A candidate super-Earth planet orbiting near the snow line of Barnard's star.

Barnard's star is a red dwarf, and has the largest proper motion (apparent motion across the sky) of all known stars. At a distance of 1.8 parsecs1, it is the closest single star to the Sun; only the three stars in the α Centauri system are closer. Barnard's star is also among the least magnetically active red dwarfs known2,3 and has an estimated age older than the Solar System. Its properties make it a prime target for planetary searches; various techniques with different sensitivity limits have been used previously, including radial-velocity imaging4-6, astrometry7,8 and direct imaging9, but all ultimately led to negative or null results. Here we combine numerous measurements from high-precision radial-velocity instruments, revealing the presence of a low-amplitude periodic signal with a period of 233 days. Independent photometric and spectroscopic monitoring, as well as an analysis of instrumental systematic effects, suggest that this signal is best explained as arising from a planetary companion. The candidate planet around Barnard's star is a cold super-Earth, with a minimum mass of 3.2 times that of Earth, orbiting near its snow line (the minimum distance from the star at which volatile compounds could condense). The combination of all radial-velocity datasets spanning 20 years of measurements additionally reveals a long-term modulation that could arise from a stellar magnetic-activity cycle or from a more distant planetary object. Because of its proximity to the Sun, the candidate planet has a maximum angular separation of 220 milliarcseconds from Barnard's star, making it an excellent target for direct imaging and astrometric observations in the future.

In Situ Production of Zoospores by Five Species of Phytophthora in Aqueous Environments for Use as Inocula.

The goal of this study was to develop a procedure that could be used to evaluate the potential susceptibility of aquatic plants used in constructed wetlands to species of Phytophthora commonly found in nurseries. V8 agar plugs from actively growing cultures of three or four isolates of Phytophthora cinnamomi, P. citrophthora, P. cryptogea, P. nicotianae, and P. palmivora were used to produce inocula. In a laboratory experiment, plugs were placed in plastic cups and covered with 1.5% nonsterile soil extract solution (SES) for 29 days, and zoospore presence and activity in the solution were monitored at 2- or 3-day intervals with a rhododendron leaf disk baiting bioassay. In a greenhouse experiment, plugs of each species of Phytophthora were placed in plastic pots and covered with either SES or Milli-Q water for 13 days during both summer and winter months, and zoospore presence in the solutions were monitored at 3-day intervals with the baiting bioassay and by filtration. Zoospores were present in solutions throughout the 29-day and 13-day experimental periods but consistency of zoospore release varied by species. In the laboratory experiment, colonization of leaf baits decreased over time for some species and often varied among isolates within a species. In the greenhouse experiment, bait colonization decreased over time in both summer and winter, varied among species of Phytophthora in the winter, and was better in Milli-Q water. Zoospore densities in solutions were greater in the summer than in the winter. Decreased zoospore activities for some species of Phytophthora were associated with prolonged temperatures below 13 or above 30°C in the greenhouse. Zoospores from plugs were released consistently in aqueous solutions for at least 13 days. This procedure can be used to provide in situ inocula for the five species of Phytophthora used in this study so that aquatic plant species can be evaluated for potential susceptibility.

Management of Daylily Rust with Different Fungicides and Application Methods.

The objectives of this study were to assess the efficacy of various fungicides applied as root dips, soil drenches, or foliar sprays to daylily plants grown in containers and planted in the field to manage rust caused by Puccinia hemerocallidis. Soil drenches and foliar sprays were evaluated in field experiments in Griffin, GA in 2010 and 2011. Dipping bare-root daylily plants for 5 min in azoxystrobin, tebuconazole, or thiophanate-methyl significantly reduced lesion development compared with nontreated control plants. Drenches with azoxystrobin, fluoxastrobin, or tebuconazole, each at three rates (0.06, 0.12, and 0.24 g of active ingredient [a.i.]/container), significantly reduced development of rust lesions on container-grown daylily plants for up to 9 weeks after treatment and 6 weeks after inoculation. One early-season drench of azoxystrobin at 0.12 g a.i‥/plant provided season-long reduction in disease incidence and disease progress that was comparable with foliar sprays with azoxystrobin or chlorothalonil applied at 14-day intervals. Dip or drench applications of fungicides would allow growers to diversify rust management options and could reduce the number of foliar fungicide applications.

