Enantioselective (3+2) Annulation of Donor-Acceptor Cyclopropanes with Aldehydes and Ketones Catalyzed by Brønsted Bases.

The substituted tetrahydrofuran core is a structural motif in many biologically active and natural compounds. However, the scarcity of enantioselective methods developed towards its synthesis makes this field challenging and attractive to explore. Herein, the first Brønsted-base catalyzed enantioselective (3+2) annulation of donor-acceptor cyclopropanes with aldehydes and ketones affording enantioenriched 2,3,5-substituted tetrahydrofurans is reported. The reaction concept is based on activation of racemic ß-cyclopropyl ketones by a chiral bifunctional Brønsted base which catalyzes the (3+2) annulation for a range of aldehydes and ketones. For aldehydes, the annulation furnished tetrahydrofurans in excellent yield, good diastereoselectivity and with excellent enantioselectivity up to >99 % ee. Surprisingly, aromatic aldehydes afforded the cis-2,5-substituted tetrahydrofurans as the major diastereoisomer, while for aliphatic aldehydes the trans-cycloadduct was favored. The reaction also proceeds well for ketones affording spiro tetrahydrofurans in excellent yields and enantioselectivities (up to 99 % ee). Hammett studies have been conducted to elucidate the influence of the electronic nature of benzaldehydes on the stereoselectivity. Based on the diastereochemical outcome for the aldehydes, two reaction paths for aromatic and aliphatic aldehydes are proposed. Finally, two diastereoselective synthetic transformations have been conducted to demonstrate the synthetic potential of the obtained products.

Enantioselective Synthesis of Tropane Scaffolds by an Organocatalyzed 1,3-Dipolar Cycloaddition of 3-Oxidopyridinium Betaines and Dienamines.

Tropane alkaloids constitute a compound-class which is structurally defined by a central 8-azabicyclo[3.2.1]octane core. A diverse bioactivity profile combined with an unusual aza-bridged bicyclic framework has made tropanes molecules-of-interest within organic chemistry. Enantioselective examples of (5+2) cycloadditions between 3-oxidopyridinium betaines and olefins remain unexplored, despite 3-oxidopyridinium betaines being useful reagents in organic synthesis. The first asymmetric (5+2) cycloaddition of 3-oxidopyridinium betaines is reported, affording tropane derivatives in up to quantitative yield and with excellent control of peri-, regio-, diastereo-, and enantioselectivity. The reactivity is enabled by dienamine-activation of α,ß-unsaturated aldehydes combined with in situ formation of the pyridinium reaction-partner. A simple N-deprotection protocol allows for liberation of the tropane alkaloid motif, and synthetic elaborations of the cycloadducts demonstrate their synthetic utility to achieve highly diastereoselective modification around the bicyclic framework. DFT computations suggest a stepwise mechanism where regio- and stereoselectivity are defined during the first bond-forming step in which the pyridinium dipole exerts critical conformational control over its dienamine partner. In the second bond-forming step, a kinetic preference toward an initial (5+4) cycloadduct was identified; however, a lack of catalyst turn-over, reversibility, and thermodynamic bias favoring a (5+2) cycloadduct rendered the reaction fully periselective.

A standard 96-well based high throughput microfluidic perfusion biofilm reactor for in situ optical analysis.

Biofilm infections represent a major public health threat due to their high tolerance to antimicrobials and the lack of specific anti-biofilm drugs. To develop such drugs, it is crucial to have high-throughput biofilm growth systems that can emulate in vivo conditions without the cost and complexity of animal models. However, no current biofilm reactor can provide in vivo-like conditions in a high throughput standard microtiter format. This paper demonstrates a novel high-throughput (HT) microfluidic perfusion biofilm reactor (HT-µPBR) compatible with a standard 96-well microtiter plate for in situ optical analysis. A snap-on liquid-tight cover for standard microtiter plates was designed and fabricated with fluidic channels to provide closed-loop recirculating perfusion. Our system takes steps toward providing in vivo-like conditions with controlled shear stress and nutrient delivery. We describe the system fabrication and usage in optical analysis of biomass and viability of Escherichia coli (E. coli) biofilms. The HT-µPBR was set to perfuse at 1 mL/min corresponding to an average shear rate of approximately [Formula: see text] on the bottom surface of a single well. Biofilms were detected on well plate bottoms and measured using a fluorescence microscope and plate reader to determine biomass and viability. Samples cultured in the HT-µPBR showed increased biomass while maintaining viability after 24 h. The HT-µPBR can further be combined with HT antibiotic susceptibility testing and additional optical techniques such as time-lapse imaging to improve understanding of the drug reaction mechanism as well as the optimization of drug combinations and delivery profiles.

