Radical Perfluoroalkylation of Arenes via Carbanion Intermediates.

The use of sodium dithionite with perfluoroalkyl iodides under basic conditions facilitates the direct perfluoroalkylation of arenes with pendant benzylic electron-withdrawing groups. This occurs via attack of the arene on the electrophilic perfluoroalkyl radical, through the donation of electron density from a benzylic anion. The substrate scope was expanded beyond benzylic nitriles with cyclic substrates bearing electron-withdrawing groups at the benzylic position-enforcing donation of electron density to the aromatic ring and enabling attack on the perfluoroalkyl radical.

Palladium(0)-Catalyzed Directed syn-1,2-Carboboration and -Silylation: Alkene Scope, Applications in Dearomatization, and Stereocontrol by a Chiral Auxiliary.

We report the development of palladium(0)-catalyzed syn-selective 1,2-carboboration and -silylation reactions of alkenes containing cleavable directing groups. With B2 pin2 or PhMe2 Si-Bpin as nucleophiles and aryl/alkenyl triflates as electrophiles, a broad range of mono-, di-, tri- and tetrasubstituted alkenes are compatible in these transformations. We further describe a directed dearomative 1,2-carboboration of electron-rich heteroarenes by employing this approach. Through use of a removable chiral directing group, we demonstrate the viability of achieving stereoinduction in Heck-type alkene 1,2-difunctionalization. This work introduces new avenues to access highly functionalized boronates and silanes with precise regio- and stereocontrol.

Improving Robustness: In Situ Generation of a Pd(0) Catalyst for the Cyanation of Aryl Bromides.

Conditions have been developed for the palladium-catalyzed cyanation of aryl bromides utilizing the air-stable XantPhos-PdCl2 precatalyst. By employing a trialkylamine as a reducing agent, the active Pd(0) species is generated in situ, alleviating the need to employ the air-sensitive Pd2(dba)3. Twenty-two substituted benzonitriles have been synthesized using this method.

Catalytic Enantioselective Functionalization of Unactivated Terminal Alkenes.

Terminal alkenes are readily available functional groups which appear in α-olefins produced by the chemical industry, and they appear in the products of many contemporary synthetic reactions. While the organic transformations that apply to alkenes are amongst the most studied reactions in all of chemical synthesis, the number of reactions that apply to nonactivated terminal alkenes in a catalytic enantioselective fashion is small in number. This Minireview highlights the cases where stereocontrol in catalytic reactions of 1-alkenes is high enough to be useful for asymmetric synthesis.

Enantiomerically enriched tris(boronates): readily accessible conjunctive reagents for asymmetric synthesis.

The catalytic enantioselective diboration of vinyl boronate esters furnishes chiral tris(boronates) in a selective fashion. Subsequent deborylative alkylation occurs in a diastereoselective fashion, both for intermolecular and intramolecular processes.

Scope and mechanism of the Pt-catalyzed enantioselective diboration of monosubstituted alkenes.

The Pt-catalyzed enantioselective diboration of terminal alkenes can be accomplished in an enantioselective fashion in the presence of chiral phosphonite ligands. Optimal procedures and the substrate scope of this transformation are fully investigated. Reaction progress kinetic analysis and kinetic isotope effects suggest that the stereodefining step in the catalytic cycle is olefin migratory insertion into a Pt-B bond. Density functional theory analysis, combined with other experimental data, suggests that the insertion reaction positions platinum at the internal carbon of the substrate. A stereochemical model for this reaction is advanced that is in line both with these features and with the crystal structure of a Pt-ligand complex.

Discovery of Annulating Reagents Enabling the One-Step and Highly Stereoselective Synthesis of Cyclopentyl and Cyclohexyl Cores.

The use of the unprecedented annulating reagents methyl N-(tert-butylsulfinyl)-4-chlorobutanimidate and methyl N-(tert-butylsulfinyl)-5-bromopentanimidate enables the diastereoselective preparation of 5- and 6-membered carbocycles bearing three contiguous stereocenters. These synthons undergo cycloaddition with a variety of Michael acceptors to form cyclopentane/cyclohexane rings with excellent stereochemical control, generating only one of the eight possible diastereomers. This novel methodology has enabled the highly enantioselective and high yielding synthesis of novel chemotypes of pharmacological relevance.

Budgetary impact of treatment with adjuvant imatinib for 1 year following surgical resection of Kit-positive localized gastrointestinal stromal tumors.