Fungicides Used Alone, in Combinations, and in Rotations for Managing Gladiolus Rust in Mexico.

Gladiolus rust, caused by Uromyces transversalis, is a quarantine-significant pathogen in the United States. However, the fungus is endemic to commercial gladiolus-producing areas in Mexico and has been intercepted frequently on gladiolus plants entering the United States for the cut-flower market. The present study assessed 15 fungicide active ingredients (five quinone outside inhibitors: azoxystrobin, fluoxastrobin, kresoxim-methyl, pyraclostrobin, and trifloxystrobin; six triazoles: cyproconazole, difenoconazole, epoxiconazole, myclobutanil, propiconazole, and tebuconazole; three succinate dehydrogenase inhibitors: boscalid, flutolanil, and oxycarboxin; and one broad-spectrum protectant: chlorothalonil) and one plant activator, acibenzolar-S-methyl, applied alone, in combinations, and in various rotations for efficacy against U. transversalis on field-grown gladiolus plants in Mexico. Experiments were conducted in 2010, 2011, and 2012 in commercial fields in Atlixco and Santa Isabel Cholula in Puebla and Cuautla and Tlayacapan in Morelos. Fungicides were applied at 2-week intervals starting when plants had three full leaves. Disease severity was recorded each week for at least 7 weeks after the first application. Under high disease pressure in 2010, fungicides were less effective than in 2011 and 2012, when disease pressure was not as high. In all 3 years, most fungicide treatments significantly reduced disease severity. Triazoles were more effective than quinone outside inhibitors when applied as individual products in 2010, and combinations of two fungicides in different mode-of-action groups were more effective than fungicides applied individually in 2011. In 2012, rotations of fungicides, either with individual products or with combinations of two products, provided excellent rust management. Reducing disease development by U. transversalis on commercial gladiolus plants in Mexico will reduce the potential for introducing this pathogen on cut flowers into the United States.

Diversity and Mefenoxam Sensitivity of Phytophthora spp. Associated with the Ornamental Horticulture Industry in the Southeastern United States.

Phytophthora isolates associated with ornamental plants or recovered from irrigation water in six states in the southeastern United States (Georgia, North Carolina, South Carolina, Tennessee, Texas, and Virginia) were identified and screened for sensitivity to mefenoxam. Isolates from forest and suburban streams in Georgia and Virginia were included for comparison. A new in vitro assay, utilizing 48-well tissue culture plates, was used to screen for mefenoxam sensitivity; this assay allowed high throughput of isolates and used less material than the traditional petri plate assay. In total, 1,483 Phytophthora isolates were evaluated, and 27 species were identified with Phytophthora nicotianae, P. hydropathica, and P. gonapodyides, the most abundant species associated with plants, irrigation water, and streams, respectively. Only 6% of isolates associated with plants and 9% from irrigation water were insensitive to mefenoxam at 100 µg a.i./ml. Approximately 78% of insensitive isolates associated with plants were P. nicotianae, and most of these (67%) came from herbaceous annual plants. Most of the insensitive isolates recovered from irrigation water were P. gonapodyides, P. hydropathica, P. megasperma, and P. pini, and 83% of the insensitive isolates from streams were P. gonapodyides. Overall, this study suggests that mefenoxam should continue to be a valuable tool in the management of Phytophthora diseases affecting ornamental plants in the southeastern United States.

Effects of Fuel Reduction Treatments on Incidence of Phytophthora Species in Soil of a Southern Appalachian Mountain Forest.

