Minimally invasive surgery for suspected early-stage ovarian cancer; a cost-effectiveness study.

OBJECTIVE: While there are a number of benefits to minimally invasive surgery (MIS) for women with ovarian cysts, there is an increased risk of ovarian capsule rupture during the procedure, which could potentially seed the abdominal cavity with malignant cells. We developed a decision model to compare the risks, benefits, effectiveness and cost of MIS versus laparotomy in women with ovarian masses. DESIGN: Cost-effectiveness study POPULATION: Hypothetical cohort of 10 000 women with ovarian masses who were undergoing surgical management. METHODS: The initial decision point in the model was performance of surgery via laparotomy or a MIS approach. Model probabilities, costs and utility values were derived from published literature and administrative data sources. Extensive sensitivity analyses were conducted to assess the robustness of the findings. MAIN OUTCOME MEASURES: The primary outcome was the cost-effectiveness of MIS versus laparotomy for women with a pelvic mass measured by incremental cost-effectiveness ratios (ICERs). RESULTS: MIS was the least costly strategy at $7,732 per women on average, compared with $17,899 for laparotomy. In our hypothetical cohort of 10 000 women, there were 64 cases of ovarian rupture in the MIS group and 53 in the laparotomy group, while there were 26 cancer-related deaths in the MIS group and 25 in the laparotomy group. MIS was more effective than laparotomy (188 462 QALYs for MIS versus 187 631 quality adjusted life years [QALYs] for laparotomy). Thus, MIS was a dominant strategy, being both less costly and more effective than laparotomy. These results were robust in a variety of sensitivity analyses. CONCLUSION: MIS constitutes a cost-effective management strategy for women with suspicious ovarian masses. TWEETABLE ABSTRACT: MIS is a cost-effective management strategy for women with suspicious ovarian masses.

Measurement and validation of frailty as a predictor of outcomes in women undergoing major gynaecological surgery.

OBJECTIVE: Frailty is the loss of physical or mental reserve that impairs function, often in the absence of a defined comorbidity. Our aim was to determine whether a modified frailty index (mFI) correlates with morbidity and mortality in patients undergoing hysterectomy. DESIGN: Retrospective cohort study. SETTING: Hospitals across the USA participating in the National Surgical Quality Improvement Program (NSQIP). SAMPLE: Patients who underwent hysterectomy from 2008 to 2012. METHODS: An mFI was calculated using 11 variables in NSQIP. The associations between mFI and morbidity and mortality were assessed. Model fit statistics (c-statistics) were utilised to evaluate the ability of mFI to distinguish outcomes. MAIN OUTCOME MEASURE: Wound infection, severe complications and mortality. RESULTS: A total of 66 105 patients were identified. Wound complications increased from 2.4% in patients with an mFI of zero to 4.8% in those with mFI ≥ 0.5 (P < 0.0001). Similarly, severe complications increased from 0.98% to 7.3% (P < 0.0001), overall complications rose from 3.7% to 14.5% (P < 0.0001) and mortality increased from 0.06% to 3.2% (P < 0.0001) for patients with a frailty index of zero compared with those with an index of ≥ 0.5. Versus chance, the goodness-of-fit c-statistics suggested that mFI increases the ability to detect wound complications by 11.4%, severe complications by 22.0% and overall complications by 11.0%. CONCLUSIONS: The mFI is easily reproducible from routinely collected clinical data and predictive of outcomes in patients undergoing hysterectomy. Frailty may be useful in the preoperative risk assessment of women undergoing gynaecological surgery. TWEETABLE ABSTRACT: Frailty may be useful in the preoperative risk assessment of women undergoing gynaecological surgery.

Effects of a green tea extract, Polyphenon E, on systemic biomarkers of growth factor signalling in women with hormone receptor-negative breast cancer.