BACKGROUND: Imatinib mesylate, an orally administered kinase inhibitor that targets the Kit (CD117) protein, currently has 10 approved indications including treatment of chronic myelogenous leukemia and metastatic gastrointestinal stromal tumors (GIST). Treatment with adjuvant imatinib following surgical resection of localized Kit-positive GIST, the most recent FDA-approved indication (December 2008), has been shown to significantly improve recurrence-free survival (RFS) compared with surgical resection alone. Although adjuvant imatinib has proven effective in clinical trials, it is important to consider the economic impact to health plans of introducing imatinib in accordance with its new labeled indication. OBJECTIVE: To evaluate the budgetary impact over a 3-year time horizon of treating patients with localized Kit-positive GIST with 1 year of adjuvant imatinib following surgical resection. METHODS: A Markov model was developed to predict patients' transitions across health states defined by initial treatment (surgical resection followed by adjuvant imatinib 400 milligrams [mg] daily versus surgical resection alone), recurrence, and progression. Treatments for a first recurrence were (a) imatinib 400 mg daily for recurrences following resection only or after completion of 1 year of treatment with imatinib 400 mg daily and (b) imatinib 800 mg daily for recurrence during active treatment with imatinib 400 mg daily. Treatments for further progression were imatinib 800 mg daily, sunitinib, or best supportive care (BSC) following imatinib 400 mg per day, and sunitinib or BSC following imatinib 800 mg daily. Recurrence rates were derived from the American College of Surgeons Oncology Group (ACOSOG) Z9001 clinical trial, which compared 1 year of adjuvant imatinib following surgical resection with surgical resection only. The total number of patients with localized and surgically resected GIST (incidence rate of 0.36 per 100,000) was estimated from epidemiologic studies of GIST. Uptake of treatment with imatinib was estimated from unpublished data from qualitative market research funded by the study sponsor. The uptake rate assumptions reflected both (a) the percentage of patients with Kitpositive disease and (b) the percentage of clinically eligible patients who would use imatinib. Costs were estimated by combining unit costs from published sources with expected resource utilization based on the clinical trial publication and National Comprehensive Cancer Network guidelines on the treatment of patients with GIST. To obtain estimates of the budgetary impact, we compared estimated health care costs with versus without adjuvant imatinib, where health care costs with imatinib reflected the costs of treatment minus cost offsets associated with delayed or avoided recurrence or progression. All "with" scenarios assumed no additional uses other than surgically resected localized Kit-positive GIST (i.e., no change in off-label use of imatinib). The budgetary impact was estimated for the first 3 years after the introduction of adjuvant imatinib in accordance with its new labeled indication in a hypothetical plan population of 10 million persons. Results were calculated both as total budgetary impact and as per member per month (PMPM) cost in 2009 dollars. Sensitivity analyses were performed to test the robustness of model results to changes in parameter estimates. RESULTS: The model predicted 36 incident resected GIST cases per year in a health plan of 10 million members. The estimated counts of cases treated with adjuvant imatinib were 10.8, 16.2, and 21.6 in the first, second, and third years after introduction, respectively, with the annual increases attributable to changes in the proportion of patients with resected GIST assumed to use imatinib (30% in year 1, rising to 45% in year 2 and 60% in year 3). The model predicted that treatment of these cases with imatinib will increase pharmacy costs by an additional $505,144 in the first year, $757,717 in the second year, and $1,010,289 in the third year. Increased resource use associated with monitoring patients during and after treatment with adjuvant imatinib would cost an additional $21,564, $38,145, and $56,605 in the first, second, and third years, respectively. Recurrence would be avoided or delayed in 7 patients over the 3-year period. Avoided or delayed recurrences would result in cost offsets of $61,583 in the first year, $156,702 in the second year, and $233,849 in the third year. The net budgetary impact was estimated to be $465,126 in the first year (less than $0.01 PMPM), $639,159 in the second year ($0.01 PMPM), and $833,044 in the third year ($0.01 PMPM). Results of sensitivity analyses indicated that the budgetary impact in the third year is most sensitive to changes in the price of adjuvant imatinib and recurrence rates. CONCLUSIONS: The model predicted that the introduction of adjuvant imatinib for treatment of surgically resected, localized, Kit-positive GIST will lead to a net budgetary impact of $0.01 PMPM in the third year after introduction assuming change in use only in accordance with the new labeled indication. Approximately 11.7%-21.9% of the cost of adjuvant imatinib is offset by the reduction in costs associated with GIST recurrence.