The National Fire and Fire Surrogate Study was initiated to study the effects of fuel reduction treatments on forest ecosystems. Four fuel reduction treatments were applied to three sites in a southern Appalachian Mountain forest in western North Carolina: prescribed burning, mechanical fuel reduction, mechanical fuel reduction followed by prescribed burning, and a nontreated control. To determine the effects of fuel reduction treatments on Phytophthora spp. in soil, incidences were assessed once before and twice after fuel reduction treatments were applied. Also, the efficiency of the baiting bioassay used to detect species of Phytophthora was evaluated, and the potential virulence of isolates of Phytophthora spp. collected from forest soils was determined. Phytophthora cinnamomi and P. heveae were the only two species recovered from the study site. Incidences of these species were not significantly affected by fuel reduction treatments, but incidence of P. cinnamomi increased over time. In the baiting bioassay, camellia leaf disks were better than hemlock needles as baits. P. cinnamomi was detected best in fresh soil, whereas P. heveae was detected best when soil was air-dried and remoistened prior to baiting. Isolates of P. heveae were weakly virulent and, therefore, potentially pathogenic-causing lesions only on wounded mountain laurel and rhododendron leaves; however, isolates of P. cinnamomi were virulent and caused root rot and mortality on mountain laurel and white pine plants.

A nearby transiting rocky exoplanet that is suitable for atmospheric investigation.

Spectroscopy of transiting exoplanets can be used to investigate their atmospheric properties and habitability. Combining radial velocity (RV) and transit data provides additional information on exoplanet physical properties. We detect a transiting rocky planet with an orbital period of 1.467 days around the nearby red dwarf star Gliese 486. The planet Gliese 486 b is 2.81 Earth masses and 1.31 Earth radii, with uncertainties of 5%, as determined from RV data and photometric light curves. The host star is at a distance of ~8.1 parsecs, has a J-band magnitude of ~7.2, and is observable from both hemispheres of Earth. On the basis of these properties and the planet's short orbital period and high equilibrium temperature, we show that this terrestrial planet is suitable for emission and transit spectroscopy.

A multiplanet system of super-Earths orbiting the brightest red dwarf star GJ 887.

The closet exoplanets to the Sun provide opportunities for detailed characterization of planets outside the Solar System. We report the discovery, using radial velocity measurements, of a compact multiplanet system of super-Earth exoplanets orbiting the nearby red dwarf star GJ 887. The two planets have orbital periods of 9.3 and 21.8 days. Assuming an Earth-like albedo, the equilibrium temperature of the 21.8-day planet is ~350 kelvin. The planets are interior to, but close to the inner edge of, the liquid-water habitable zone. We also detect an unconfirmed signal with a period of ~50 days, which could correspond to a third super-Earth in a more temperate orbit. Our observations show that GJ 887 has photometric variability below 500 parts per million, which is unusually quiet for a red dwarf.

A giant exoplanet orbiting a very-low-mass star challenges planet formation models.

Surveys have shown that super-Earth and Neptune-mass exoplanets are more frequent than gas giants around low-mass stars, as predicted by the core accretion theory of planet formation. We report the discovery of a giant planet around the very-low-mass star GJ 3512, as determined by optical and near-infrared radial-velocity observations. The planet has a minimum mass of 0.46 Jupiter masses, very high for such a small host star, and an eccentric 204-day orbit. Dynamical models show that the high eccentricity is most likely due to planet-planet interactions. We use simulations to demonstrate that the GJ 3512 planetary system challenges generally accepted formation theories, and that it puts constraints on the planet accretion and migration rates. Disk instabilities may be more efficient in forming planets than previously thought.

Baseline and Differential Sensitivity to Two QoI Fungicides Among Isolates of Phytophthora cactorum That Cause Leather Rot and Crown Rot on Strawberry.