Influence of Achiral Phosphine Ligands on a Synergistic Organo- and Palladium-Catalyzed Asymmetric Allylic Alkylation.

An unusual diastereodivergent stereoselective allylation reaction is presented. It consists of a palladium-catalyzed allylation reaction of an organocatalytically generated amino isobenzofulvene, where the diastereoselectivity is controlled by the electronic properties of a monodentate, achiral ligand on palladium. One major diastereoisomer is formed using triarylphosphines substituted with neutral or electron-donating substituents of the aryl group, while those with electron-withdrawing substituents favor the other diastereoisomer. The diastereoselectivity correlates with the Taft inductive parameter of substituents on the triarylphosphine ligand on palladium. The synergistic reaction involves both a catalytic secondary amine catalyst for the indene-aldehyde activation and the monodentate phosphine ligands on palladium, affording a highly enantioselective reaction with up to 98 % enantiomeric excess. Based on computational investigations, the role of the monodentate phosphine ligand on the diastereoselectivity is discussed.

The Pericapsular Nerve Group (PENG) block combined with Local Infiltration Analgesia (LIA) compared to placebo and LIA in hip arthroplasty surgery: a multi-center double-blinded randomized-controlled trial.

BACKGROUND: The PEricapsular Nerve Group (PENG) block is a novel regional analgesia technique that provides improved analgesia in patients undergoing hip surgery while preserving motor function. In this study the PENG block was investigated for analgesia in elective total hip arthroplasty (THA). METHODS: In this multi-centre double-blinded randomized-controlled trial, in addition to spinal anesthesia and local infiltration analgesia (LIA), THA patients received either a PENG block or a sham block. The primary outcome was pain score (numeric rating scale 0-10) 3 h postoperatively (Day 0). Secondary outcomes were postoperative quadriceps muscle strength, postoperative Day 1 pain scores, opiate use, complications, length of hospital stay, and patient-reported outcome measures. RESULTS: Sixty patients were randomized and equally allocated between groups. Baseline demographics were similar. Postoperative Day 0, the PENG group experienced less pain compared to the sham group (PENG: 14 (47%) patients no pain, 14 (47%) mild pain, 2 (6%) moderate/severe pain versus sham: 6 (20%) no pain, 14 (47%) mild pain, 10 (33%) moderate/severe pain; p = 0.03). There was no difference in quadriceps muscle strength between groups on Day 0 (PENG: 23 (77%) intact versus sham: 24 (80%) intact; p = 0.24) and there were no differences in other secondary outcomes. CONCLUSIONS: Patients receiving a PENG block for analgesia in elective THA experience less postoperative pain on Day 0 with preservation of quadriceps muscle strength. Despite these short-term benefits, no quality of recovery or longer lasting postoperative effects were detected.

Enantioselective (8+3) Cycloadditions by Activation of Donor-Acceptor Cyclopropanes Employing Chiral Brønsted Base Catalysis.

A novel enantioselective (8+3) cycloaddition between donor-acceptor cyclopropanes and heptafulvenoids catalysed by a chiral bifunctional Brønsted base is described. Importantly, the reaction, which leverages an anionic activation strategy, is divergent from prototypical Lewis-acid activation protocols. A series of cyclopropylketones react with tropones affording the desired (8+3) cycloadducts in high yield and enantiomeric excess. For barbiturate substituted heptafulvenes, the (8+3) cycloaddition with cyclopropylketones proceeds in good yield, excellent diastereoselectivity and high enantiomeric excess. The experimental work is supported by DFT calculations, which indicate that the bifunctional organocatalyst activates both the donor-acceptor cyclopropane and tropone; the reaction proceeds in a step-wise manner with the ring-closure being the stereodetermining step.