BACKGROUND: Observational and experimental data support a potential breast cancer chemopreventive effect of green tea. METHODS: We conducted an ancillary study using archived blood/urine from a phase IB randomised, placebo-controlled dose escalation trial of an oral green tea extract, Polyphenon E (Poly E), in breast cancer patients. Using an adaptive trial design, women with stage I-III breast cancer who completed adjuvant treatment were randomised to Poly E 400 mg (n = 16), 600 mg (n = 11) and 800 mg (n = 3) twice daily or matching placebo (n = 10) for 6 months. Blood and urine collection occurred at baseline, and at 2, 4 and 6 months. Biological endpoints included growth factor [serum hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF)], lipid (serum cholesterol, triglycerides), oxidative damage and inflammatory biomarkers. RESULTS: From July 2007-August 2009, 40 women were enrolled and 34 (26 Poly E, eight placebo) were evaluable for biomarker endpoints. At 2 months, the Poly E group (all dose levels combined) compared to placebo had a significant decrease in mean serum HGF levels (-12.7% versus +6.3%, P = 0.04). This trend persisted at 4 and 6 months but was no longer statistically significant. For the Poly E group, serum VEGF decreased by 11.5% at 2 months (P = 0.02) and 13.9% at 4 months (P = 0.05) but did not differ compared to placebo. At 2 months, there was a trend toward a decrease in serum cholesterol with Poly E (P = 0.08). No significant differences were observed for other biomarkers. CONCLUSIONS: Our findings suggest potential mechanistic actions of tea polyphenols in growth factor signalling, angiogenesis and lipid metabolism.

Characterization of Fusarium Strains Recovered From Wheat With Symptoms of Head Blight in Kentucky.

Fusarium graminearum species complex (FGSC) members cause Fusarium head blight (FHB) of wheat (Triticum aestivum L.) and small grains in the United States. The U.S. population is diverse and includes several genetically distinct local emergent subpopulations, some more aggressive and toxigenic than the majority population. Kentucky is a transition zone between the Mid-Atlantic and Midwestern wheat production areas. Sixty-eight Fusarium strains were isolated from symptomatic wheat heads from central and western Kentucky and southern Indiana in 2007. A multilocus genotyping assay and a variety of additional molecular markers, including some novel markers developed using the F. graminearum genome sequence, were used to characterize the pathogen population. Five of the isolates were identified as members of two non-FGSC species, F. acuminatum and F. cf. reticulatum, but they did not cause symptoms in greenhouse tests. All the FGSC isolates belonged to the 15-ADON chemotype of F. graminearum. Comparative genetic analysis using variable nuclear tandem repeat (VNTR) markers indicated that the population in Kentucky and Indiana belonged to the dominant North American population, with some diversification likely due to local evolution. Telomere and RFLP fingerprinting markers based on repetitive sequences revealed a high degree of genetic diversity within the population, with unique genotypes found at each location, and multiple genotypes isolated from the same head.

Germline genetic variants in ABCB1, ABCC1 and ALDH1A1, and risk of hematological and gastrointestinal toxicities in a SWOG Phase III trial S0221 for breast cancer.

Hematological and gastrointestinal toxicities are common among patients treated with cyclophosphamide and doxorubicin for breast cancer. To examine whether single-nucleotide polymorphisms (SNPs) in key pharmacokinetic genes were associated with risk of hematological or gastrointestinal toxicity, we analyzed 78 SNPs in ABCB1, ABCC1 and ALDH1A1 in 882 breast cancer patients enrolled in the SWOG trial S0221 and treated with cyclophosphamide and doxorubicin. A two-SNP haplotype in ALDH1A1 was associated with an increased risk of grade 3 and 4 hematological toxicity (odds ratio=1.44, 95% confidence interval=1.16-1.78), which remained significant after correction for multiple comparisons. In addition, four SNPs in ABCC1 were associated with gastrointestinal toxicity. Our findings provide evidence that SNPs in pharmacokinetic genes may have an impact on the development of chemotherapy-related toxicities. This is a necessary first step toward building a clinical tool that will help assess risk of adverse outcomes before undergoing chemotherapy.

A Coordinated Effort to Manage Soybean Rust in North America: A Success Story in Soybean Disease Monitoring.

