Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children's Oncology Group study AALL0232.

Minimal residual disease (MRD) is highly prognostic in pediatric B-precursor acute lymphoblastic leukemia (B-ALL). In Children's Oncology Group high-risk B-ALL study AALL0232, we investigated MRD in subjects randomized in a 2 × 2 factorial design to receive either high-dose methotrexate (HD-MTX) or Capizzi methotrexate (C-MTX) during interim maintenance (IM) or prednisone or dexamethasone during induction. Subjects with end-induction MRD ≥0.1% or those with morphologic slow early response were nonrandomly assigned to receive a second IM and delayed intensification phase. MRD was measured by 6-color flow cytometry in 1 of 2 reference labs, with excellent agreement between the two. Subjects with end-induction MRD <0.01% had a 5-year event-free survival (EFS) of 87% ± 1% vs 74% ± 4% for those with MRD 0.01% to 0.1%; increasing MRD amounts was associated with progressively worse outcome. Subjects converting from MRD positive to negative by end consolidation had a relatively favorable 79% ± 5% 5-year disease-free survival vs 39% ± 7% for those with MRD ≥0.01%. Although HD-MTX was superior to C-MTX, MRD retained prognostic significance in both groups (86% ± 2% vs 58% ± 4% for MRD-negative vs positive C-MTX subjects; 88% ± 2% vs 68% ± 4% for HD-MTX subjects). Intensified therapy given to subjects with MRD >0.1% did not improve either 5-year EFS or overall survival (OS). However, these subjects showed an early relapse rate similar to that seen in MRD-negative ones, with EFS/OS curves for patients with 0.1% to 1% MRD crossing those with 0.01% to 0.1% MRD at 3 and 4 years, thus suggesting that the intensified therapy altered the disease course of MRD-positive subjects. Additional interventions targeted at the MRD-positive group may further improve outcome. This trial was registered at www.clinicaltrials.gov as #NCT00075725.

A Pilot Study of Intensified PEG-Asparaginase in High-risk Acute Lymphoblastic Leukemia: Children's Oncology Group Study AALL08P1.

AALL08P1 was designed to determine whether biweekly intensified pegaspargase (I-PEG) was feasible and safe in pediatric patients with newly diagnosed high-risk B-precursor lymphoblastic leukemia when given with Children's Oncology Group hemiaugmented BFM therapy. High-risk average (HR-Avg) patients received standard pegaspargase dosing (6 doses), whereas high-risk high (HR-High) patients received I-PEG biweekly from the start of Consolidation until day 1 of Maintenance. Feasibility and safety were defined in advance as ≥65% of patients tolerating at least 8 doses of I-PEG and 90% requiring ≤49 weeks from day 1 of Consolidation to the initiation of Maintenance. Targeted toxicities included allergic reactions, anaphylaxis, pancreatitis, thrombosis, bleeding, central nervous system events, and sepsis. AALL08P1 enrolled 104 patients; 54 were classified as HR-Avg and 30 as HR-High after completion of induction therapy. Only 53% (16/30) of the HR-High patients received ≥8 total doses of I-PEG and 50% (15/30) took ≤49 weeks from start of Consolidation to the initiation of Maintenance. I-PEG did not significantly increase grade 2 to 5 targeted toxicities. I-PEG was not feasible or safe as defined in AALL08P1. Complete assessment of this regimen was limited due to removal of patients from I-PEG regimen and early closure of the study.

Safe integration of nelarabine into intensive chemotherapy in newly diagnosed T-cell acute lymphoblastic leukemia: Children's Oncology Group Study AALL0434.