Organocatalytic Asymmetric Multicomponent Cascade Reaction for the Synthesis of Contiguously Substituted Tetrahydronaphthols.

Isobenzopyrylium ions are unique, highly reactive, aromatic intermediates which are largely unexplored in asymmetric catalysis despite their high potential synthetic utility. In this study, an organocatalytic asymmetric multicomponent cascade via dienamine catalysis, involving a cycloaddition, a nucleophilic addition, and a ring-opening reaction, is disclosed. The reaction furnishes chiral tetrahydronaphthols containing four contiguous stereocenters in good to high yield, high diastereoselectivity (up to >20:1), and excellent enantioselectivity (93-98% ee). The obtained products are important synthetic intermediates, and it is demonstrated that they can be used for the generation of frameworks such as octahydrobenzo[h]isoquinoline and [2.2.2]octane scaffolds. Furthermore, mechanistic experiments involving oxygen-18-labeling studies and density functional theory calculations provide a vivid picture of the reaction mechanism. Finally, the bioactivity of 16 representative tetrahydronaphthol compounds has been evaluated in U-2OS cancer cells with some compounds showing a unique profile and a clear morphological change.

Timing of Androgen Deprivation Treatment for Men with Biochemical Recurrent Prostate Cancer in the Context of Novel Therapies.

PURPOSE: There were 3 recent U.S. Food and Drug Administration approvals for drugs to be used in nonmetastatic castration resistant prostate cancer, a state that arises from the unproven start of continuous androgen deprivation therapy (ADT) for biochemical recurrent prostate cancer (BCR), before metastatic disease is evident. This report examines the outcome of men with BCR who defer ADT until time of metastasis. MATERIALS AND METHODS: Retrospective review of men diagnosed with clinically localized prostate cancer who underwent radical prostatectomy at Johns Hopkins Hospital and Walter Reed National Military Medical Center and developed BCR with a prostate specific antigen doubling time of not more than 10 months (806 patients). The primary end points were metastasis-free survival and overall survival from time of local treatment among men who delayed ADT until time of metastasis. RESULTS: The median metastasis-free survival of men with BCR and a prostate specific antigen doubling time <6 months and 10 months who delay ADT until metastasis is 144 months (95% CI 48-not reached) and 192 months (95% CI 72-not reached), respectively, with a median overall survival of 168 months (95% CI 96-276 months) and 204 months (95% CI 120-276), respectively. CONCLUSIONS: Metastasis-free survival and overall survival of men with BCR who delay hormone therapy is long. This underscores the need to reevaluate when to start primary ADT in this patient population.

Multi-omic serum biomarkers for prognosis of disease progression in prostate cancer.

BACKGROUND: Predicting the clinical course of prostate cancer is challenging due to the wide biological spectrum of the disease. The objective of our study was to identify prostate cancer prognostic markers in patients 'sera using a multi-omics discovery platform. METHODS: Pre-surgical serum samples collected from a longitudinal, racially diverse, prostate cancer patient cohort (N = 382) were examined. Linear Regression and Bayesian computational approaches integrated with multi-omics, were used to select markers to predict biochemical recurrence (BCR). BCR-free survival was modeled using unadjusted Kaplan-Meier estimation curves and multivariable Cox proportional hazards analysis, adjusted for key pathologic variables. Receiver operating characteristic (ROC) curve statistics were used to examine the predictive value of markers in discriminating BCR events from non-events. The findings were further validated by creating a training set (N = 267) and testing set (N = 115) from the cohort. RESULTS: Among 382 patients, 72 (19%) experienced a BCR event in a median follow-up time of 6.9 years. Two proteins-Tenascin C (TNC) and Apolipoprotein A1V (Apo-AIV), one metabolite-1-Methyladenosine (1-MA) and one phospholipid molecular species phosphatidic acid (PA) 18:0-22:0 showed a cumulative predictive performance of AUC = 0.78 [OR (95% CI) = 6.56 (2.98-14.40), P < 0.05], in differentiating patients with and without BCR event. In the validation set all four metabolites consistently reproduced an equivalent performance with high negative predictive value (NPV; > 80%) for BCR. The combination of pTstage and Gleason score with the analytes, further increased the sensitivity [AUC = 0.89, 95% (CI) = 4.45-32.05, P < 0.05], with an increased NPV (0.96) and OR (12.4) for BCR. The panel of markers combined with the pathological parameters demonstrated a more accurate prediction of BCR than the pathological parameters alone in prostate cancer. CONCLUSIONS: In this study, a panel of serum analytes were identified that complemented pathologic patient features in predicting prostate cancer progression. This panel offers a new opportunity to complement current prognostic markers and to monitor the potential impact of primary treatment versus surveillance on patient oncological outcome.

