Gemtuzumab ozogamicin as postremission treatment in AML at 60 years of age or more: results of a multicenter phase 3 study

In older patients with acute myeloid leukemia (AML), the prevention of relapse has remained one of the major therapeutic challenges, with more than 75% relapses after complete remission. The anti-CD33 immunotoxin conjugate gemtuzumab ozogamicin (GO) has shown antileukemic remission induction activity in patients with relapsed AML. Patients with AML or refractory anemia with excess blasts in first complete remission attained after intensive induction chemotherapy were randomized between 3 cycles of GO (6 mg/m(2) every 4 weeks) or no postremission therapy (control) to assess whether GO would improve outcome. The 2 treatment groups (113 patients receiving GO vs 119 control patients) were comparable with regard to age (60-78 years, median 67 years), performance status, and cytogenetics. A total of 110 of 113 received at least 1 cycle of GO, and 65 of 113 patients completed the 3 cycles. Premature discontinuation was mainly attributable to incomplete hematologic recovery or intercurrent relapse. Median time to recovery of platelets 50 x 10(9)/L and neutrophils 0.5 x 10(9)/L after GO was 14 days and 20 days. Nonhematologic toxicities were mild overall, but there was 1 toxic death caused by liver failure. There were no significant differences between both treatment groups with regard to relapse probabilities, nonrelapse mortality, overall survival, or disease-free survival (17% vs 16% at 5 years). Postremission treatment with GO in older AML patients does not provide benefits regarding any clinical end points. The HOVON-43 study is registered at The Netherlands Trial Registry (number NTR212) and at http://www.controlled-trials.com as ISRCTN77039377.

Evaluation of Hay-Type and Grazing Tolerant Alfalfa Hybrids in Season-Long or Complementary Rotational Stocking Systems for Beef Cows

Pastures containing hay-type and grazing tolerant alfalfa hybrids were grazed in a season-long or complementary rotational stocking system with Nfertilized smooth bromegrass. The pastures were stocked at a seasonal density of .8 cow-calf pairs per acre for 120 days in 1998 and 141 days in 1999. Pastures were intensively managed by daily stripstocking with the assumptions that 50% of live forage was available and daily live dry matter consumption of each cow-calf pair was 3.5% of the cow’s body weight. First-cutting forage was harvested as hay from 40% of the pasture acres to remove excess forage growth early in the grazing season. Grazing occurred on the remaining 60% of each pasture for the first 44 and 54 days and 100% of each pasture after days 45 and 55 in 1998 and 1999, respectively. Proportions of ‘Amerigraze’ and ‘Affinity’ alfalfa in the live forage dry matter decreased by 70% and 55% in pastures stocked season-long and by 60% and 42% in pastures used for complementary stocking (alfalfa type, p<.05; grazing management, p<.05) in 1998, but decreased by a mean of 72% and was unaffected by hybrid or stocking system in 1999. Cows grazing either alfalfa hybrid by either grazing system had greater weight gains during the breeding and overall grazing seasons and greater increases in body condition score pre-breeding and during the breeding season than the cows that grazed smooth bromegrass for the entire season in 1998. Also, cows grazing either alfalfa hybrid in the season-long system had greater breeding season increases in body condition score than cows grazing alfalfa in the complementary system with smooth bromegrass in 1998. Cows grazing in the season-long alfalfa system had greater prebreeding season weight (p<.10) increases and condition score (p<.05) increases than cows grazing alfalfa in the complementary system in 1999. Daily and seasonal body weight gains of calves were not affected (p>.10) by the presence of alfalfa in 1998 or by alfalfa type and grazing management in 1998 and 1999. Total animal production (cow and calf) in 1998 was greater (p<.10) from the season-long alfalfa pastures compared with the complementary stocked pastures. Total (p<.10) and live (p<.05) forage masses, estimated by monthly clippings, were greater in September of 1998 from the season-long alfalfa pastures than pastures using alfalfa for complementary stocking. Total (p<.10) and live (p<.05) forage masses were greater in August of 1999 from season-long alfalfa pastures than pastures using alfalfa for complementary stocking.

Evaluation of Hay-Type and Grazing Tolerant Alfalfa Hybrids in Season-Long or Complementary Rotational Stocking Systems for Beef Cows