Sensitivities of 89 isolates of Phytophthora cactorum, the causal agent of crown rot and leather rot on strawberry plants, from seven states (Florida, Maine, North Carolina, Ohio, Oregon, South Carolina, and New York) to the QoI fungicide azoxystrobin were determined based on mycelium growth and zoospore germination. Radial growth of mycelia on lima bean agar amended with azoxystrobin at 0.001, 0.01, 0.1, 1.0, 10, and 30 µg/ml and salicylhydroxamic acid (SHAM) at 100 µg/ml was measured after 6 days. Effect on zoospore germination was evaluated in aqueous solutions of azoxystrobin at 0.005, 0.01, 0.05, 0.1, 0.5, and 1.0 µg/ml in 96-well microtiter plates by counting germinated and nongerminated zoospores after 4 h at room temperature. SHAM was not used to evaluate zoospore sensitivity. The effective dose to reduce mycelium growth by 50% (ED50) ranged from 0.16 to 12.52 µg/ml for leather rot isolates and 0.10 to 15 µg/ml for crown rot isolates. The Kolmogorov-Smirnov test showed significant differences (P < 0.001) between the two distributions. Zoospores were much more sensitive to azoxystrobin than were mycelia. Differences between sensitivity distributions for zoospores from leather rot and crown rot isolates were significant at P = 0.05. Estimated ED50 values ranged from 0.01 to 0.24 µg/ml with a median of 0.04 µg/ml. Experiments with pyraclostrobin, another QoI fungicide, demonstrated that both mycelia and zoospores of P. cactorum were more sensitive to pyraclostrobin than to azoxystrobin. Sensitivities to azoxystrobin and pyraclostrobin were moderately but significantly correlated (r = 0.60, P = 0.0001).

A glycerophospholipid-specific pocket in the RVFV class II fusion protein drives target membrane insertion.

The Rift Valley fever virus (RVFV) is transmitted by infected mosquitoes, causing severe disease in humans and livestock across Africa. We determined the x-ray structure of the RVFV class II fusion protein Gc in its postfusion form and in complex with a glycerophospholipid (GPL) bound in a conserved cavity next to the fusion loop. Site-directed mutagenesis and molecular dynamics simulations further revealed a built-in motif allowing en bloc insertion of the fusion loop into membranes, making few nonpolar side-chain interactions with the aliphatic moiety and multiple polar interactions with lipid head groups upon membrane restructuring. The GPL head-group recognition pocket is conserved in the fusion proteins of other arthropod-borne viruses, such as Zika and chikungunya viruses, which have recently caused major epidemics worldwide.

Prolonged continuous infusion of fluorouracil with weekly bolus leucovorin: a phase II study in patients with disseminated colorectal cancer.

BACKGROUND: Biochemical modulation of bolus fluorouracil (5-FU) by addition of leucovorin to the treatment regimen has increased response in patients with disseminated colorectal cancer from fewer than 20% to more than 40%. In view of the short half-life of 5-FU and its cell cycle specificity, it may be that infusion rather than intravenous bolus injection would increase efficacy. Furthermore, the advent of safer indwelling intravenous catheters and pump technology, allowing home and ambulatory treatment, has made protracted infusion clinically feasible. To examine these questions, we conducted a phase I trial using protracted infusion of 5-FU by indwelling catheter and pump, with leucovorin given by bolus injection, and reported 40% partial response. PURPOSE: We have now initiated a phase II study of 5-FU given by prolonged continuous infusion with weekly bolus injections of leucovorin in previously untreated patients with measurable, disseminated colorectal cancer. METHODS: Forty-one patients were treated. The regimen consisted of treatment for 4 weeks with 5-FU at a dose of 200 mg/m2 daily as a continuous infusion by indwelling intravenous catheter and pump, followed by a 2-week rest and then by monthly cycles of 3 weeks of treatment and 1-week rest until disease progression. Leucovorin was given as a bolus injection of 20 mg/m2 at the beginning of each week of treatment with 5-FU. RESULTS: Nineteen (46%) of 41 patients had objective response: Three complete responses and 16 partial responses were seen. Overall, the median duration of response was 8 months. The median duration of survival was 16 months: 18 months for responders and 10 months for nonresponders. In general, toxic effects were mild and consisted primarily of stomatitis and palmar-plantar erythrodysesthesia (hand-foot syndrome). Neither grade 4 toxic effects nor treatment-related deaths were observed. The only serious side effects were catheter thrombosis (three patients) and catheter sepsis (one patient). CONCLUSION: We conclude that this safe regimen is one of the most effective for the treatment of disseminated colorectal cancer. IMPLICATIONS: The regimen should be tested prospectively against other regimens in use for this disease. It is currently included in a phase III study of the Southwest Oncology Group for this purpose. That study will assess quality of life as well as response rates and survival duration.