Expanding the Frontiers of Higher-Order Cycloadditions.

The concept of pericyclic reactions and the explanation of their specificity through orbital symmetries introduced a new way of understanding reactions and looking for new ones. One of the 1965 Woodward-Hoffmann communications described "the (as yet unobserved) symmetry-allowed 6 + 4 combination", the prediction of a new field of "higher-order" cycloadditions, involving more than six electrons. Later these authors predicted exo-stereoselectivity for the [6 + 4]-cycloaddition. Chemists rushed to test this prediction (for the most part successfully). For more than half a century, chemists have hunted for additional higher-order cycloadditions. The application of catalysis within organic chemistry allows the accomplishment of previously unattainable reactions, including higher-order cycloadditions. The many examples of [8 + 2], [6 + 4], and cycloadditions of even higher electron-counts discovered since the Woodward-Hoffmann rules were introduced illustrate the difficulty in predicting which of these transformations will occur when two highly unsaturated molecules react. Periselectivity has been a challenge, and the development of enantioselective variants has been elusive. While progress was made, the rise of organocatalysis in asymmetric synthesis has led to a surge of interest in stereoselective versions of higher-order cycloadditions. Through organocatalytic activation of conjugated cyclic polyenes and heteroaromatic compounds, asymmetric [8 + 2]-, [6 + 4]-, and [10 + 4]-cycloadditions have been realized by our groups. In this century, [6 + 4]-cycloadditions have been found also to occur in enzyme-catalyzed reactions for the biosynthesis of spinosyn A, heronamide, and streptoseomycin natural products. A whole new class of enzymes, the pericyclases that catalyze pericyclic reactions, has been discovered. A remarkable aspect of these recent developments is the cross-disciplinary research involved: from organic synthesis to computational studies integrated with experimental studies of reaction mechanisms, intermediates, and dynamics, to understanding mechanisms of enzyme catalysis and engineering of enzymes. This Account describes how our groups have been involved in the expansion of the higher-order cycloaddition frontiers. We describe both the history and recent progress in higher-order cycloadditions, and how these advances have been made by our collaborative experimental and computational studies. Progress in asymmetric organocatalysis, incorporating enantioselective higher-order cycloadditions in organic synthesis, and the stereoselective synthesis of important scaffolds will be highlighted. Experimental progress and computational modeling with density functional theory (DFT) has identified ambimodal cycloaddition pathways and led to the realization that multiple products of pericyclic reactions are linked by common transition states. Molecular dynamic simulations have provided fundamental understanding of factors controlling periselectivity and have led to discoveries of a group of enzymes, the pericyclases, which catalyze pericyclic reactions such as [6 + 4]-cycloadditions.

Organocatalytic Enantioselective 1,3-Dipolar [6+4] Cycloadditions of Tropone.

A highly stereoselective 1,3-dipolar [6+4] cycloaddition towards bridged azabicyclo[4.3.1]decane scaffolds has been developed, reacting aldehydes, 2-aminomalonates and tropone under mild conditions in the presence of a chiral phosphoric acid catalyst. The scope is demonstrated for a series of aldehydes and 2-aminomalonates, and the reaction proceeds in high yields, >95:5 d.r. and up to 99 % ee. A series of transformations, as well as a mechanistic proposal, are presented.

Enantioselective 1,3-Dipolar [6+4] Cycloaddition of Pyrylium Ions and Fulvenes towards Cyclooctanoids.