One-Step Diastereoselective Pyrrolidine Synthesis Using a Sulfinamide Annulating Reagent.

This communication highlights the use of chiral sulfinamides as nitrogen nucleophiles in intermolecular aza-Michael reactions. When chiral sulfinamides are coupled to a chloroethyl group, the corresponding novel annulating reagents can be used to streamline the stereoselective synthesis of complex pyrrolidine-containing molecules. As a result, it has enabled a medicinal chemistry campaign for the synthesis of biologically active RORγt inverse agonists.

Survey correlations: proficiency and adequacy of nutrition training of medical students.

OBJECTIVE: The majority of graduating US medical students reported inadequate nutrition training over the past decade. This trend could in part be due to the lack of valid measures to assess the relationship between adequacy of nutrition training and proficiency on nutrition topics deemed essential. The study's objective was to test the hypothesis that self-reported nutrition proficiency is positively correlated with the perceived adequacy (quality, quantity, coverage and importance) of nutrition training of University of Washington medical students. METHOD: Cross-sectional e-mail survey of 1st to 4th year medical students (n = 708), including a survey prompt and three e-mail follow-up measures. To reduce and interpret the survey data, principal components analysis was employed, followed by Varimax rotation with Kaiser normalization. To assess internal consistency reliability, alpha (alpha) of nutrition proficiency items and factors was determined. RESULTS: A 44.5% response rate was achieved (n = 315 respondents). The 31-item questionnaire was reduced to 6 factors, explaining 60.2% of the total variance (alpha = 0.947). Self reported nutrition proficiency was positively correlated with the perceived quality, quantity and coverage of nutrition training in all 6 essential nutrition factors or topics determined after factor analysis (P < 0.01). CONCLUSION: Quality and coverage may be effective gauges of adequacy of nutrition training and related nutrition proficiency in medical education. Current national medical education evaluation measures focus on the quantity of nutrition instruction. The lowest reported proficiency topics; nutrition and disease management, micronutrients and complementary and alternative medicine are recommended for particular curricular emphasis.

Enantioselective Synthesis of Nonracemic Geminal Silylboronates by Pt-Catalyzed Hydrosilylation.

A Pt-catalyzed enantioselective hydrosilylation of alkenylboronates is described. This reaction occurs with high regio- and enantioselectivity, providing a convenient route to chiral non-racemic geminal silylboronates. These compounds are useful reagents in stereoselective synthesis.

Regional solutions to the physician workforce shortage: the WWAMI experience.

With major medical organizations predicting a national shortage of physicians in coming years, a number of institutional models are being considered to increase the numbers of medical students. At a time when the cost of building new medical schools is extremely expensive, many medical schools are considering alternative methods for expansion. One method is regional expansion. The University of Washington School of Medicine (UWSOM) has used regional expansion to extend medical education across five states without the need to build new medical schools or campuses. The WWAMI program (the acronym for Washington, Wyoming, Alaska, Montana, Idaho), which was developed in the early 1970s, uses existing state universities in five states for first-year education, the Seattle campus for second-year education, and clinical sites across all five states for clinical education. Advantages of regional expansion include increasing enrollment in a cost-effective fashion, increasing clinical training opportunities, responding to health care needs of surrounding regions and underserved populations, and providing new opportunities for community-based physicians to enhance their practice satisfaction. Challenges include finding basic-science faculty at regional sites with backgrounds appropriate to medical students, achieving educational equivalence across sites, and initiating new research programs. UWSOM's successful long-term regional development, recent expansion to Wyoming in 1997, and current consideration of adding a first-year site in Spokane, Washington, indicate that regional expansion is a viable option for expanding medical education.

Synthesis of vinyl boronates from aldehydes by a practical boron-Wittig reaction.

A highly stereoselective boron-Wittig reaction between stable and readily accessible 1,1-bis(pinacolboronates) and aldehydes furnishes a variety of synthetically useful di- and trisubstituted vinyl boronate esters.

Self-reported nutrition proficiency is positively correlated with the perceived quality of nutrition training of family physicians in Washington State.