Pastures containing hay-type and grazing tolerant alfalfa hybrids were grazed in a season-long or complimentary rotational stocking system with Nfertilized smooth bromegrass. The pastures were stocked at a seasonal density of .8 cow-calf pairs per acre for 120 days. Pastures were intensively managed by daily strip-stocking with the assumptions that 50% of live forage was available and daily live dry matter consumption of each cow-calf pair was 3.5% of the cow’s body weight. First-cutting forage was harvested as hay from 40% of pasture acres to remove excess forage growth early in the grazing season. Forage was grazed from the remaining 60% of each pasture for the first 44 days of the experiment and then from the entire pasture thereafter. Live forage yields, estimated by monthly clippings, were greater in May and September on the season-long alfalfa pastures compared with the complementary pastures and on the alfalfa pastures compared with the N-fertilized smooth bromegrass pastures. The proportions of legumes in the live dry matter in pastures with grazing tolerant and hay-type alfalfas in the season-long grazing systems declined by 70% and 50%, respectively, in the 120 day trial. The proportions of legumes in the live dry matter in pastures with grazing tolerant and the hay-type alfalfas in the complementary grazing system declined 60% and 42%, respectively, in the 120 day trial. Cows grazing either alfalfa hybrid by either management system had greater weight gains during the breeding and grazing seasons and greater increases in body condition score prebreeding and during the breeding season than the cows that grazed N-fertilized smooth bromegrass for the entire season. Also, cows grazing either alfalfa in the season-long system had greater breeding season increases in body condition score than cows grazing alfalfa in the complementary system with N-fertilized smooth bromegrass. Daily gains and seasonal gains of calves from cows grazing the alfalfa pastures tended to be greater than those grazing N-fertilized smooth bromegrass. Within alfalfa treatments, calves of cows grazing alfalfa pastures in the season-long system tended to produce more pounds per acre than those of cows grazing alfalfa in the complementary systems.

S9511: a Southwest Oncology Group phase II study of trimetrexate, 5-fluorouracil, and leucovorin in unresectable or metastatic adenocarcinoma of the stomach.

OBJECTIVE: The primary objective of this trial was to evaluate the response rate for trimetrexate in conjunction with 5-FU and leucovorin (LV) (= TFL) in the treatment of advanced gastric cancer in a phase II, cooperative group setting. METHODS: Patients with locally advanced, unresectable, or metastatic adenocarcinoma of the stomach received trimetrexate 110 mg/m IV over 60 minutes day 1, followed by 5-FU 500 mg/m IV bolus and LV 200 mg/m IV over 60 minutes day 2, followed by oral LV 15 mg every 6 hours x 7 doses, all weekly for 6 weeks followed by 2 weeks of rest, continued until progression. RESULTS: Characteristics for 37 eligible patients: median age 63 (range: 23-83); male/female: 69% of 31%; performance status 0/1/2 15/20/1. The confirmed response rate was 19%, and median overall survival was 6 months. Two patients died as a result of therapy, 1 because of infection without significant neutropenia, and 1 due to perforation of a responding gastric lesion. Seventy-two percent experienced grades 3 and 4 toxicity, most commonly diarrhea, fatigue, and lymphopenia. CONCLUSIONS: This regimen achieves response rates comparable to other 5-FU-based regimens, when used in treatment of incurable gastric cancer. Toxicity appears manageable.

LGM Summer Climate on the Southern Margin of the Laurentide Ice Sheet: Wet Or Dry?

Regional climate simulations are conducted using the Polar fifth-generation Pennsylvania State University (PSU)-NCAR Mesoscale Model (MM5) with a 60-km horizontal resolution domain over North America to explore the summer climate of the Last Glacial Maximum (LGM: 21 000 calendar years ago), when much of the continent was covered by the Laurentide Ice Sheet (LIS). Output from a tailored NCAR Community Climate Model version 3 (CCM3) simulation of the LGM climate is used to provide the initial and lateral boundary conditions for Polar MM5. LGM boundary conditions include continental ice sheets, appropriate orbital forcing, reduced CO2 concentration, paleovegetation, modified sea surface temperatures, and lowered sea level. The simulated LGM summer climate is characterized by a pronounced low-level thermal gradient along the southern margin of the LIS resulting from the juxtaposition of the cold ice sheet and adjacent warm ice-free land surface. This sharp thermal gradient anchors the midtropospheric jet stream and facilitates the development of synoptic cyclones that track over the ice sheet, some of which produce copious liquid precipitation along and south of the LIS terminus. Precipitation on the southern margin is orographically enhanced as moist southerly low-level flow (resembling a contemporary, Great Plains low-level jet configuration) in advance of the cyclone is drawn up the ice sheet slope. Composites of wet and dry periods on the LIS southern margin illustrate two distinctly different atmospheric flow regimes. Given the episodic nature of the summer rain events, it may be possible to reconcile the model depiction of wet conditions on the LIS southern margin during the LGM summer with the widely accepted interpretation of aridity across the Great Plains based on geological proxy evidence.

Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial

BACKGROUND Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone. METHODS Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544). FINDINGS 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc. INTERPRETATION Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy. FUNDING Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.