Existing crop monitoring programs determine the incidence and distribution of plant diseases and pathogens and assess the damage caused within a crop production region. These programs have traditionally used observed or predicted disease and pathogen data and environmental information to prescribe management practices that minimize crop loss. Monitoring programs are especially important for crops with broad geographic distribution or for diseases that can cause rapid and great economic losses. Successful monitoring programs have been developed for several plant diseases, including downy mildew of cucurbits, Fusarium head blight of wheat, potato late blight, and rusts of cereal crops. A recent example of a successful disease-monitoring program for an economically important crop is the soybean rust (SBR) monitoring effort within North America. SBR, caused by the fungus Phakopsora pachyrhizi, was first identified in the continental United States in November 2004. SBR causes moderate to severe yield losses globally. The fungus produces foliar lesions on soybean (Glycine max) and other legume hosts. P. pachyrhizi diverts nutrients from the host to its own growth and reproduction. The lesions also reduce photosynthetic area. Uredinia rupture the host epidermis and diminish stomatal regulation of transpiration to cause tissue desiccation and premature defoliation. Severe soybean yield losses can occur if plants defoliate during the mid-reproductive growth stages. The rapid response to the threat of SBR in North America resulted in an unprecedented amount of information dissemination and the development of a real-time, publicly available monitoring and prediction system known as the Soybean Rust-Pest Information Platform for Extension and Education (SBR-PIPE). The objectives of this article are (i) to highlight the successful response effort to SBR in North America, and (ii) to introduce researchers to the quantity and type of data generated by SBR-PIPE. Data from this system may now be used to answer questions about the biology, ecology, and epidemiology of an important pathogen and disease of soybean.

Active symptom monitoring for premenopausal women with breast cancer initiating adjuvant endocrine therapy: Protocol for the SWOG S2010 randomized controlled efficacy trial.

BACKGROUND: Premenopausal women with early stage, high risk hormone receptor positive breast cancer are at risk of early discontinuation of adjuvant endocrine therapy (ET), primarily because of toxicity, which can increase the risk of disease recurrence and death. We hypothesize that identification of bothersome symptoms between clinic visits, and automated notification of clinicians about symptoms, will result in improved persistence with ET. METHODS: Pre- and perimenopausal women planning to receive adjuvant treatment with tamoxifen or an aromatase inhibitor plus ovarian function suppression or ablation for treatment of breast cancer are eligible. A total of 540 participants will be enrolled and randomized 1:1 to patient education with or without Active Symptom Monitoring (ASM). The ASM intervention includes 6 symptom questions (hot flashes, sadness, anxiety, insomnia, vaginal dryness, joint pain) that will be completed via text, email, or telephone weekly for 24 weeks, then every 4 weeks for 48 weeks. All participants will complete a battery of questionnaires every 12 weeks to examine symptoms, beliefs about medicine, self-efficacy, and ET adherence. Optional blood draws will be collected at baseline and after 12, 48, and 72 weeks of therapy to examine estradiol and ET concentrations. The primary endpoint is time to nonpersistence with initially prescribed ET within the first 72 weeks, evaluated using Kaplan-Meier plots and multivariable Cox regression. CONCLUSION: We expect early identification and management of ET-related toxicities to improve persistence with breast cancer therapy, breast cancer outcomes, and quality of life for premenopausal women at high risk of breast cancer recurrence. CLINICALTRIALS: govNCT05568472.

Making Informed Choices On Incorporating Chemoprevention into carE (MiCHOICE, SWOG 1904): Design and methods of a cluster randomized controlled trial.

INTRODUCTION: Women with atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS) have a significantly increased risk of breast cancer, which can be substantially reduced with antiestrogen therapy for chemoprevention. However, antiestrogen therapy for breast cancer risk reduction remains underutilized. Improving knowledge about breast cancer risk and chemoprevention among high-risk patients and their healthcare providers may enhance informed decision-making about this critical breast cancer risk reduction strategy. METHODS/DESIGN: We are conducting a cluster randomized controlled trial to evaluate the effectiveness and implementation of patient and provider decision support tools to improve informed choice about chemoprevention among women with AH or LCIS. We have cluster randomized 26 sites across the U.S. through the SWOG Cancer Research Network. A total of 415 patients and 200 healthcare providers are being recruited. They are assigned to standard educational materials alone or combined with the web-based decision support tools. Patient-reported and clinical outcomes are assessed at baseline, after a follow-up visit at 6 months, and yearly for 5 years. The primary outcome is chemoprevention informed choice after the follow-up visit. Secondary endpoints include other patient-reported outcomes, such as chemoprevention knowledge, decision conflict and regret, and self-reported chemoprevention usage. Barriers and facilitators to implementing decision support into clinic workflow are assessed through patient and provider interviews at baseline and mid-implementation. RESULTS/DISCUSSION: With this hybrid effectiveness/implementation study, we seek to evaluate if a multi-level intervention effectively promotes informed decision-making about chemoprevention and provide valuable insights on how the intervention is implemented in U.S. TRIAL REGISTRATION: NCT04496739.