BACKGROUND: Despite concerted scientific, educational, and congressional calls to increase nutrition coverage in medicine for more than half a century, most graduating medical students report an inadequate quality and quantity of nutrition training. Furthermore, practicing physicians report a lack of confidence and related proficiency in nutrition counseling skills because of inadequate training. Assessment of nutrition proficiency and related training of practicing physicians may support the prioritization of nutrition topics to be included in medical education. OBJECTIVE: We tested the hypothesis that the perceived adequacy of nutrition training (quality and quantity) of family physicians in Washington State is positively correlated with self-reported nutrition proficiency in 5 nutrition factors determined after confirmatory factor analysis. DESIGN: A randomized mail survey method (n = 778 possible respondents), which involved one mass-mailing follow-up, was used. RESULTS: A 39.3% response rate was achieved (n = 306 respondents). The 31-item questionnaire was reduced to 5 factors, explaining 48.5% of the total variance (alpha = 0.916). Perceived quality (poor to excellent) of nutrition training was positively correlated with self-reported nutrition proficiency scores for all 5 factors (P < 0.01). No significant differences were noted between zip code or sex and mean nutrition proficiency scores for all 5 factors. CONCLUSION: The examination of correlations between perceived quality of education and self-reported proficiency may be a useful gauge of effectiveness of nutrition training in medicine. Prioritization of nutrition information based on proficiency levels, including information on complementary and alternative medicines and nutritional management of disease, merits further investigation.

Physician informational needs in providing nutritional guidance to patients.

OBJECTIVES: This study's objective was to assess patient nutrition inquiries and related physician resources to identify the nutrition topics about which physicians most need information for patients and practice. METHODS: A survey was mailed to a 50% random sample of Washington Academy of Family Physicians (WAFP) members (n=778) to identify the top 10 patient nutrition inquiries that the physician would like to be better equipped to answer. The responding physicians' use of nutrition resources (journals, pamphlets, Web resources, toll-free numbers, and referrals to registered dietitians) was also recorded. RESULTS: A total of 306 (39.3%) physicians responded. The majority wanted more information on weight management (66.5%), followed by information on herbals, botanicals, and other complementary and alternative medicines (CAM) (36.4%) and vitamin and mineral supplements (24.4%). Other common nutrition inquiries for which respondents wanted more information included diet for prevention of disease, high protein-low carbohydrate diets, and childhood nutrition. A minority of respondents used nutrition Web resources and toll-free numbers. Nearly all respondents reported referring patients to registered dietitians. CONCLUSIONS: Physicians in our survey expressed a need for information on topics such as obesity, CAM, and life cycle and disease-specific diets. Medical nutrition educators should consider the educational needs of the practicing physician.

Compliance and refill pattern behavior with HMG-CoA reductase inhibitors after acute myocardial infarction.

Patients who had an acute myocardial infarction or other atherosclerotic event and had filled a prescription for an HMG-CoA reductase inhibitor were identified for analysis. Compliance was assessed using a multiple-interval refill compliance score. The mean compliance score was 80% and six refill patterns were identified. Regression analysis revealed three factors associated with compliance: (1) days' supply, (2) number of total concomitant medications, and (3) cost sharing. Strategies for improving compliance that may have merit include providing patients with 60- or 90-day supplies (rather than 30-day supplies), controlling the number of other medications prescribed, and lowering copayments for these important medications.

Enantioselective carbocycle formation through intramolecular Pd-catalyzed allyl-aryl cross-coupling.

Aryl electrophiles containing tethered allylboronate units undergo efficient intramolecular coupling in the presence of a chiral palladium catalyst to give enantioenriched carbocyclic products. The reaction is found to be quite general, affording 5, 6, and 7-membered carbocyclic products as single regioisomers and with moderate enantioselectivities. Examination of differential coupling partners points to rapid allyl-equilibration as a key stereodefining feature.

Comparison of different adjuvant therapies for 9 resectable cancer types.

PURPOSE: The objective of this study was to compare the clinical benefit across adjuvant therapies for cancer treatment, including adjuvant imatinib, and to quantify the results using the number-needed-to-treat (NNT) approach. METHOD: We reviewed studies meeting the following criteria: 1) US and European randomized clinical trial populations consisting of patients with cancer who underwent surgical resection of the primary tumor and were considered cancer free; 2) comparators were either placebo or no treatment; and 3) recurrence-free survival (RFS) and overall survival (OS) rates were reported and showed benefit with the experimental treatment. The NNT was calculated as the inverse of the difference in event rate between the study groups in each trial. RESULTS: We identified 26 adjuvant treatment trials in 9 cancer types. With longer follow-up (3 years vs 1 year), 62.5% of treatments compared with placebo showed a decreased RFS NNT, including imatinib (7 vs 4). The largest relative decrease in RFS NNT over time was 91% (with trastuzumab or cyclophosphamide therapy). Approximately 25% of the treatments resulted in an increase in RFS NNT over time. The RFS NNT for imatinib was lower than that for all other treatments at 3 years of follow-up and lower than that for all but 2 treatments at 1 year. At both year 1 and year 3, the NNT for OS ranged from 6 to 100. Imatinib had an OS NNT of 31 at 3 years. CONCLUSION: With longer follow-up duration, most adjuvant cancer treatments showed a decreased NNT. Imatinib had one of the lowest NNTs among the adjuvant treatments at 1 and 3 years of follow-up using the RFS data.