Geochemistry at DSDP Site 60-456

Basalts in two holes spaced 200 meters apart at DSDP Site 456 in the Mariana Trough both show a downward sequence of nonoxidative and oxidative zones of alteration, each 10 to 15 meters thick, overlying fresh basalts. Basalts in the nonoxidative zone have been extensively chloritized and have vein and vesicle fillings of quartz, opal, chlorite, calcite, and pyrite. Minor sulfides are chalcopyrite and digenite. Basalts in the oxidative zone have abundant smectites and iron hydroxides and are variably enriched in K, Rb, and Ba, unlike the nonoxidative basalts above them. We propose that the oxidative zone was a zone of mixing between high-temperature, reduced hydrothermal fluids moving horizontally beneath impermeable sediments at the top of the pillowed basement lavas and cold, oxygenated seawater in interpillow voids deeper in the basement. Recrystallized vitric tuffs immediately above the basalts containing authigenic quartz and wairakite, as well as occurrence of chlorite, epidote, and chalcopyrite in the basalts, suggest temperatures of alteration in excess of 200°C.

Petrography and mineral compositions of gabbros at DSDP Leg 60 Holes

The compositions, mineralogies, and textures of gabbros recovered in polymict breccias in Hole 453 indicate that they are the cumulus assemblages of calc-alkalic crystal fractional on that occurred beneath the West Mariana Ridge. They are among a class of gabbros known only from other calc-alkalic associations (e.g., the Lesser Antilles and the Peninsular Ranges batholith of Southern California) and differ from gabbros of stratiform complexes, ophiolites, and the ocean crust. Particularly abundant in the Hole 453 breccias are olivine-bearing gabbros with extremely calcic Plagioclase (An94-97) but with fairly iron-rich olivines (Fo76-77). Other gabbros contain biotite and amphibole and occur in breccias with fairly high-grade greenschist facies (amphibole-chlorite-stilpnomelane) metabasalts. One unusual gabbro has experienced almost complete subsolidus recrystallization to an assemblage of aluminous magnesio-hornblende, anorthite, and green hercynitic spinel. This reaction, the extremely calcic Plagioclase, the occurrence of biotite and amphibole, and the association with greenschist facies metamorphic rocks suggest that crystallization of the gabbros occurred at elevated P(H2O). Comparisons with other calc-alkalic gabbro suites suggest pressures in excess of 4 kbar (about 12 km depth). The gabbros were exposed by the early stages of opening of the Mariana Trough and imply that considerable uplift may have attended rifting. They were also subjected to hydrothermal alteration after breccia formation, resulting in formation of chlorite, epidote, actinolite, and prehnite. Temperatures of at least 200°C - and probably 350°C - were reached, and most likely could not have been attained without extrusion or intrusion of magmas nearby, even though no such rocks were cored.

1.2 Ma stacked benthic foraminiferal carbon isotope record

Pleistocene stable carbon isotope (d13C) records from surface and deep dwelling foraminifera in all major ocean basins show two distinct long-term carbon isotope fluctuations since 1.00 Ma. The first started around 1.00 Ma and was characterised by a 0.35 per mil decrease in d13C values until 0.90 Ma, followed by an increase of 0.60 per mil lasting until 0.50 Ma. The subsequent fluctuation started with a 0.40 per mil decrease between 0.50 and 0.25 Ma, followed by an increase of 0.30 per mil between 0.25 and 0.10 Ma. Here, we evaluate existing evidence and various hypotheses for these global Pleistocene d13C fluctuations and present an interpretation, where the fluctuations most likely resulted from concomitant changes in the burial fluxes of organic and inorganic carbon due to ventilation changes and/or changes in the production and export ratio. Our model indicates that to satisfy the long-term 'stability' of the Pleistocene lysocline, the ratio between the amounts of change in the organic and inorganic carbon burial fluxes would have to be close to a 1:1 ratio, as deviations from this ratio would lead to sizable variations in the depth of the lysocline. It is then apparent that the mid-Pleistocene climate transition, which, apart from the glacial cycles, represents the most fundamental change in the Pleistocene climate, was likely not associated with a fundamental change in atmospheric pCO2. While recognising that high frequency glacial/interglacial cycles are associated with relatively large (100 ppmv) changes in pCO2, our model scenario (with burial changes close to a 1:1 ratio) produces a maximum long-term variability of only 20 ppmv over the fluctuation between 1.00 and 0.50 Ma.