Phytophthora tropicalis Isolated from Diseased Leaves of Pieris japonica and Rhododendron catawbiense and Found in Irrigation Water and Soil in Virginia.

An unidentified species of Phytophthora was isolated from irrigation water at a production nursery in Suffolk, VA in 2000 and 2001. Water samples were assayed using a filtration method (3). A similar species was recovered from soil samples collected in two mixed-hardwood forests in Fairfax County in 2002. Soil samples were air dried, remoistened, flooded, and then baited with rhododendron and camellia leaf pieces at room temperature (22 to 24°C) (2). A Phytophthora sp. was recovered from bait pieces cultured on PARPH-V8 selective medium (2). This same species also was isolated from symptomatic leaves of Pieris japonica cv. Temple Bells and Rhododendron catawbiense cv. Maximum Roseum at a garden center in Virginia Beach in 2004. On P. japonica, symptoms appeared as water-soaked, necrotic lesions and marginal necrosis on leaves and necrosis of shoot tips; on R. catawbiense, symptoms were wilting, dieback, and death of shoots. Representative isolates produced semipapillate to papillate sporangia with tapered bases that were caducous and had long pedicels (16 to 120 µm). Sporangia on four isolates were measured: mean lengths were 40.6 to 48.4 µm, mean widths were 26.9 to 31.4 µm, and length/width ratios consistently were 1.5. Sporangia occasionally were distorted and had dual apices, and they often contained a large globule after zoospore release. Chlamydospores ranged from 25 to 32 µm in diameter. All isolates were heterothallic; four isolates paired with known isolates of P. nicotianae were found to be mating type A1. Optimum temperature for mycelium growth on cornmeal agar was 25°C with slight growth at 35°C by some isolates and no growth at 4°C. These morphological characteristics were mostly consistent with those of P. tropicalis (1). P. tropicalis is reported to have sporangia that are papillate, have lengths of 40 to 55 µm, widths of 19 to 27 µm, and length/width ratios of 1.8 to 2.4 (1). The identity of these isolates as P. tropicalis was confirmed using single-strand conformational polymorphism analysis with comparison to a reference isolate (4). These isolates have been retained in permanent collections in the Hong and Jeffers labs. One isolate from each host plant and one isolate from irrigation water were tested for pathogenicity; agar blocks of mycelium (4 × 4 mm) were placed on wounded and nonwounded leaves of P. japonica cv. Mountain Fire and R. catawbiense cv. Olga plants and wrapped with Parafilm to prevent desiccation. Lesions formed on wounded and nonwounded leaves after 4 days at 20 to 30°C, and P. tropicalis was reisolated; no lesions formed on noninoculated control leaves. To our knowledge, this is the first report of P. tropicalis in the continental United States, in irrigation water systems, and as a cause of Phytophthora foliage blight on P. japonica and R. catawbiense (1). This study suggests that the host range of this pathogen is not limited to tropical plants. Although this pathogen did not cause significant economic loss in the garden center surveyed, it was isolated in irrigation water at the production nursery from late spring through fall. An investigation of its impact on nursery crops is warranted. References: (1) M. Aragaki and J. Y. Uchida. Mycologia 93:137, 2001. (2) A. J. Ferguson and S. N. Jeffers. Plant Dis. 83:1129, 1999. (3) C. X. Hong et al. Phytopathology 92:610, 2002. (4) P. Kong et al. Fungal Genet. Biol. 39:238, 2003.