BACKGROUND: Nelarabine has shown impressive single agent clinical activity in T-cell acute lymphoblastic leukemia (T-ALL), but has been associated with significant neurotoxicities in heavily pre-treated patients. We showed previously that it was safe to add nelarabine to a BFM-86 chemotherapy backbone (AALL00P2). Children's Oncology Group (COG) AALL0434 is a Phase III study designed to test the safety and efficacy of nelarabine when incorporated into a COG augmented BFM-based regimen, which increases exposure to agents with potential neurotoxicity compared to the historical AALL00P2 regimen. PROCEDURE: AALL0434 included a safety phase to assess nelarabine toxicity. Patients with high-risk (HR) T-ALL were randomized to receive Capizzi-style escalating methotrexate (MTX) plus pegaspargase or high dose (HD) MTX with/without six five-days courses of nelarabine. We report results from 94 patients who participated in the initial safety phase of the study. RESULTS: There were no differences in the incidence of peripheral motor neuropathies, sensory neuropathies or central neurotoxicities among those randomized to the nelarabine (n = 47) and non-nelarabine arms (n = 47). CONCLUSIONS: The addition of nelarabine to COG-augmented BFM chemotherapy regimen is safe and feasible. The ongoing AALL0434 Efficacy Phase will determine whether the addition of nelarabine treatment improves outcome for patients with T-ALL.

Complexes with mixed primary and secondary cellulose synthases are functional in Arabidopsis plants.

In higher plants, cellulose is synthesized by so-called rosette protein complexes with cellulose synthases (CESAs) as catalytic subunits of the complex. The CESAs are divided into two distinct families, three of which are thought to be specialized for the primary cell wall and three for the secondary cell wall. In this article, the potential of primary and secondary CESAs forming a functional rosette complex has been investigated. The membrane-based yeast two-hybrid and biomolecular fluorescence systems were used to assess the interactions between three primary (CESA1, CESA3, CESA6), and three secondary (CESA4, CESA7, CESA8) Arabidopsis (Arabidopsis thaliana) CESAs. The results showed that all primary CESAs can physically interact both in vitro and in planta with all secondary CESAs. Although CESAs are broadly capable of interacting in pairwise combinations, they are not all able to form functional complexes in planta. Analysis of transgenic lines showed that CESA7 can partially rescue defects in the primary cell wall biosynthesis in a weak cesa3 mutant. Green fluorescent protein-CESA protein fusions revealed that when CESA3 was replaced by CESA7 in the primary rosette, the velocity of the mixed complexes was slightly faster than the native primary complexes. CESA1 in turn can partly rescue defects in secondary cell wall biosynthesis in a cesa8ko mutant, resulting in an increase of cellulose content relative to cesa8ko. These results demonstrate that sufficient parallels exist between the primary and secondary complexes for cross-functionality and open the possibility that mixed complexes of primary and secondary CESAs may occur at particular times.

Identification of a cellulose synthase-associated protein required for cellulose biosynthesis.

Cellulose synthase-interactive protein 1 (CSI1) was identified in a two-hybrid screen for proteins that interact with cellulose synthase (CESA) isoforms involved in primary plant cell wall synthesis. CSI1 encodes a 2,150-amino acid protein that contains 10 predicted Armadillo repeats and a C2 domain. Mutations in CSI1 cause defective cell elongation in hypocotyls and roots and reduce cellulose content. CSI1 is associated with CESA complexes, and csi1 mutants affect the distribution and movement of CESA complexes in the plasma membrane.

Real-time imaging of cellulose reorientation during cell wall expansion in Arabidopsis roots.

Cellulose forms the major load-bearing network of the plant cell wall, which simultaneously protects the cell and directs its growth. Although the process of cellulose synthesis has been observed, little is known about the behavior of cellulose in the wall after synthesis. Using Pontamine Fast Scarlet 4B, a dye that fluoresces preferentially in the presence of cellulose and has excitation and emission wavelengths suitable for confocal microscopy, we imaged the architecture and dynamics of cellulose in the cell walls of expanding root cells. We found that cellulose exists in Arabidopsis (Arabidopsis thaliana) cell walls in large fibrillar bundles that vary in orientation. During anisotropic wall expansion in wild-type plants, we observed that these cellulose bundles rotate in a transverse to longitudinal direction. We also found that cellulose organization is significantly altered in mutants lacking either a cellulose synthase subunit or two xyloglucan xylosyltransferase isoforms. Our results support a model in which cellulose is deposited transversely to accommodate longitudinal cell expansion and reoriented during expansion to generate a cell wall that is fortified against strain from any direction.