Safety and efficacy of neratinib (HKI-272) plus vinorelbine in the treatment of patients with ErbB2-positive metastatic breast cancer pretreated with anti-HER2 therapy.

BACKGROUND: Neratinib (HKI-272) is a potent irreversible pan-ErbB tyrosine kinase inhibitor with clinical activity in patients with ErbB2/HER2-positive breast cancer. PATIENTS AND METHODS: Phase I of this open-label, phase I/II study investigated the maximum tolerated dose (MTD) of oral neratinib (160 or 240 mg/day) plus vinorelbine (25 mg/m2; days 1 and 8 of each 21-day cycle) in patients with solid tumors. Phase II assessed the safety, clinical activity, and pharmacokinetics of the combination in patients with HER2-positive metastatic breast cancer; the primary efficacy end point was objective response (OR). RESULTS: In phase I (n=12), neratinib (240 mg) plus vinorelbine (25 mg/m2) was established as the MTD. In phase II, 79 patients with HER2-positive metastatic breast cancer were treated at the MTD. The most common treatment-related adverse events were diarrhea (96%), neutropenia (54%), and nausea (50%). Three patients discontinued treatment due to diarrhea. No clinically important skin side-effects were observed. The OR rate in assessable phase II patients was 41% (no prior lapatinib) and 8% (prior lapatinib). There was no evidence of pharmacokinetic interaction between neratinib and vinorelbine. CONCLUSION: Neratinib plus vinorelbine showed promising antitumor activity and no unexpected toxic effects in HER2-positive metastatic breast cancer patients. Trial registration ClinicalTrials.gov #NCT00706030.

Toxicity burden score: a novel approach to summarize multiple toxic effects.

BACKGROUND: Toxicity data from cancer trials are summarized into a single outcome, dose-limiting toxicity (DLT), which does not account for multiple lower grade toxic effects nor differentiates between toxicity types and gradations within DLT. METHODS: Toxicity data were summarized into a toxicity burden score (TBS) using a weighted sum. The severity weights were estimated via regression using historical data. We demonstrated the method using historical data from a bortezomib trial and illustrated the advantages of defining DLT based on TBS in a simulated dose-finding trial. RESULTS: The estimated weights were 0.17, 0.40 and 0.85 for grade 1/2, grade 3 and grade 4 platelets, respectively; 0.19, 0.64, 1.03 and 2.53 for grade 1, 2, 3 and 4 neuropathy, respectively and 0.17 for each grade 3 or higher nonhematologic toxic effects unrelated to treatment. In the simulated trial, the probability of selecting doses above the maximum tolerated dose decreased when using the DLT defined based on TBS. CONCLUSIONS: TBS is a feasible approach to summarize toxicity. It includes information from the grades and types of multiple toxic effects and can be applied in all phases of drug development. Further efforts should focus on validating the method in a large prospective study before applying it in practice.

Influence of health insurance, hospital factors and physician volume on receipt of immediate post-mastectomy reconstruction in women with invasive and non-invasive breast cancer.

For women with breast cancer who undergo mastectomy, immediate breast reconstruction (IR) offers a cosmetic and psychological advantage. We evaluated the association between demographic, hospital, surgeon and insurance factors and receipt of IR. We conducted a retrospective hospital-based analysis with the Perspective database. Women who underwent a mastectomy for invasive breast cancer (IBC) and ductal carcinoma in situ (DCIS) from 2000 to 2010 were included. Logistic regression analysis was used to determine factors predictive of IR. Analyses were stratified by age (<50 vs. ≥ 50) and IBC versus DCIS. Of the 108,992 women with IBC who underwent mastectomy, 30,859 (28.3 %) underwent IR, as compared to 6,501 (44.2 %) of the 14,710 women with DCIS who underwent mastectomy underwent IR. In a multivariable model for IBC, increasing age, black race, being married, rural location, and increased comorbidities were associated with decreased IR. Odds ratios (OR) of IR increased with commercial insurance (OR 3.38) and Medicare (OR 1.66) insurance (vs. self-pay), high surgeon-volume (OR 1.19), high hospital-volume (OR 2.24), and large hospital size (OR 1.20). The results were identical for DCIS, and by age category. The absolute difference between the proportion of patients who received IR with commercial insurance compared to other insurance, increased over time. Immediate in-hospital complication rates were higher for flap reconstruction compared to implant or no reconstruction (15.2, 4.0, and 6.1 %, respectively, P < .0001). IR has increased significantly over time; however, modifiable factors such as insurance status, hospital size, hospital location, and physician volume strongly predict IR. Public policy should ensure that access to reconstructive surgery is universally available.

