); 3. NPM1−/FLT3−, N=276 (40%); NPM1−/FLT3+ (9%).The CR-rates were significantly higher in NPM1+ (74,4%) than in NPM1− (55,9%) patients, but were unaffected by the FLT3-ITD status. Overall survival (OS), event-free survival (EFS) and relapse free survival (RFS) was significantly higher in NPM1 positive and FLT3-ITD negative patients. In a multivariate analysis age, WBC, the presence of the NPM1 mutation and de novo AML were independent prognostic factors for the CR-rate. The NPM1− and FLT3 mutation status, age and LDH were identified as independent prognostic factors for RFS.To further characterize the biological effects of NPM1 and FLT3 mutations, we analyzed the in vivo blast cell clearance measured by the residual bone marrow blast cells one week after the end of the first induction cycle (d+16 blasts). The percentage of patients with adequate blast cell reduction (residual bone marrow blast <10%) was significantly higher in NPM1+ patients (87,3%) compared to NPM1− (65,7%) patients. The presence of a FLT3-ITD mutation had no effect on early blast cell clearance.Conclusions: The presence of a NPM1 mutation represents an independent positive prognostic factor for the CR-rate and RFS/OS. In contrast, FLT3-ITD mutations do not affect the CR-rate, but have a negative prognostic impact on RFS and OS. The higher sensitivity of NPM1-positive blasts towards the induction therapy point to a central role of NPM1 in the regulation of apoptotic cell death in AML.

Very Early Post-Treatment PET/CT Scan Performed One Week after First Chemotherapy Course Compared Against the Standard PET after Third Course in Histologically Aggressive Lymphoma (NHL).

The FDG-PET/CT scan has become a standard tool in the management of NHL. Failure to achieve an early metabolic CR (mCR) is associated with a poor outcome and this information can be used to modify subsequent management. However, several issues still need to be resolved, including: 1-What is the best time to perform a post-treatment PET scan? Is very early (i.e. 1 week) after the first chemotherapy superior to the traditional 3rd course PET scan? 2-What criteria can we use to define mCR? Is there an SUV threshold on the very early PET scan that best defines mCR? In order to answer these questions we designed a study in which patients with histologically aggressive NHLs had 3 sequential PET scans: 1st one at baseline, a 2nd one on week 1 after the 1st course of chemotherapy (W1 PET) and the 3rd one after course 3 of chemotherapy (C3 PET). We have entered 32 patients of which 30 are currently assessable. Histologies were: DLCL=26, FLCL=4. IPI was ≥2 in 69%. At baseline, median SUVmax=17.14 (range 5.6–47.1). In the 30 cases who had a W1 PET, the mean SUVmax dropped to 4.4 (0.7–21.3, corrected for background). In the 24 who have completed their C3 PET the mean SUVmax was 1.55 (0–15.2) and only 6 patients had an SUV >0: 0.9, 3.7, 3.9, 5.1, 8.3, 15.2. We then examined the correlation between the SUVmax of W1 PET with SUVmax of C3 PET. 24 cases have already had both a W1 PET and a C3 PET. Table 1 shows that the W1 PET correlated well with 17 (71%) of the 24 C3 PETs. All 14 who achieved SUVmax <4.0 on W1 PET had an SUVmax <4.0 on C3 PET (all of the latter achieved SUVs <1.0). However, of 10 cases who failed to attain SUVmax <4.0 on W1 PET, 7 went on to achieve SUVmax <4.0 on C3 PET, and 2 of these 7 relapsed. For the purpose of determining the best SUV cut-off that can be used to define mCR, we examined the failure free survival (FFS) at various cut-offs ranging from 0 to 8.0 for both W1 PETs and C3 PETs. The best cut-off for both W1 PET and C3 PET was observed at 4.0 (table 2). We thus defined mCR as a post-treatment SUVmax <4.0. Those who achieved mCR on the W1 PET had a significantly superior FFS (Kaplan-Meier method) than those who didn't reach mCR (table 2). The results for the C3 PET didn't reach statistical significance (table 2).Conclusions: 1- Striking improvements in the PET scan are seen as early as 1 week after the first chemotherapy course. 2-The results of the W1 PET anticipated correctly 71% of C3 PET results. 3- Patients who attained an SUVmax <4.0 on the W1 PET had a remarkably superior outcome than those with SUV max ≥4.0 and was associated with a 91% FFS. Thus an SUV cut-off of <4.0 at W1 PET can be used to define mCR. This finding should be confirmed in an independent set of patients. 4- The W1 PET is more sensitive and specific than the C3 PET and is preferable to the C3 PET in predicting clinical outcome.Correlation of W1PET SUVmax With C3PET SUVmaxW1PET SUVmaxNC3PET SUVmax<4.0C3PET SUVmax≥4.0<4.014140≥4.01073Correlation of W1PET SUVmax and C3PET SUVmax With OutcomeW1PET SUVmaxN%FFS 8 mos.P value<4.01891%≥4.0120%.01C3PET SUVmax<4.02173%≥4.0367%.19