Raman imaging of cell wall polymers in Arabidopsis thaliana.

We present chemical images of Arabidopsis thaliana stem cross-sections acquired by confocal Raman microscopy. Using green light (532 nm) from a continuous wave laser, the spatial distributions of cell wall polymers in Arabidopsis are visualized for the first time with lateral resolution that is sub-mum. Our results facilitate the label-free in situ characterization and screening of cell wall composition in this plant biology and genetics model organism, contributing ultimately towards an understanding of the molecular biology of many plant traits.

Children's Oncology Group AALL0434: A Phase III Randomized Clinical Trial Testing Nelarabine in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia.

PURPOSE: Nelarabine is effective in inducing remission in patients with relapsed and refractory T-cell acute lymphoblastic leukemia (T-ALL) but has not been fully evaluated in those with newly diagnosed disease. PATIENTS AND METHODS: From 2007 to 2014, Children's Oncology Group trial AALL0434 (ClinicalTrials.gov identifier: NCT00408005) enrolled 1,562 evaluable patients with T-ALL age 1-31 years who received the augmented Berlin-Frankfurt-Muenster (ABFM) regimen with a 2 × 2 pseudo-factorial randomization to receive escalating-dose methotrexate (MTX) without leucovorin rescue plus pegaspargase (C-MTX) or high-dose MTX (HDMTX) with leucovorin rescue. Intermediate- and high-risk patients were also randomly assigned after induction to receive or not receive six 5-day courses of nelarabine that was incorporated into ABFM. Patients who experienced induction failure were nonrandomly assigned to HDMTX plus nelarabine. Patients with overt CNS disease (CNS3; ≥ 5 WBCs/µL with blasts) received HDMTX and were randomly assigned to receive or not receive nelarabine. All patients, except those with low-risk disease, received cranial irradiation. RESULTS: The 5-year event-free and overall survival rates were 83.7% ± 1.1% and 89.5% ± 0.9%, respectively. The 5-year disease-free survival (DFS) rates for patients with T-ALL randomly assigned to nelarabine (n = 323) and no nelarabine (n = 336) were 88.2% ± 2.4% and 82.1% ± 2.7%, respectively (P = .029). Differences between DFS in a four-arm comparison were significant (P = .01), with no interactions between the MTX and nelarabine randomizations (P = .41). Patients treated with the best-performing arm, C-MTX plus nelarabine, had a 5-year DFS of 91% (n = 147). Patients who received nelarabine had significantly fewer isolated and combined CNS relapses compared with patients who did not receive nelarabine (1.3% ± 0.63% v 6.9% ± 1.4%, respectively; P = .0001). Toxicities, including neurotoxicity, were acceptable and similar between all four arms. CONCLUSION: The addition of nelarabine to ABFM therapy improved DFS for children and young adults with newly diagnosed T-ALL without increased toxicity.

Improved Survival for Children and Young Adults With T-Lineage Acute Lymphoblastic Leukemia: Results From the Children's Oncology Group AALL0434 Methotrexate Randomization.