Organocatalytic enantioselective 1,3-dipolar [6+4] cycloadditions of pyrylium ion intermediates with fulvenes promoted by a chiral primary amine catalyst have been developed to proceed in moderate to good yields and high enantioselectivities. The resultant chiral bicyclo[6.3.0]undecane scaffold containing a transannular bridging ether is densely functionalised providing a rigid scaffold for further manipulations. Computational studies give important insights into the role of the primary amine catalyst. Analysis of the reaction shows that the catalytic reaction proceeds in a step-wise manner and rationalises the stereochemical outcome of the reaction. Several stereoselective complexity-generating transformations, facilitated by the diverse functional groups and transannular bridge, are presented, highlighting the versatility of the core towards a number of the cyclooctanoid natural products.

Social evolution under demographic stochasticity.

How social traits such as altruism and spite evolve remains an open question in evolutionary biology. One factor thought to be potentially important is demographic stochasticity. Here we provide a general theoretical analysis of the role of demographic stochasticity in social evolution. We show that the evolutionary impact of stochasticity depends on how the social action alters the recipient's life cycle. If the action alters the recipient's death rate, then demographic stochasticity always favours altruism and disfavours spite. On the other hand, if the action alters the recipient's birth rate, then stochasticity can either favour or disfavour both altruism and spite depending on the ratio of the rate of population turnover to the population size. Finally, we also show that this ratio is critical to determining if demographic stochasticity can reverse the direction of selection upon social traits. Our analysis thus provides a general understanding of the role of demographic stochasticity in social evolution.

Acid Exfoliation of Imine-linked Covalent Organic Frameworks Enables Solution Processing into Crystalline Thin Films.

Covalent organic frameworks (COFs) are highly modular porous crystalline polymers that are of interest for applications such as charge-storage devices, nanofiltration membranes, and optoelectronic devices. COFs are typically synthesized as microcrystalline powders, which limits their performance in these applications, and their limited solubility precludes large-scale processing into more useful morphologies and devices. We report a general, scalable method to exfoliate two-dimensional imine-linked COF powders by temporarily protonating their linkages. The resulting suspensions were cast into continuous crystalline COF films up to 10 cm in diameter, with thicknesses ranging from 50 nm to 20 µm depending on the suspension composition, concentration, and casting protocol. Furthermore, we demonstrate that the film fabrication process proceeds through a partial depolymerization/repolymerization mechanism, providing mechanically robust films that can be easily separated from their substrates.

Real-world outcomes of sipuleucel-T treatment in PROCEED, a prospective registry of men with metastatic castration-resistant prostate cancer.

BACKGROUND: The large registry, PROVENGE Registry for the Observation, Collection, and Evaluation of Experience Data (PROCEED)(NCT01306890), evaluated sipuleucel-T immunotherapy for asymptomatic/minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). METHODS: PROCEED enrolled patients with mCRPC receiving 3 biweekly sipuleucel-T infusions. Assessments included overall survival (OS), serious adverse events (SAEs), cerebrovascular events (CVEs), and anticancer interventions (ACIs). Follow-up was for ≥3 years or until death or study withdrawal. RESULTS: In 2011-2017, 1976 patients were followed for 46.6 months (median). The median age was 72 years, and the baseline median prostate-specific antigen level was 15.0 ng/mL; 86.7% were white, and 11.6% were African American. Among the patients, 1902 had 1 or more sipuleucel-T infusions. The median OS was 30.7 months (95% confidence interval [CI], 28.6-32.2 months). Known prognostic factors were independently associated with OS in a multivariable analysis. Among the 1255 patients who died, 964 (76.8%) died of prostate cancer (PC) progression. The median time from the first infusion to PC death was 42.7 months (95% CI, 39.4-46.2 months). The incidence of sipuleucel-T-related SAEs was 3.9%. The incidence of CVEs was 2.8%, and the rate per 100 person-years was 1.2 (95% CI, 0.9-1.6). The CVE incidence among 11,972 patients with mCRPC from the Surveillance, Epidemiology, and End Results-Medicare database was 2.8%; the rate per 100 person-years was 1.5 (95% CI, 1.4-1.7). One or more ACIs (abiraterone, enzalutamide, docetaxel, cabazitaxel, or radium 223) were received by 77.1% of the patients after sipuleucel-T; 32.5% and 17.4% of the patients experienced 1- and 2-year treatment-free intervals, respectively. CONCLUSIONS: PROCEED provides contemporary survival data for sipuleucel-T-treated men in a real-world setting of new life-prolonging agents, which will be useful in discussing treatment options with patients and in powering future trials with sipuleucel-T. The safety and tolerability of sipuleucel-T in PROCEED were consistent with previous findings.