Interaction of the early 3d transition metals Sc, Ti, V, and Cr with N2: An ab initio study

The interaction of the early 3d transition elements M=Sc, Ti, V, and Cr with N2(X 1Sigmag+) has been studied by coupled-cluster and multiconfigurational techniques in conjunction with quantitative basis sets. We investigated both triatomic (MN2) and tetratomic (M2N2) species but focused mainly on high-spin linear and T-shaped triatomics. The lowest bound states of ScN2(4B1),TiN2(5Delta), and VN2(6Sigma+) correlate to the first excited state of the M atom, with M-N2 binding energies (De) of 24, 14, and 8 kcal/mol, respectively. In CrN2, the first bound state (7) product operator correlates to the sixth excited state of the Cr atom (7P) with De = 27 kcal/mol. The M-N2-M bond strength of high-spin linear tetratomics is twice as large the binding energy of the corresponding M-N2 linear triatomics, M = Sc, Ti, V, and Cr.

The Impact of Relative Dose Intensity on Response and Survival in a Series of 180 Newly Diagnosed Patients with Hodgkin's Lymphoma.

To improve ABVD results we first developed a protocol which adds G-CSF to the standard ABVD treatment. From March 1997 to May 2004 69 patients with HL were treated with ABVD+G-CSF and 22 with a standard ABVD. Recently we designed a new dose-dense and dose-intensity ABVD scheme (escABVD-21) for advanced HL; in this new schedule the adriamycin was escalated from 25 to 35 mg/m2 (cycles 1,2,3,4) and the inter-cycle period was shortened from 28 to 21 days (for all 6 cycles); primary G-CSF was administered from d3 to d8 and drugs were delivered at d10 and d21 of every cycle. From June 2004, 19 patients were treated with this protocol.Relative dose-intensity (RDI) was calculated for any of these 110 newly diagnosed HL patients treated with ABVD. The results were also compared with a historical group of 70 patients who had undergone hybrid MOPP/ABVD.HL patients received from 4 to 8 cycles of CT +/− IF-RT. Patients were divided in 4 groups according to the RDI. The first group included 20 (11%) pts with RDI less than 0.80; the 2nd group, 64 (36%) pts with RDI values between 0.80 and 0.95, the 3rd group, 74 (42%) pts with RDI values between 0.96 and 1.10 and, finally, the 4th group included pts with RDI values of more than 1.10. In Tab 2 we report the CR, EFS and OS rates according to the 4 levels of RDI. Figures 1 shows EFS curve according to Kaplan-Meyer.Response and survival rates of groups 1,2,3 and 4 were: 50%vs91%vs97% vs 100%, for CR (p<0.0001); 20%vs78%vs92%vs100% for EFS (p< 0.0001); and 25%vs91%vs99%vs100% for OS (p< 0.0001).The best progression rates of CR, EFS and OS were seen in patients with RDI >1.10. In particular, the new dose-dense and dose-intensity escABVD-21 protocol seems very promising in terms of complete response and toxicity profile: 19/19 pts (100%) obtained an early CR; (PET negative at the end of the 2nd cycle), and, as on 8th August 2005, all these19 patients were disease-free. The dose-escalation of adriamycin and the dose-density of the schedule were well-tolerated; toxicity was mild. These results show that subptimal RDI may compromise outcomes proportionally to the level of RDI reduction. On the contrary, Primary G-CSF permits to deliver dose-dense and dose intense schedules such as escABVD-21 maintaining the same profile of toxicity of standard ABVD, higher RDI levels, and consequently, a significant impact on complete response and survival rates.tab1Presentation featuresn. of ptsmale sexage>45 yrsadvanced stageE sites>1bulkyB symptomsIPI score ≥ 3180924314823808356%51%24%82%13%44%46%31%tab.2Response and Survival according to 4 RDI levelsRDI level (range 0.5–1.5)N. of pts. (%)CR rateFisher's Exact test (2-sided)EFS ratelog-rank statistic0S ratelog-rank statisticoverall180(100%)90%80%88%<0.8020 (11%)50%20%25%0.80–0.9564 (36%)91%28.39178%74.9991%96.760.96–1.1076 (42%)97%92%99%>1.1020 (11%)100%100%100%significance<0.0001<0.0001<0.0001 [Display omitted]