PURPOSE: Early intensification with methotrexate (MTX) is a key component of acute lymphoblastic leukemia (ALL) therapy. Two different approaches to MTX intensification exist but had not been compared in T-cell ALL (T-ALL): the Children's Oncology Group (COG) escalating dose intravenous MTX without leucovorin rescue plus pegaspargase escalating dose, Capizzi-style, intravenous MTX (C-MTX) regimen and the Berlin-Frankfurt-Muenster (BFM) high-dose intravenous MTX (HDMTX) plus leucovorin rescue regimen. PATIENTS AND METHODS: COG AALL0434 included a 2 × 2 randomization that compared the COG-augmented BFM (ABFM) regimen with either C-MTX or HDMTX during the 8-week interim maintenance phase. All patients with T-ALL, except for those with low-risk features, received prophylactic (12 Gy) or therapeutic (18 Gy for CNS3) cranial irradiation during either the consolidation (C-MTX; second month of therapy) or delayed intensification (HDMTX; seventh month of therapy) phase. RESULTS: AALL0434 accrued 1,895 patients from 2007 to 2014. The 5-year event-free survival and overall survival rates for all eligible, evaluable patients with T-ALL were 83.8% (95% CI, 81.2% to 86.4%) and 89.5% (95% CI, 87.4% to 91.7%), respectively. The 1,031 patients with T-ALL but without CNS3 disease or testicular leukemia were randomly assigned to receive ABFM with C-MTX (n = 519) or HDMTX (n = 512). The estimated 5-year disease-free survival ( P = .005) and overall survival ( P = .04) rates were 91.5% (95% CI, 88.1% to 94.8%) and 93.7% (95% CI, 90.8% to 96.6%) for C-MTX and 85.3% (95% CI, 81.0%-89.5%) and 89.4% (95% CI, 85.7%-93.2%) for HDMTX. Patients assigned to C-MTX had 32 relapses, six with CNS involvement, whereas those assigned to HDMTX had 59 relapses, 23 with CNS involvement. CONCLUSION: AALL0434 established that ABFM with C-MTX was superior to ABFM plus HDMTX for T-ALL in approximately 90% of patients who received CRT, with later timing for those receiving HDMTX.

Impact of Initial CSF Findings on Outcome Among Patients With National Cancer Institute Standard- and High-Risk B-Cell Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group.

Purpose To determine the prognostic significance of blasts, and of white and red blood cells, in CSF samples at diagnosis of acute lymphoblastic leukemia (ALL), a uniform CSF and risk group classification schema was incorporated into Children's Oncology Group B-cell ALL (B-ALL) clinical trials. Methods CSF status was designated as follows: CNS1, no blasts; CNS2a to 2c, < 5 WBCs/µL and blasts with/without ≥ 10 RBCs/µL or ≥ 5 WBCs/µL plus blasts, with WBCs ≥ 5 times the number of RBCs; CNS3a to 3c, ≥ 5 WBCs/µL plus blasts with/without ≥ 10 RBCs/µL or clinical signs of CNS disease. CNS2 status did not affect therapy; patients with CNS3 status received two extra intrathecal treatments during induction and augmented postinduction therapy with 18 Gy of cranial radiation. Results Among 8,379 evaluable patients enrolled from 2004 to 2010, 7,395 (88.3%) had CNS1 status; 857 (10.2%), CNS2; and 127 (1.5%), CNS3. The 5-year event-free and overall survival rates were, respectively, 85% and 92.7% for CNS1, 76% and 86.8% for CNS2, and 76% and 82.1% for CNS3 ( P < .001). In multivariable analysis that included age, race/ethnicity, initial WBC, and day-29 minimal residual disease < 0.1%, CSF blast, regardless of cell count, was an independent adverse predictor of outcome for patients with standard- or high-risk disease according to National Cancer Institute criteria. The EFS difference reflected a significant difference in the incidence of CNS, not marrow, relapse in patients with CNS1 versus CNS2 and/or CNS3 status. Conclusion Low levels of CNS leukemia, regardless of RBCs, predict inferior outcome and higher rates of CNS relapse. These data suggest that additional augmentation of CNS-directed therapy is warranted for CNS2 disease.

Functional morphology of prey capture in the sturgeon, Scaphirhynchus albus.

Acipenseriformes (sturgeon and paddlefish) are basal actinopterygians with a highly derived cranial morphology that is characterized by an anatomical independence of the jaws from the neurocranium. We examined the morphological and kinematic basis of prey capture in the Acipenseriform fish Scaphirhynchus albus, the pallid sturgeon. Feeding pallid sturgeon were filmed in lateral and ventral views and movement of cranial elements was measured from video sequences. Sturgeon feed by creating an anterior to posterior wave of cranial expansion resulting in prey movement through the mouth. The kinematics of S. albus resemble those of other aquatic vertebrates: maximum hyoid depression follows maximum gape by an average of 15 ms and maximum opercular abduction follows maximum hyoid depression by an average of 57 ms. Neurocranial rotation was not a part of prey capture kinematics in S. albus, but was observed in another sturgeon species, Acipenser medirostris. Acipenseriformes have a novel jaw protrusion mechanism, which converts rostral rotation of the hyomandibula into ventral protrusion of the jaw joint. The relationship between jaw protrusion and jaw opening in sturgeon typically resembles that of elasmobranchs, with peak upper jaw protrusion occurring after peak gape.