Cost-effectiveness of 3-years of adjuvant imatinib in gastrointestinal stromal tumors (GIST) in the United States.

BACKGROUND: Recent clinical trial data have demonstrated that 3 years vs 1 year of adjuvant imatinib therapy for patients with surgically resected Kit+ Gastrointestinal Stromal Tumors (GIST) leads to a significant improvement in recurrence-free survival and overall survival. This study assesses the cost-effectiveness of treating patients with 3 years vs 1 year of imatinib from a US payer's perspective. METHODS: A Markov model was developed to predict GIST recurrence and treatment costs. Patients enter the model after surgery and transition among three health states: free of recurrence, recurrence, and death. Recurrence, mortality, costs, and utilities were derived from clinical trial and published literature. Expected costs and quality-adjusted life years (QALYs) were estimated and discounted at 3%/year. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: Patients receiving 3 years of imatinib had higher QALYs (8.53 vs 7.18) than those receiving 1 year of imatinib. Total lifetime per-patient cost was $302,100 for 3 years vs $217,800 for 1 year of imatinib. Incremental cost effectiveness ratio of 3 years vs 1 year of imatinib was $62,600/QALY. Model results were sensitive to long-term rate of GIST recurrence (beyond 5 years) and cost of imatinib. At a threshold of $100,000/QALY, 3 years vs 1 year of imatinib was cost-effective in 100% of simulations. LIMITATIONS: The model is a simplified representation of disease natural history and may not account for all possible health states and complications associated with disease. Resource utilization on treatment was estimated using the resource use data from previous trials, therefore calculated medical costs might be over-estimated compared to the real-world setting. CONCLUSIONS: Model results suggest that treatment with 3 years vs 1 year of imatinib is cost-effective at a $100,000/QALY threshold. Clinical and economic results suggest treating surgically resected Kit+ GIST patients with 3 years of imatinib would result in improved quality-adjusted survival.

The patient journey in chronic myeloid leukemia patients on tyrosine kinase inhibitor therapies: qualitative insights using a global ethnographic approach.

BACKGROUND: The advent and approval of tyrosine kinase inhibitors (TKIs) have dramatically improved the life expectancy of patients with chronic myeloid leukemia (CML), which has been transformed into a chronically manageable disease. OBJECTIVE: The objective was to qualitatively assess the effects of diagnosis and treatment on patients with CML to offer recommendations for health-care providers (HCPs) for the better support of patients. METHODS: By use of an ethnographic approach based on in-home interviews, photo journals, and an optional telephone debriefing interview, this study included 50 patients with CML from Brazil, France, Germany, Russia, and Spain, including patients within 18 months of diagnosis and receiving frontline TKI therapy (n = 20), patients between >18 months and 7 years from diagnosis and receiving ongoing frontline therapy (n = 20), and patients who switched to second- or third-line TKI therapy (n = 10). In-home interviews were designed to address patient perceptions and experiences regarding such issues as adherence, disease knowledge, disease management, and relationships with HCPs. Transcripts from these interviews and other data were analyzed to identify similar patterns and themes experienced by patients with CML. RESULTS: The investigation generated a five-stage, patient-centered model of the experience of the patient throughout diagnosis, treatment, and management of CML: crisis, hope, adaptation, new normal, and uncertainty. Patients proceeded through these stages in the course of their disease management. The stages were affected by the patients' emotional and social experiences, their knowledge about CML, their positive experiences with their HCPs and/or treatment, and their optimism about their long-term prognosis. CONCLUSIONS: We identified five common stages experienced by patients with CML and suggest several recommendations for HCPs on the management of patients through their disease journey. By providing support, education, and reassurance, HCPs can help patients as they move through the early stages of crisis and hope. When patients are in the adaptation and new-normal stages, HCPs can help patients achieve and maintain a new normality by setting expectations for the risks/benefits of long-term chronic drug therapy and disease monitoring and by continuing to support patient adherence.