Using artificial neural networks to develop molecular mechanics parameters for the modelling of metalloporphyrins. III. Five coordinate Zn(II) porphyrins and the metalloprophyrins of the early 3d metals

Artificial neural networks (ANNs) are used as an aid in developing force field parameters for modelling, using molecular mechanics methods and the MM2 force field, the porphyrins of the early transition metals, Sc(III), Ti(II), Ti(III), Ti(IV), V(II), V(III), V(IV), Cr(III), Cr(IV) and Cr(V), in which the metal is either five- or six-coordinate. The porphyrin ring itself was modelled with previously derived parameters and attention was focussed on deriving parameters to model the coordination sphere of the metal. By modelling five-coordinate Zn(II) porphyrins with an axial pyridine ligand, for which there are many structures, we demonstrate that the length of the metal–N porph bond is relatively insensitive to the length of the metal–N axial bond, and vice versa. There are relatively few crystal structures of the early 3d metalloporphyrins available and very few which contain the same axial ligand. Hence, preliminary parameters for modelling a wide variety of axial ligands are reported; these were typically derived by initially setting the strain free bond length and bond angles involving the metal and the axial donor atom to the crystallographically observed value, and varying the bond stretching and angle bending parameter, or the strain free bond length and bond angles iteratively, until the bond length and angles were reproduced to within 0.01 Å and 2.5°, respectively. Since the modelling of the [Zn(porphyrin)(pyridine)] complexes demonstrated the relative insensitivity of the equatorial metal–ligand parameters to the axial metal–ligand parameters and vice-versa, the paucity of structures and hence the necessarily preliminary values of the parameters for the modelling of the axial ligands did not preclude the development of parameters for the equatorial ligands. The strain free bond length l o, and the stretching force constant k s for the metal–N porph bond length was varied in a grid-like pattern. The mean difference between the metal–N porph bond length observed experimentally and determined by MM was defined as the error function. The minimum value of the error function was found using ANNs. Modelling the structures with the values of k s and l o that correspond to the minimum of the error function gave mean metal–N porph bonds that differed from crystallographically observed values by at most 0.008 Å, within the experimental standard deviation of this parameter. The deviations from planarity found in many of the modelled structures were usually well reproduced in the modelling. Where significant differences were noted, these could sometimes (but not always) be shown to be due to packing forces in the crystal lattice. As expected, the orientation of axial ligands and substituents on the periphery of the porphyrin ring was often significantly different in the modelled and the solid-state structure because of the conformational freedom of these groups.

Limitations of integral XMCD sum-rules for the early 3d elements

We report on XMCD measurements at the L2,3 edges of the early 3d transition metals, Ti, V and Cr, polarized by Fe. In contrast to the classical ferromagnets Fe, Co and Ni, the XMCD spectra reveal a complex and detailed fine structure. We analyze the experimental data with the help of full-relativistic ab initio calculations of the x-ray absorption cross section μ(E) that provide the energy-dependent XMCD spectrum and the correlated magnetic moments μs and μl. We demonstrate that the use of the so-called integral sum-rules, which interrelate certain areas of the XMCD spectra to μs and μl, yield erroneous results for the early 3d elements due to 2p-3d core hole correlations in L2,3 absorption spectra.