Phase I and pharmacologic study of estramustine phosphate and short infusions of paclitaxel in women with solid tumors.

PURPOSE: We sought to determine the tolerance of estramustine phosphate (EMP) combined with a 3-hour paclitaxel infusion in women with solid paclitaxel-pretreated solid tumors. Paclitaxel pharmacology was to be studied at the recommended phase II dose. PATIENTS AND METHODS: Paclitaxel was administered to cohorts of at least three assessable patients at doses of 150, 180, 210, and 225 mg/m2, while EMP was given at 900 and 1,200 mg/m2/d in divided doses orally for 2 days preceding and on the day of paclitaxel. The pharmacologic study was performed at 225 mg/m2 paclitaxel given in the absence and 3 weeks later in the presence of EMP 900 mg/m2/d. RESULTS: Thirty-eight patients received a total of 178 courses. Grade 3 nausea, vomiting, and diarrhea were common at EMP 1,200 mg/m2 and paclitaxel 225 mg/ m2; this was considered the maximum-tolerated dose. Since these toxicities appeared related to EMP, the pharmacologic study used a dose of 900 mg/m2 of this agent with 225 mg/m2 paclitaxel. Antitumor activity was documented against breast and ovarian cancers at all levels. Paclitaxel pharmacokinetics without and with EMP did not differ. CONCLUSION: EMP 900 mg/m2 for 3 days and 225 mg/m2 paclitaxel by 3-hour infusion are well tolerated; antitumor activity was seen in women with paclitaxel-pretreated solid tumors. This apparent enhancement of antitumor effects is unlikely to be mediated by P-glycoprotein.

Liposomal doxorubicin: antitumor activity and unique toxicities during two complementary phase I studies.

PURPOSE: The purpose of our studies was to define the maximal-tolerated dose of liposomal doxorubicin (DOX-SL; Liposome Technology Inc, Menlo Park, CA), a doxorubicin formulation of polyethyleneglycol-coated liposomes, characterize the toxicities associated with this formulation, and evaluate any indication of antitumor activity within a phase I setting. PATIENTS AND METHODS: Two separate phase I studies were conducted following the initial human pharmacokinetic testing at one of the sites (Hadassah). The starting dose of 20 mg/m2 at the University of Southern California was just below the dose without toxicity in the pharmacokinetic study. At Hadassah, the phase I starting dose was just above their earlier safe single doses, 60 mg/m2. Both studies involved cohorts of at least three patients and redosing every 3 to 4 weeks. To determine the recommended dose for phase II trials, an additional level of 50 mg/m2 every 3 weeks was explored, and the level of 60 mg/m2 every 4 weeks was expanded. RESULTS: A total of 56 patients receiving 281 courses of DOX-SL was accrued and evaluated for toxicity. Hand-foot (H-F) syndrome and stomatitis are the two main dose-limiting factors of DOX-SL. Stomatitis was dose-limiting for high single doses of DOX-SL greater than 70 mg/m2. Skin toxicity manifested primarily as H-F syndrome was dose-limiting for repetitive dosing, but acceptable at either 50 mg/m2 every 3 weeks or 60 mg/m2 every 4 weeks. Attenuation of acute subjective symptoms and lack of alopecia were generally observed. Patients with carcinomas of the breast, ovary, prostate, and head and neck were among those showing objective antitumor responses or improvement based, in part, on blood levels of tumor markers. CONCLUSION: The toxicity profile of DOX-SL differs prominently from that of the free drug administered by bolus or rapid infusion and with some differences, resembles that of prolonged continuous infusion. This finding, as well as the antitumor activity observed, supports wide phase II testing of DOX-SL in solid tumors.

Phase II study of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity modification by liposomal encapsulation.