Phase I-II study of vorinostat plus paclitaxel and bevacizumab in metastatic breast cancer: evidence for vorinostat-induced tubulin acetylation and Hsp90 inhibition in vivo.

In preclinical models, the histone deacetylase inhibitor vorinostat sensitizes breast cancer cells to tubulin-polymerizing agents and to anti-vascular endothelial growth factor-directed therapies. We sought to determine the safety and efficacy of vorinostat plus paclitaxel and bevacizumab as first-line therapy in metastatic breast cancer (MBC), and the biological effects of vorinostat in vivo. For this purpose of this study, 54 patients with measurable disease and no prior chemotherapy for MBC received vorinostat (200 or 300 mg PO BID) on days 1-3, 8-10, and 15-17, plus paclitaxel (90 mg/m(2)) on days 2, 9, 16, and bevacizumab (10 mg/kg) on days 2 and 16 every 28 days. The primary objective of the phase I study was to determine the recommended phase II dose (RPTD) of vorinostat, and for the phase II to detect an improvement of response rate from 40 to 60% (alpha = 0.10, beta = 0.10). No dose limiting toxicities were observed, and the RPTD of vorinostat was 300 mg BID. For the primary efficacy analysis in 44 patients at the RPTD, we observed 24 objective responses (55%, 95% confidence intervals (C.I) 39%, 70%). The adverse event profile was consistent with paclitaxel-bevacizumab, with the exception of increased diarrhea with the addition of vorinostat. Analysis of serial tumor biopsies in seven patients showed increased acetylation of Hsp90 and α-tubulin following vorinostat. Vorinostat induces histone and alpha tubulin acetylation and functional inhibition of Hsp90 in breast cancer in vivo and can be safely combined with paclitaxel and bevacizumab.

Efficacy and Stability of Integrating Fungicide and Cultivar Resistance to Manage Fusarium Head Blight and Deoxynivalenol in Wheat.

Integration of host resistance and prothioconazole + tebuconazole fungicide application at anthesis to manage Fusarium head blight (FHB) and deoxynivalenol (DON) in wheat was evaluated using data from over 40 trials in 12 U.S. states. Means of FHB index (index) and DON from up to six resistance class-fungicide management combinations per trial (susceptible treated [S_TR] and untreated [S_UT]; moderately susceptible treated [MS_TR] and untreated [MS_UT]; moderately resistant treated [MR_TR] and untreated [MR_UT]) were used in multivariate meta-analyses, and mean log response ratios across trials were estimated and transformed to estimate mean percent control ( ) due to the management combinations relative to S_UT. All combinations led to a significant reduction in index and DON (P < 0.001). MR_TR was the most effective combination, with a of 76% for index and 71% for DON, followed by MS_TR (71 and 58%, respectively), MR_UT (54 and 51%, respectively), S_TR (53 and 39%, respectively), and MS_UT (43 and 30%, respectively). Calculations based on the principle of treatment independence showed that the combination of fungicide application and resistance was additive in terms of percent control for index and DON. Management combinations were ranked based on percent control relative to S_UT within each trial, and nonparametric analyses were performed to determine management combination stability across environments (trials) using the Kendall coefficient of concordance (W). There was a significant concordance of management combinations for both index and DON (P < 0.001), indicating a nonrandom ranking across environments and relatively low variability in the within-environment ranking of management combinations. MR_TR had the highest mean rank (best control relative to S_UT) and was one of the most stable management combinations across environments, with low rank stability variance (0.99 for index and 0.67 for DON). MS_UT had the lowest mean rank (poorest control) but was also one of the most stable management combinations. Based on Piepho's nonparametric rank-based variance homogeneity U test, there was an interaction of management combination and environment for index (P = 0.011) but not for DON (P = 0.147), indicating that the rank ordering for index depended somewhat on environment. In conclusion, although the magnitude of percent control will likely vary among environments, integrating a single tebuconazole + prothioconazole application at anthesis with cultivar resistance will be a more effective and stable management practice for both index and DON than either approach used alone.