Pharmacokinetic and pharmacodynamic properties of calaspargase pegol Escherichia coli L-asparaginase in the treatment of patients with acute lymphoblastic leukemia: results from Children's Oncology Group Study AALL07P4.

PURPOSE: Asparaginase is a critical agent used to treat acute lymphoblastic leukemia (ALL). Pegaspargase (SS-PEG), a pegylated form of Escherichia coli L-asparaginase with a succinimidyl succinate (SS) linker, is the first-line asparaginase product used in Children's Oncology Group (COG) ALL trials. Calaspargase pegol (SC-PEG) replaces the SS linker in SS-PEG with a succinimidyl carbamate linker, creating a more stable molecule. COG AALL07P4 was designed to determine the pharmacokinetic and pharmacodynamic comparability of SC-PEG to SS-PEG in patients with newly diagnosed high-risk (HR) B-cell ALL. PATIENTS AND METHODS: A total of 165 evaluable patients were randomly assigned at a 2:1 ratio to receive SC-PEG at 2,100 (SC-PEG2100; n = 69) or 2,500 IU/m(2) (SC-PEG2500; n = 42) versus SS-PEG 2,500 IU/m(2) (SS-PEG2500; n = 54) as part of an otherwise identical chemotherapy regimen. The groups were similar demographically, except more female patients received SC-PEG2500. RESULTS: The mean half-life of plasma asparaginase activity for both SC-PEG doses was approximately 2.5× longer than that of SS-PEG2500. The total systemic exposure, as defined by induction area under the curve from time 0 to 25 days, was greater with SC-PEG2500 than with SS-PEG2500 or SC-PEG2100. The proportion of patients with plasma asparaginase activity ≥ 100 mIU/mL and ≥ 400 mIU/mL was higher in patients who received SC-PEG as compared with SS-PEG2500. After one dose of pegylated asparaginase on induction day 4, plasma asparagine was undetectable for 11 days for SS-PEG2500 and 18 days for both SC-PEG groups. CONCLUSION: SC-PEG2500 achieves a significantly longer period of asparaginase activity above defined thresholds and asparagine depletion compared with SS-PEG2500 and has a comparable toxicity profile in children with HR B-cell ALL.

Cellulosic biofuels.

The development of sustainable, low-carbon, liquid fuels from cellulosic biomass will require advances in many areas of science and engineering. This review describes the major topics of enquiry concerning cellulosic biofuels with an emphasis on those areas of research and development that include research problems of interest to plant biologists.

Mutations in UDP-Glucose:sterol glucosyltransferase in Arabidopsis cause transparent testa phenotype and suberization defect in seeds.

In higher plants, the most abundant sterol derivatives are steryl glycosides (SGs) and acyl SGs. Arabidopsis (Arabidopsis thaliana) contains two genes, UGT80A2 and UGT80B1, that encode UDP-Glc:sterol glycosyltransferases, enzymes that catalyze the synthesis of SGs. Lines having mutations in UGT80A2, UGT80B1, or both UGT80A2 and UGT8B1 were identified and characterized. The ugt80A2 lines were viable and exhibited relatively minor effects on plant growth. Conversely, ugt80B1 mutants displayed an array of phenotypes that were pronounced in the embryo and seed. Most notable was the finding that ugt80B1 was allelic to transparent testa15 and displayed a transparent testa phenotype and a reduction in seed size. In addition to the role of UGT80B1 in the deposition of flavanoids, a loss of suberization of the seed was apparent in ugt80B1 by the lack of autofluorescence at the hilum region. Moreover, in ugt80B1, scanning and transmission electron microscopy reveals that the outer integument of the seed coat lost the electron-dense cuticle layer at its surface and displayed altered cell morphology. Gas chromatography coupled with mass spectrometry of lipid polyester monomers confirmed a drastic decrease in aliphatic suberin and cutin-like polymers that was associated with an inability to limit tetrazolium salt uptake. The findings suggest a membrane function for SGs and acyl SGs in trafficking of lipid polyester precursors. An ancillary observation was that cellulose biosynthesis was unaffected in the double mutant, inconsistent with a predicted role for SGs in priming cellulose synthesis.