PURPOSE: A phase II study of liposomal doxorubicin was conducted in patients with ovarian cancer who failed to respond to platinum- and paclitaxel-based regimens. Liposomal doxorubicin was selected as a result of its superior activity against ovarian cancer xenografts relative to free doxorubicin and activity in refractory ovarian cancer patients that was noted during the phase I study. PATIENTS AND METHODS: Thirty-five consecutive patients were accrued in two institutions (22 in one and 13 in the other). All had progressive disease after either cisplatin or carboplatin and paclitaxel, or at least one platinum-based and one paclitaxel-based regimen. Patients received intravenous (I.V.) liposomal doxorubicin 50 mg/m2 every 3 weeks with a dose reduction to 40 mg/m2 in the event of grade 3 or 4 toxicities, or a lengthening of the interval to 4 weeks (and occasionally to 5 weeks) with persistence of grade 1 or 2 toxicities beyond 3 weeks. RESULTS: Nine clinical responses (one complete response [CR], eight partial responses [PRs]) were observed in 35 patients (25.7%), with seven of these having been confirmed by two consecutive computed tomographic (CT) measurements. The median progression-free survival was 5.7 months with an overall survival of 1.5 to 24+ months (median, 11 months). Although 13 patients experienced grade 3 or 4 nonhematologic skin and mucosal toxicities (either hand-foot syndrome or stomatitis), with dose modifications, the treatment was very well tolerated. Nausea that was clearly attributable to the drug, hair loss, extravasation necrosis, or decreases in ejection fraction did not occur. CONCLUSION: Liposomal doxorubicin has substantial activity against ovarian cancer refractory to platinum and paclitaxel. The responses achieved with liposomal doxorubicin were durable and maintained with minimal toxicity. This liposomal formulation should be evaluated further in combination with other drugs in less refractory patients.

Phase I and pharmacokinetic study of oral UFT, a combination of the 5-fluorouracil prodrug tegafur and uracil.

UFT is an oral preparation combining the 5-fluorouracil (FU) prodrug tegafur (FT) and uracil (U) in a 1:4 ratio, which is commercially available in Japan for the treatment of breast and gastrointestinal cancers. We sought to determine the tolerance of daily oral UFT and to relate this tolerance to the pharmacokinetics of FT and/or the derived FU, while exploring the possibility of circadian FU kinetics contributing to the results. A 28-day schedule followed by 2 weeks rest was began at the initial level of 300 mg/m2/day administered either at 8 a.m. or at 6 p.m. At the following level, 400 mg/m2/day patients were randomly assigned to a split-dose administration or to the above single, timed dose administration. Intolerance to single dosing was clearly demonstrated, and only the split dosing was advanced to 500 mg/m2/day. When this level proved too toxic, 400 mg/m2 was studied further on a 7 a.m., 3 p.m., and 11 p.m. (every 8 h) schedule. Pharmacology was determined on selected patients. In the single dose administration, areas under the curves of FU were higher following p.m. dosing, although substantial interpatient variation was present. Toxicities (diarrhea and neutropenia) were more severe in patients receiving the drug in single daily doses. We conclude that the kinetics of FT are saturable, with disproportionate increases in area under the curve (and toxicities) as dose levels are increased. With divided dosing, tolerance improves. UFT at a dose of 400 mg/m2/day administered as three divided doses (every 8 h) is suitable for Phase II studies, although toxicity requiring cessation of drug administration prior to completion of 28-day cycles will occur in some patients.

Toxicity of Fungicides to Urediniospores of Six Rust Fungi That Occur on Ornamental Crops.