All-Trans-Retinoic Acid andBleeding/Thrombosis

Hematology-Oncology Department Ospedali Riuniti Largo Barozzi, 1 24128 Bergamo (Italy) Tel. 39 035 269492, Fax 39 035 266659 E-Mail annafalanga@yahoo.com All-trans-retinoic acid (ATRA) inhibits cell growth and proliferation by inducing cyto-differentiation and/or apoptosis in several cell types. These effects have become a therapeutic objective in human cancers. In addition to these functions, ATRA has been shown to affect cellular hemostatic properties [1]. Much understanding in this field has come from the clinical and experimental studies of human acute promyelocytic leukemia (APL), a distinct subtype of acute myelogenous leukemia (AML-M3), cytogenetically characterized by the balanced reciprocal translocation between chromosomes 15 and 17. In these cells, the fusion of the nuclear retinoic acid receptor (RAR ) gene on chromosome 17 with part of the PML gene on chromosome 15 results in the expression of a chimeric PML/RAR protein, which is involved in the leukemogenesis and is the target for the myeloid differentiation effect induced by ATRA. The disease typically presents with a life-threatening hemorrhagic diathesis, which is worsened by cytotoxic chemotherapy. The bleeding disorder is particularly severe in the microgranular variant of APL (M3v), which is characterized by marked hyperleukocytosis. Before the introduction of ATRA for the management of APL patients, fatal hemorrhages due to the associated coagulopathy were a major cause of induction remission failure. In a large retrospective study, the overall remission rate was 62% and the prevalence of hemorrhagic deaths in induction 14% [2]. The use of ATRA for the remission induction therapy of APL has raised the complete remission rate to greater than 90%, together with a rapid resolution of the coagulopathy, without causing bone marrow hypoplasia. ATRA promotes the terminal differentiation of leukemic promyelocytes, which is accompanied by prompt improvement of the coagulopathy typical of this disease [3]. Consistent with that, normalization in the plasma levels of hypercoagulation markers and downregulation of the two major blast cellassociated procoagulants (i.e. tissue factor, TF, and cancer procoagulant, CP) were observed [4]. A number of laboratory studies have subsequently confirmed the decrease or normalization of clotting and fibrinolytic variables during the first 1 or 2 weeks of therapy with ATRA. Inspite of that, the impact of ATRA therapy on early hemorrhagic deaths and CR rate in APL remains uncertain compared to chemotherapy alone. In nonrandomized studies, APL patients administered ATRA showed 9% to 20% improvement of CR rate and 5% to 6% reduction of early hemorrhagic deaths, compared to historical controls receiving conventional chemotherapy [1, 5–8]. These preliminary findings have been more recently confirmed by randomized clinical trials. APL patients treated with different combinations of ATRA plus chemotherapy show a prevalence of early hemorrhagic deaths from 2.4% to 6.5% [9–13]. However, both nonrandomized and randomized clinical trials clearly show an improvement of event free and overall survival in patients receiving induction therapy All-Trans-Retinoic Acid and Bleeding/Thrombosis

Early constriction or expansion of the external elastic membrane area determines the late remodeling response and cumulative lumen loss in transplant vasculopathy: an intravascular ultrasound study with 4-year follow-up

Background: Early constriction of the external elastic membrane (EEM) area has been observed after cardiac transplantation. The aim of this study was to compare the late disease process of transplant vasculopathy between coronary segments with early constrictive and expansive remodeling. Methods: Serial intravascular ultrasound data obtained annually for 4 years after transplantation in 38 transplant recipients was available. In 135 matched segments from 59 coronary arteries ultrasound images were digitized at 1-mm intervals. Mean values of the external elastic membrane (EEM), lumen and intimal areas were calculated. On the basis of a decrease or increase in EEM area within the first year after transplantation, we defined segments with early constrictive remodeling (CR, n = 71) or early expansive remodeling (ER, n = 64). Results: Annual changes in intimal area were similar between segments with early CR and ER throughout the follow-up period. However, during the second and third year, annual increases in EEM area were greater in segments with early CR than in segments with early ER (second year: 1.5 ± 2.7 vs 0.6 ± 2.8 mm 2, p = 0.052; third year: 1.3 ± 2.5 vs −0.03 ± 2.6 mm 2, p = 0.003). Despite this late expansion, segments with early CR showed a cumulative decrease in the EEM area and a greater lumen loss than segments with early ER (−2.5 ± 3.4 vs −0.6 ± 2.6 mm 2, p < 0.001). Conclusions: In transplant vasculopathy, the late remodeling response was different between segments with early constrictive and expansive remodeling, despite similar intimal thickening. Early constriction caused an overall decrease in EEM area and greater loss of lumen during follow-up.