Meta-analysis of the effects of triazole-based fungicides on wheat yield and test weight as influenced by Fusarium head blight intensity.

ABSTRACT Multivariate random-effects meta-analyses were conducted on 12 years of data from 14 U.S. states to determine the mean yield and test-weight responses of wheat to treatment with propiconazole, prothioconazole, tebuconazole, metconazole, and prothioconazole+tebuconazole. All fungicides led to a significant increase in mean yield and test weight relative to the check (D; P < 0.001). Metconazole resulted in the highest overall yield increase, with a D of 450 kg/ha, followed by prothioconazole+ tebuconazole (444.5 kg/ha), prothioconazole (419.1 kg/ha), tebuconazole (272.6 kg/ha), and propiconazole (199.6 kg/ha). Metconazole, prothioconazole+tebuconazole, and prothioconazole also resulted in the highest increases in test weight, with D values of 17.4 to 19.4 kg/m(3), respectively. On a relative scale, the best three fungicides resulted in an overall 13.8 to 15.0% increase in yield but only a 2.5 to 2.8% increase in test weight. Except for prothioconazole+tebuconazole, wheat type significantly affected the yield response to treatment; depending on the fungicide, D was 110.0 to 163.7 kg/ha higher in spring than in soft-red winter wheat. Fusarium head blight (FHB) disease index (field or plot-level severity) in the untreated check plots, a measure of the risk of disease development in a study, had a significant effect on the yield response to treatment, in that D increased with increasing FHB index. The probability was estimated that fungicide treatment in a randomly selected study will result in a positive yield increase (p(+)) and increases of at least 250 and 500 kg/ha (p(250) and p(500), respectively). For the three most effective fungicide treatments (metconazole, prothioconazole+tebuconazole, and prothioconazole) at the higher selected FHB index, p(+) was very large (e.g., >/=0.99 for both wheat types) but p(500) was considerably lower (e.g., 0.78 to 0.92 for spring and 0.54 to 0.68 for soft-red winter wheat); at the lower FHB index, p(500) for the same three fungicides was 0.34 to 0.36 for spring and only 0.09 to 0.23 for soft-red winter wheat.

Phase II trial of the farnesyltransferase inhibitor tipifarnib plus fulvestrant in hormone receptor-positive metastatic breast cancer: New York Cancer Consortium Trial P6205.

BACKGROUND: Fulvestrant produces a clinical benefit rate (CBR) of approximately 45% in tamoxifen-resistant, hormone receptor (HR)-positive metastatic breast cancer (MBC) and 32% in aromatase inhibitor (AI)-resistant disease. The farnesyltransferase inhibitor tipifarnib inhibits Ras signaling and has preclinical and clinical activity in endocrine therapy-resistant disease. The objective of this study was to determine the efficacy and safety of tipifarnib-fulvestrant combination in HR-positive MBC. PATIENTS AND METHODS: Postmenopausal women with no prior chemotherapy for metastatic disease received i.m. fulvestrant 250 mg on day 1 plus oral tipifarnib 300 mg twice daily on days 1-21 every 28 days. The primary end point was CBR. RESULTS: The CBR was 51.6% [95% confidence interval (CI) 34.0% to 69.2%] in 31 eligible patients and 47.6% (95% CI 26.3% to 69.0%) in 21 patients with AI-resistant disease. A futility analysis indicated that it was unlikely to achieve the prespecified 70% CBR. Tipifarnib dose modification was required in 8 of 33 treated patients (24%). CONCLUSIONS: The target CBR of 70% for the tipifarnib-fulvestrant combination in HR-positive MBC was set too high and was not achieved. The 48% CBR in AI-resistant disease compares favorably with the 32% CBR observed with fulvestrant alone in prior studies and merit further clinical and translational evaluation.

Efficacy of triazole-based fungicides for fusarium head blight and deoxynivalenol control in wheat: a multivariate meta-analysis.