No Idle Threat: Coercive Control and Enacted Violence in the Pre-Prison Relationships of Incarcerated Women.

While much research documents physical and sexual abusive experiences in the lives of women prisoners, less is known about their experiences with coercive control. Utilizing Dutton, Goodman, and Schmidt's (2008) measures of coercive control and framed by a feminist pathways approach, this study examines the connections between experiences of coercive control and physical and sexual violence in adult intimate relationships, including how women perceive and respond to experiences of coercion. Findings demonstrate how incarcerated women experience significant levels of control, manipulation, threats, and demands from their partners in relation to personal activities, financial resources, interpersonal interactions, illegal activities, and other areas. Moreover, findings show these threats and demands to be aggressively enforced and directly related to physical and sexual violence against these women, as well as threats to the safety and security of their family, friends, and children. Additional findings and details are discussed.

The Role of Phenotypic Plasticity in Moderating Evolutionary Conflict.

Evolutionary conflicts arise when the fitness interests of interacting individuals differ. Well-known examples include sexual conflict between males and females and antagonistic coevolution between hosts and parasites. A common feature of such conflicts is that compensating evolutionary change in each of the parties can lead to little overt change in the interaction itself. As a result, evolutionary conflict is expected to persist even if the evolutionary dynamic between the parties reaches an equilibrium. In these cases, it is of interest to know whether certain kinds of interactions are expected to lead to greater or lesser evolutionary conflict at such evolutionary stalemates. Here we present a theoretical analysis showing that when one of the interacting parties can respond to the other through adaptive phenotypic plasticity, evolutionary conflict is reduced. Paradoxically, however, it is the party that does not express adaptive plasticity that experiences less conflict. Conflict for the party displaying adaptive plasticity can increase or decrease, depending on the situation.

High Intensity Focused Ultrasound for Radiorecurrent Prostate Cancer: A North American Clinical Trial.

PURPOSE: We determined the safety and efficacy of whole gland high intensity focused ultrasound in men with radiorecurrent prostate cancer. MATERIALS AND METHODS: A total of 100 men with clinically localized recurrent prostate cancer at least 2 years after external beam radiation therapy underwent whole gland high intensity focused ultrasound in an open label trial from 2009 to 2012. Treatments were performed at 16 sites, including 14 in the United States and 2 in Canada. The primary end point was the combination of a prostate specific antigen nadir of 0.5 ng/ml or less and negative biopsy at 12 months. Validated questionnaires were administered to monitor changes in urinary and sexual function. RESULTS: Of the 100 treated men, in whom mean age was 70 years (range 53 to 83), 78 completed the 12-month biopsy, which was negative in 63 (81%). Mean prostate specific antigen was 4.9 ng/ml (range 0.4 to 14) and the median Gleason score was 7. The 1-year end point of a prostate specific antigen nadir of 0.5 ng/ml or less plus negative biopsy was achieved in 50 men. During post-trial followup mean prostate specific antigen at 2 years was 1.1 ng/ml (range 0.1 to 17) in 33 patients. Adverse events developed in 91 men through 12 months, which were CTCAE grade 1 in 67, grade 2 in 80 and grade 3 in 20. Treatment related grade 3 adverse events included rectal fistulas in 5 men, which required surgery in 3, osteitis pubis in 3 and hematuria requiring intervention in 3. Treatment related grade 3 adverse events developed early in the trial and appeared related to operator experience. There were no life threatening adverse events or treatment related deaths. CONCLUSIONS: Whole gland high intensity focused ultrasound appears reasonably safe and effective to treat radiorecurrent prostate cancer. The rate of complications, which are potentially severe, was acceptable, especially considering the advanced, refractory nature of the disease and the limited treatment options.

Androgen Receptor Targeted Treatments of Prostate Cancer: 35 Years of Progress with Antiandrogens.