Suction feeding mechanics, performance, and diversity in fishes.

Despite almost 50 years of research on the functional morphology and biomechanics of suction feeding, no consensus has emerged on how to characterize suction-feeding performance, or its morphological basis. We argue that this lack of unity in the literature is due to an unusually indirect and complex linkage between the muscle contractions that power suction feeding, the skeletal movements that underlie buccal expansion, the sharp drop in buccal suction pressure that occurs during expansion, the flow of water that enters the mouth to eliminate the pressure gradient, and the forces that are ultimately exerted on the prey by this flow. This complexity has led various researchers to focus individually on suction pressure, flow velocity, or the distance the prey moves as metrics of suction-feeding performance. We attempt to integrate a mechanistic view of the ability of fish to perform these components of suction feeding. We first discuss a model that successfully relates aspects of cranial morphology to the capacity to generate suction pressure in the buccal cavity. This model is a particularly valuable tool for studying the evolution of the feeding mechanism. Second, we illustrate the multidimensional nature of suction-feeding performance in a comparison of bluegill, Lepomis macrochirus, and largemouth bass, Micropterus salmoides, two species that represent opposite ends of the spectrum of performance in suction feeding. As anticipated, bluegills had greater accuracy, lower peak flux into the mouth, and higher flow velocity and acceleration of flow than did bass. While the differences between species in accuracy of strike and peak water flux were substantial, peak suction velocity and acceleration were only about 50% higher in bluegill, a relatively modest difference. However, a hydrodynamic model of the forces that suction feeders exert on their prey shows that this difference in velocity is amplified by a positive effect of the smaller mouth aperture of bluegill on force exerted on the prey. Our model indicates that the pressure gradient in front of a fish that is feeding by suction, associated with the gradient in water velocity, results in a force on the prey that is larger than drag or acceleration reaction. A smaller mouth aperture results in a steeper pressure gradient that exerts a greater force on the prey, even when other features of the suction flow are held constant. Our work shows that some aspects of suction-feeding performance can be determined from morphology, but that the complexity of the behavior requires a diversity of perspectives to be used in order to adequately characterize performance.

Genetic evidence for three unique components in primary cell-wall cellulose synthase complexes in Arabidopsis.

In higher plants, cellulose is synthesized at the plasma membrane by the cellulose synthase (CESA) complex. The catalytic core of the complex is believed to be composed of three types of CESA subunits. Indirect evidence suggests that the complex associated with primary wall cellulose deposition consists of CESA1, -3, and -6 in Arabidopsis thaliana. However, phenotypes associated with mutations in two of these genes, CESA1 and -6, suggest unequal contribution by the different CESAs to overall enzymatic activity of the complex. We present evidence that the primary complex requires three unique types of components, CESA1-, CESA3-, and CESA6-related, for activity. Removal of any of these components results in gametophytic lethality due to pollen defects, demonstrating that primary-wall cellulose synthesis is necessary for pollen development. We also show that the CESA6-related CESAs are partially functionally redundant.

Muscle activation and strain during suction feeding in the largemouth bass Micropterus salmoides.