The effects of propiconazole, prothioconazole, tebuconazole, metconazole, and prothioconazole+tebuconazole (as a tank mix or a formulated premix) on the control of Fusarium head blight index (IND; field or plot-level disease severity) and deoxynivalenol (DON) in wheat were determined. A multivariate random-effects meta-analytical model was fitted to the log-transformed treatment means from over 100 uniform fungicide studies across 11 years and 14 states, and the mean log ratio (relative to the untreated check or tebuconazole mean) was determined as the overall effect size for quantifying fungicide efficacy. Mean log ratios were then transformed to estimate mean percent reduction in IND and DON relative to the untreated check (percent control: C(IND) and C(DON)) and relative to tebuconazole. All fungicides led to a significant reduction in IND and DON (P < 0.001), although there was substantial between-study variability. Prothioconazole+tebuconazole was the most effective fungicide for IND, with a C(IND) of 52%, followed by metconazole (50%), prothioconazole (48%), tebuconazole (40%), and propiconazole (32%). For DON, metconazole was the most effective treatment, with a [Formula: see text](DON) of 45%; prothioconazole+tebuconazole and prothioconazole showed similar efficacy, with C(DON) values of 42 and 43%, respectively; tebuconazole and propiconazole were the least effective, with C(DON) values of 23 and 12%, respectively. All fungicides, with the exception of propiconazole, were significantly more effective than tebuconazole for control of both IND and DON (P < 0.001). Relative to tebuconazole, prothioconazole, metconazole, and tebuconzole+prothioconzole reduced disease index a further 14 to 20% and DON a further 25 to 29%. In general, fungicide efficacy was significantly higher for spring wheat than for soft winter wheat studies; depending on the fungicide, the difference in percent control between spring and soft winter wheat was 5 to 20% for C(IND) and 7 to 16% for C(DON). Based on the mean log ratios and between-study variances, the probability that IND or DON in a treated plot from a randomly selected study was lower than that in the check by a fixed margin was determined, which confirmed the superior efficacy of prothioconazole, metconazole, and tebuconzole+prothioconzole for Fusarium head blight disease and toxin control.

Soybean Cyst Nematode, Heterodera glycines, Populations Adapting to Resistant Soybean Cultivars in Kentucky.

Soybean cyst nematode (SCN), Heterodera glycines, is the most limiting biotic factor of soybean (Glycine max) production in Kentucky (KY). Unpublished results of a survey of commercial soybean fields in KY in the late 1980s indicated that H. glycines (HG) type 0 (race 3) was the most common HG type in the state. HG type 0 populations cannot reproduce (female index [FI] <10% compared with reproduction on a standard susceptible cultivar) on PI88788, which is the basis of H. glycines resistance in >90% of the soybean cultivars grown in the United States. Recent reports from Illinois (4), Missouri (3), and North Carolina (2) indicate that most populations of H. glycines in those states are now able to reproduce on resistant soybean cultivars derived from PI88788. Because cultivars derived from PI88788 are grown almost exclusively in KY to manage H. glycines, a limited survey was needed to update information on H. glycines populations. Most soybean fields in KY are grown in a 1-year rotation with corn (Zea mays), a nonhost crop for H. glycines. Therefore, the survey targeted fields that had most recently been in corn. Otherwise, fields were arbitrarily selected for sampling. Composite samples were collected in the fall of 2006 or the spring of 2007 and consisted of 20 soil cores (10 to 15 cm deep × 2.5 cm in diameter) collected following a zigzag pattern. Samples were mixed and stored at 4°C until processing. H. glycines cysts were extracted from soil by a sucrose centrifugation and flotation technique (1). Eggs were liberated by crushing cysts caught on a sieve (250-µm-diameter pores) with a rubber stopper. Liberated eggs were then collected, stained with acid fuchsin, and counted. Up to three samples from each county surveyed were sent to the University of Missouri Nematology Laboratory, Columbia, MO for HG type testing (3). A total of 139 samples, representing 19 major soybean-production counties in KY, were analyzed for H. glycines levels. H. glycines eggs were recovered from 106 (76%) samples and 16 (84%) counties. SCN population densities ranged from 38 to 4,275 eggs per 250 cm3 of soil. HG type tests were conducted on 20 populations from eight counties. HG types 1.2.5.7 (race 2) and 2.5.7 (race 1 or 5) were identified, with HG type 2.5.7 (race 1) being the most common (60% of populations screened). No HG type 0 populations were detected. All populations tested had a FI ≥10% on three of nine indicator lines (PI88788, PI209322, and PI548316). FIs on these indicators ranged from 15 to 80, 11 to 81, and 23 to 88%, respectively. Sixty percent of populations tested had FIs ≥30% on PI88788. Of the populations screened, 25 and 35% had FIs ≥10% on PI548402 (Peking) and Pickett, respectively. All populations tested had FIs = 0 on PI437654. Survey results indicate that cultivars deriving their H. glycines resistance from PI88788 may have reduced effectiveness in suppressing current H. glycines populations in KY. Consequently, producers may need to grow soybean cultivars derived from non-PI88788 resistance sources to successfully manage H. glycines in the future. References: (1) D. E. Hershman et al. Plant Dis. 74:761, 1990. (2) S. R. Koenning. Plant Dis. 88:942, 2004. (3) M. G. Mitchum et al. Plant Dis. 91:1473, 2007. (4) T. L. Niblack et al. Online publication. doi:10.1094/PHP-2008-0118-01-RS. Plant Health Progress, 2008.