PURPOSE: Antiandrogens inhibit the androgen receptor and have an important role in the treatment of prostate cancer. This review provides a historical perspective on the development and clinical benefit of antiandrogens in the treatment of prostate cancer. MATERIALS AND METHODS: We searched PubMed® for clinical trials with the search terms antiandrogens and prostate cancer combined with drug names for antiandrogens. This article represents a collaboration of clinical investigators who have made critical scientific contributions leading to the approval of antiandrogens for treating patients with prostate cancer. RESULTS: Antiandrogens differ in chemical structure and exert varying efficacy and safety profiles. The unfavorable therapeutic index of steroidal antiandrogens led to replacement by safer nonsteroidal agents. Flutamide, nilutamide and bicalutamide, which were designed to target the androgen receptor, were developed primarily for use in combination with castration to provide combined androgen blockade. Modest clinical benefits were observed with the combination of first generation antiandrogens and castration vs castration alone. With increased knowledge of androgen receptor structure and its biological functions a new generation of antiandrogens without agonist activity was designed to provide more potent inhibition of the androgen receptor. Randomized clinical trials in patients with metastatic, castration resistant prostate cancer showed significant survival benefits, which led to the approval of enzalutamide in August 2012. Apalutamide was recently approved while darolutamide is not yet approved in the United States. These next generation antiandrogens are being actively tested in earlier disease states such as nonmetastatic prostate cancer. Evolving knowledge of resistance mechanisms to androgen receptor targeted treatments will stimulate research and drug discovery for additional compounds. Further testing in nonmetastatic castration resistant prostate cancer as well as castration sensitive disease states will hopefully augment our ability to treat a broader spectrum of patients with prostate cancer. CONCLUSIONS: Antiandrogens have already provided important benefits for prostate cancer treatment. Greater knowledge about the structural and functional biology of the androgen receptor in prostate cancer will facilitate further discovery and development of further improved antiandrogens with enhanced clinical activity in patients with advanced metastatic disease. Testing these new agents earlier in the course of prostate cancer may further improve the survival and quality of life of patients with current local and/or systemic treatment modalities.

Phase II trial of docetaxel, bevacizumab, lenalidomide and prednisone in patients with metastatic castration-resistant prostate cancer.

OBJECTIVE: To determine the safety and clinical efficacy of two anti-angiogenic agents, bevacizumab and lenalidomide, with docetaxel and prednisone. PATIENTS AND METHODS: Eligible patients with metastatic castration-resistant prostate cancer enrolled in this open-label, phase II study of lenalidomide with bevacizumab (15 mg/kg), docetaxel (75 mg/m(2) ) and prednisone (10 mg daily). Docetaxel and bevacizumab were administered on day 1 of a 3-week treatment cycle. To establish safety, lenalidomide dosing in this combination was escalated in a conventional 3 + 3 design (15, 20 and 25 mg daily for 2 weeks followed by 1 week off). Patients received supportive measures including prophylactic pegfilgrastim and enoxaparin. The primary endpoints were safety and clinical efficacy. RESULTS: A total of 63 patients enrolled in this trial. Toxicities were manageable with most common adverse events (AEs) being haematological, and were ascertained by weekly blood counts. Twenty-nine patients (46%) had grade 4 neutropenia, 20 (32%) had grade 3 anaemia and seven (11%) had grade 3 thrombocytopenia. Despite frequent neutropenia, serious infections were rare. Other common non-haematological grade 3 AEs included fatigue (10%) and diarrhoea (10%). Grade 2 AEs in >10% of patients included anorexia, weight loss, constipation, osteonecrosis of the jaw, rash and dyspnoea. Of 61 evaluable patients, 57 (93%), 55 (90%) and 33 (54%) had PSA declines of >30, >50 and >90%, respectively. Of the 29 evaluable patients, 24 (86%) had a confirmed radiographic partial response. The median times to progression and overall survival were 18.2 and 24.6 months, respectively. CONCLUSIONS: With appropriate supportive measures, combination angiogenesis inhibition can be safely administered and potentially provide clinical benefit. These hypothesis-generating data would require randomized trials to confirm the findings.