The recent introduction and rapid spread of rust on daylilies, caused by Puccinia hemerocallidis, suggested a need for fungicide treatments that reduce urediniospore viability on plant surfaces. Twelve fungicides in seven chemical classes were evaluated in vitro for toxicity to urediniospores of rust fungi that occur on daylily (P. hemerocallidis), geranium P. pelargonii-zonalis), iris (P. iridis), oxalis (P. oxalis), mint (P. menthae), and Florida azalea (Pucciniastrum vaccinii). Germination of urediniospores of all six rust fungi on potato dextrose agar in the absence of fungicides ranged from 54 to 88%. Germination of urediniospores of all rust species during and after exposure to azoxystrobin, chlorothalonil, copper sulfate pentahydrate, mancozeb, and trifloxystrobin was less than or near 1%. Germination during exposure to fenhexamid, iprodione, myclobutanil, propiconazole, thiophanate-methyl, triadimefon, and triflumizole ranged from 0 to 60% and usually was greater (0 to 75%) after fungicide residues had been removed. Germination of urediniospores of P. pelargonii-zonalis decreased when exposed to azoxystrobin, copper sulfate pentahydrate, and mancozeb for 1 min and was nearly eliminated after a 30-min exposure, while exposure to trifloxystrobin and chlorothalonil eliminated germination after 4 and 8 h, respectively. Urediniospores that had been allowed to imbibe water for 4 h had no further germination or germ tube growth after a 24-h exposure to azoxystrobin, chlorothalonil, copper sulfate pentahydrate, mancozeb, and trifloxystrobin. Less than one lesion per plant developed on seedlings inoculated with urediniospores of P. pelargonii-zonalis that had been sprayed with azoxystrobin, chlorothalonil, copper sulfate pentahydrate, and mancozeb, whereas seedlings inoculated with spores not exposed to fungicides developed 148 lesions per plant. The strobilurin (azoxystrobin and trifloxystrobin), broad-spectrum protectant (chlorothalonil and mancozeb), and inorganic copper (copper sulfate pentahydrate) fungicides were fungicidal to urediniospores of the six rust fungi. However, the benzimidazole (thiophanate-methyl), dicarboximide (iprodione), hydroxyanilide (fenhexamid), and demethylation-inhibiting (myclobutanil, propiconazole, triadimefon, and triflumizole) fungicides were only fungistatic to rust urediniospores.

Tolerance of paclitaxel 3-hour infusion with and without granulocyte colony-stimulating factor on a biweekly schedule.

The object of this study was to define the toxicity and maximum tolerated dose of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) administered on a biweekly schedule, without and with granulocyte colony-stimulating factor support. Eligible patients had a diagnosis of recurrent or metastatic carcinoma and had received no more than one prior chemotherapy regimen. Patients were treated with paclitaxel administered as a 3-hour infusion. Entry dose level was 150/mg/m2. Subsequent dose levels were 175, 200, and 225 mg/m2. Granulocyte colony-stimulating factor was added at the two highest dose levels beginning on day 4, until absolute neutrophil count was above 10 x 10(9)/L. Forty-six patients were entered. Up to 175 mg/m2 could be safely administered every 2 weeks. Previously treated patients experienced severe dose-limiting neutropenia at 200 mg/m2, and at 225 mg/m2 all patients experienced treatment delays due to grade 3/4 neutropenia. Dose intensity was maintained in all patients due to the addition of granulocyte colony-stimulating factor. Escalation to 250 mg/m2 does not appear desirable, due to neurotoxicity.

Paclitaxel 3-hour infusion given alone and combined with carboplatin: preliminary results of dose-escalation trials.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) by 3-hour infusion was combined with carboplatin in a phase I/II study directed to patients with non-small cell lung cancer. Carboplatin was given at a fixed target area under the concentration-time curve of 6.0 by the Calvert formula, whereas paclitaxel was escalated in patient cohorts from 150 mg/m2 (dose level I) to 175, 200, 225, and 250 mg/m2. The 225 mg/m2 level was expanded for the phase II study since the highest level achieved (250 mg/m2) required modification because of nonhematologic toxicities (arthralgia and sensory neuropathy). Therapeutic effects were noted at all dose levels, with objective responses in 17 (two complete and 15 partial regressions) of 41 previously untreated patients. Toxicities were compared with a cohort of patients in a phase I trial of paclitaxel alone at identical dose levels. Carboplatin did not appear to add to the hematologic toxicities observed, and the paclitaxel/carboplatin combination could be dosed every 3 weeks.