Pre-surgical trial of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer: a New York Cancer Consortium trial.

INTRODUCTION: The PI3K/AKT/mTOR pathway is an oncogenic driver in breast cancer (BC). In this multi-center, pre-surgical study, we evaluated the tissue effects of the AKT inhibitor MK-2206 in women with stage I-III BC. MATERIALS AND METHODS: Two doses of weekly oral MK2206 were administered at days - 9 and - 2 before surgery. The primary endpoint was reduction of pAktSer473 in breast tumor tissue from diagnostic biopsy to surgery. Secondary endpoints included changes in PI3K/AKT pathway tumor markers, tumor proliferation (ki-67), insulin growth factor pathway blood markers, pharmacokinetics (PK), genomics, and MK-2206 tolerability. Paired t tests were used to compare biomarker changes in pre- and post-MK-2206, and two-sample t tests to compare with prospectively accrued untreated controls. RESULTS: Despite dose reductions, the trial was discontinued after 12 patients due to grade III rash, mucositis, and pruritus. While there was a trend to reduction in pAKT after MK-2206 (p = 0.06), there was no significant change compared to controls (n = 5, p = 0.65). After MK-2206, no significant changes in ki-67, pS6, PTEN, or stathmin were observed. There was no significant association between dose level and PK (p = 0.11). Compared to controls, MK-2206 significantly increased serum glucose (p = 0.02), insulin (p < 0.01), C-peptide (p < 0.01), and a trend in IGFBP-3 (p = 0.06). CONCLUSION: While a trend to pAKT reduction after MK-2206 was observed, there was no significant change compared to controls. However, the accrued population was limited, due to toxicity being greater than expected. Pre-surgical trials can identify in vivo activity in the early drug development, but side effects must be considered in this healthy population.

A quantitative review of tebuconazole effect on fusarium head blight and deoxynivalenol content in wheat.

ABSTRACT A meta-analysis of the effect of tebuconazole (e.g., Folicur 3.6F) on Fusarium head blight and deoxynivalenol (DON) content of wheat grain was performed using data collected from uniform fungicide trials (UFTs) conducted at multiple locations across U.S. wheat-growing regions. Response ratios (mean disease and DON levels from tebuconazole-treated plots, divided by mean disease and DON levels from untreated check plots) were calculated for each of 139 studies for tebuconazole effect on Fusarium head blight index (IND; field or plot-level disease severity, i.e., mean proportion of diseased spikelets per spike) and 101 studies for tebuconazole effect on DON contamination of harvested grain. A random-effects meta-analysis was performed on the log-transformed ratios, and the estimated mean log ratios were transformed to estimate the mean (expected) percent control for IND ( C(IND) ) and DON ( C(DON)). A mixed effects meta-analysis was then done to determine the effects of wheat type (spring versus winter wheat) and disease and DON levels in the controls on the log ratios. Tebuconazole was more effective at limiting IND than DON, with C(IND) and C(DON) values of 40.3 and 21.6%, respectively. The efficacy of tebuconazole as determined by the impact on both IND and DON was greater in spring wheat than in winter wheat (P < 0.01), with a 13.2% higher C(IND) and a 12.4% higher C(DON) in spring wheat than in winter wheat. In general, C(IND) and C(DON) were both at their lowest values (and not significantly different from 0) when mean IND and DON in the controls, respectively, were low (