Nutrients and oxygen concentrations measured in water samples from the North Atlantic during the James Cook cruise JC087 in March 2013

Analysis for micro-molar concentrations of nitrate and nitrite, nitrite, phosphate, silicate and ammonia was undertaken on a SEAL Analytical UK Ltd, AA3 segmented flow autoanalyser following methods described by Kirkwood (1996). Samples were drawn from Niskin bottles on the CTD into 15ml polycarbonate centrifuge tubes and kept refrigerated at approximately 4oC until analysis, which generally commenced within 30 minutes. Overall 23 runs with 597 samples were analysed. This is a total of 502 CTD samples, 69 underway samples and 26 from other sources. An artificial seawater matrix (ASW) of 40g/litre sodium chloride was used as the inter-sample wash and standard matrix. The nutrient free status of this solution was checked by running Ocean Scientific International (OSI) low nutrient seawater (LNS) on every run. A single set of mixed standards were made up by diluting 5mM solutions made from weighed dried salts in 1litre of ASW into plastic 250ml volumetric flasks that had been cleaned by washing in MilliQ water (MQ). Data processing was undertaken using SEAL Analytical UK Ltd proprietary software (AACE 6.07) and was performed within a few hours of the run being finished. The sample time was 60 seconds and the wash time was 30 seconds. The lines were washed daily with wash solutions specific for each chemistry, but comprised of MQ, MQ and SDS, MQ and Triton-X, or MQ and Brij-35. Three times during the cruise the phosphate and silicate channels were washed with a weak sodium hypochlorite solution.

Crystal morphologies and pyroxene compositions in boninites and tholeiitic basalts at DSDP Holes 60-458 and 60-459B

Not all boninites are glassy lavas. Those of Hole 458 in the Mariana fore-arc region are submarine pillow lavas and more massive flows in which glass occurs only in quenched margins. Pillow and flow interiors have abundant Plagioclase spherulites, microlites, or even larger crystals but can be recognized as boninites by (1) occurrence of bronzite, (2) presence of augite-bronzite microphenocryst intergrowths, and (3) reversal of the usual basaltic groundmass crystallization sequence of plagioclase-augite to augite-plagioclase. The latter is accentuated by sharply contrasting augite and Plagioclase crystal morphologies near pillow margins, a consequence of rapid cooling rates. This crystallization sequence appears to be a consequence of boninites having higher SiO2 and Mg/Mg + Fe than basalts but lower CaO/Al2O3. Microprobe data are used to illustrate the effects of rapid cooling on the compositions of pyroxene and microphenocrysts in a glassy boninite sample and to estimate temperatures of crystallization of coexisting bronzite and augite. A range from 1320°C to 1200°C is calculated with an average of 1250°C. This is higher by 120°-230° than the known range for western Pacific arc tholeiites and by over 300° than for calc-alkalic andesites. Boninites of Hole 458 lack olivine and clinoenstatite but are otherwise chemically and petrographically similar to boninites that have these minerals. In order to distinguish the two types, the Hole 458 lavas are here termed boninites and the others are termed olivine boninites. Arc tholeiite pillow lavas from Holes 458 and 459B are briefly described and their textures compared to fractionated, moderately iron-enriched, abyssal tholeiites. Massive tholeiite flows contain striking quartz-alkali feldspar micrographic intergrowths with coarsely spherulitic textures resulting from in situ magmatic differentiation. Such intergrowths are rare in massive abyssal tholeiites cored by DSDP and probably occur here because arc tholeiites have higher normative quartz at comparable degrees of iron enrichment - a result of higher oxygen fugacities and earlier separation of titanomagnetite - than abyssal tholeiites.

Minerals, geochemistry and x-ray power characteristics at DSDP Sites 54-424, 60-458 and 60-459

Secondary minerals filling veins and vesicles in volcanic basement at Deep Sea Drilling Project Sites 458 and 459 indicate that there were two stages of alteration at each site: an early oxidative, probably hydrothermal, stage and a later, low-temperature, less oxidative stage, probably contemporaneous with faulting in the tectonically active Mariana forearc region. The initial stage is most evident in Hole 459B, where low-Al, high Fe smectites and iron hydroxides formed in vesicles in pillow basalts and low-Al palygorskite formed in fractures. Iron hydroxides and celadonite formed in massive basalts next to quartz-oligoclase micrographic intergrowths. Palygorskite was found in only one sample near the top of basement in Hole 458, but it too is associated with iron hydroxides. Palygorskite has previously been reported only in marine sediments in DSDP and other occurrences. It evidently formed here as a precipitate from fluids in which Si, Mg, Fe, and even some Al were concentrated. Experimental data suggest that the solutions probably had high pH and somewhat elevated temperatures. The compositions of associated smectites resemble those in hydrothermal sediments and in basalts at the Galapagos mounds geothermal field. The second stage of alteration was large-scale replacement of basalt by dioctahedral, trioctahedral, or mixed-layer clays and phillipsite along zones of intense fracturing, especially near the bottom of Holes 458 and 459B. The basalts are commonly slickensided, and there are recemented microfault offsets in overlying sediments. Native copper occurs in one core of Hole 458, but associated smectites are dominantly dioctahedral, unlike Hole 459B, where they are mainly trioctahedral, indicating nonoxidative alteration. The alteration in both holes is more intense than at most DSDP ocean crust sites and may have been augmented by water derived from subducting ocean crust beneath the fore-arc region.