Activation and strain in the sternohyoideus (SH) were measured in vivo in five largemouth bass Micropterus salmoides. The SH is thought to actuate lower jaw depression, hyoid depression and suspensorial abduction during suction feeding in teleost fish. Sonomicrometry was used to measure fascicle shortening and lower jaw kinematics, while activity was measured by electromyography (EMG). SH fascicles shortened by an average of 11% during suction feeding. In three fish SH fascicles consistently shortened during fast lower jaw depression, but in two individuals they contracted isometrically or lengthened slightly during fast lower jaw depression. The SH continued shortening after peak gape, presumably actuating hyoid depression and lateral expansion of the buccal cavity. Onset of SH relengthening and onset of lower jaw elevation were simultaneous, as were the return of the SH to resting length and gape closure. Activation followed the onset of shortening by an average of 23 ms, although the muscle was active an average of 15 ms before the onset of rapid shortening. SH fascicles reached sustained shortening velocities averaging -2.5 fascicle lengths per second, and generally increased shortening velocity after peak gape. The shortening velocities measured in this study suggest that the SH actively shortens to generate power during suction feeding. This study is the first direct measurement of in vivo muscle function during suction feeding, the most common mechanism of prey capture among aquatic vertebrates.

Morphology predicts suction feeding performance in centrarchid fishes.

Suction feeding fish differ in their capacity to generate subambient pressure while feeding, and these differences appear to relate to morphological variation. We developed a morphological model of force transmission in the fish head and parameterized it with measurements from individual fish. The model was applied to 45 individuals from five species of centrarchid fishes: Lepomis macrochirus, Lepomis punctatus, Lepomis microlophus, Micropterus salmoides and Pomoxis nigromaculatus. Measurements of epaxial cross-sectional area, epaxial moment arm, buccal area and buccal area moment arm were combined to estimate pressure generation capacity for individual fish. This estimation was correlated with pressure measured in fish feeding on elusive prey to test the model's ability to predict pressure generation from morphology. The model explained differences in pressure generation found among individuals (P<0.001, r2=0.71) and produced a realistic estimate of normalized muscle stress during suction feeding (68.5+/-6.7 kPa). Fish with smaller mouths, larger epaxial cross-sectional area and longer epaxial moments, such as L. macrochirus (bluegill sunfish), generated lower pressures than fish with larger mouths, smaller cross-sectional area and shorter moments, such as M. salmoides (largemouth bass). These results reveal a direct trade-off between morphological requirements of feeding on larger prey (larger mouth size relative to body depth) and the ability to generate subambient pressure while suction feeding on elusive prey.

Adult de novo acute myeloid leukemia with t(6;11)(q27;q23): results from Cancer and Leukemia Group B Study 8461 and review of the literature.

BACKGROUND: Acute myeloid leukemia (AML) with t(6;11)(q27;q23) is a well established but rare entity, and few studies have reported the full clinical, hematologic, and outcome data of patients with this disease. METHODS: To characterize the features of t(6;11) AML, the authors searched the Cancer and Leukemia Group B (CALGB) cytogenetic database comprising 2667 adults with newly diagnosed, de novo AML and identified 16 patients (0.6%) with t(6;11). A review of the literature identified 33 adults with de novo t(6;11) AML for whom survival data were available. RESULTS: CALGB patients had a median age of 45 years (range, 22-65 years) and commonly presented with French-American-British (FAB) subtype M4 or M5 (81%). Gingival involvement at presentation was common (31%). All patients with gingival involvement had FAB M4. Compared with other patients with M4 AML in the CALGB database (n = 429), patients with M4 and t(6;11) (n = 7) had a higher frequency of gingival hypertrophy at presentation (71% vs. 17%, P = 0.003). Patients with t(6;11) were more likely to be African American (P = 0.02) and to die during induction (P = 0.03) than those without t(6;11). The complete response (CR) rate was 69% (11 of 16 patients), and CR duration was short (median, 9 months). The estimated probability of 2-year survival was 13%. Both long-term survivors received allogeneic stem cell transplantation. The estimated probability of 2-year survival of patients reported in the literature was 15%. CONCLUSIONS: Although the patient sample was small, the authors suggested that investigational approaches, including allogeneic transplantation, be considered for adults with t(6;11) AML.