Apalutamide plus androgen deprivation therapy in clinical subgroups of patients with metastatic castration-sensitive prostate cancer: A subgroup analysis of the randomised clinical TITAN study.

BACKGROUND: Whether disease burden in patients with metastatic castration-sensitive prostate cancer (mCSPC) predicts treatment outcomes is unknown. We assessed apalutamide treatment effect in TITAN patients with mCSPC by disease volume, metastasis number and timing of metastasis presentation. METHODS: These protocol-defined and post hoc analyses of the phase III randomised TITAN study evaluated clinical outcomes in patients receiving 240 mg/day apalutamide (n = 525) or placebo (n = 527) plus androgen-deprivation therapy (ADT). Subgroups were defined by volume (high: visceral and ≥1 bone metastases or ≥4 bone lesions with ≥1 beyond vertebral column/pelvis), development of metastases per conventional imaging (synchronous: at initial diagnosis; metachronous: after localised disease) and oligometastases (≤5 bone-only metastases) or polymetastases (>5 in bone ± other locations or ≤5 in bone plus other locations). Overall survival (OS), radiographic or second progression-free survival, and time to prostate-specific antigen progression or castration resistance were assessed using Cox proportional hazards models. RESULTS: Of 1052 patients, 63%, 81%, 54%, 27%, 5.7%, and 8.0% had high-volume, synchronous, synchronous/high-volume, synchronous/low-volume, metachronous/high-volume, and metachronous/low-volume disease, respectively. The OS benefit favoured apalutamide plus ADT versus ADT alone in synchronous/high-volume (hazard ratio = 0.68 [95% confidence interval: 0.53-0.87]; p = 0.002), synchronous/low-volume (0.65 [0.40-1.05]; p = 0.08), metachronous/high-volume (0.69 [0.33-1.44]; p = 0.32) and metachronous/low-volume (0.22 [0.09-0.55]; p = 0.001) subgroups. Apalutamide improved other clinical outcomes regardless of subgroup, with similar safety profiles. Most favourable outcomes were observed in oligometastatic disease. CONCLUSION: TITAN patients derived a robust benefit with apalutamide plus ADT regardless of disease volume and timing of metastasis presentation without differences in safety, supporting early apalutamide intensification in mCSPC. CLINICAL TRIAL REGISTRATION: NCT02489318.

Learning Clinical Hypnosis Wide Awake: Can We Teach Hypnosis Hypnotically?

Conversational hypnosis has been promoted as both more congruent with mechanisms of psychobiological change and more feasibly integrated into clinical care than the more dominant, ritualistic, hierarchical, induction-based Standards of Training in Clinical Hypnosis. Further, it has been argued that, in teaching the legacy standard, clinical hypnosis training lacks pedagogical integrity. This article builds on these premises by piloting a mixed-methods approach to studying the pedagogy and participant evaluations of two professional education events that focused on conversational hypnosis. Results indicate that this is an effective methodology for studying the impact of teaching hypnosis hypnotically and fostering wider integration of hypnosis into health and care.

Opioid prescribing for chronic pain in a community-based healthcare system.

OBJECTIVES: We sought to evaluate opioid prescribing in an ambulatory setting among patients with noncancer chronic pain (CP). STUDY DESIGN: Cross-sectional analysis. METHODS: We identified patients with at least 2 CP encounters at least 30 days apart in 2012 in the electronic health records of a community-based healthcare delivery system in northern California. We used logistic regression models to assess associations of receiving an opioid prescription with respect to number and type of CP conditions and patient demographics and characteristics. Odds ratios (ORs) with 95% confidence intervals (CIs) and the adjusted prevalence of receiving an opioid prescription were generated after controlling for important covariates. RESULTS: A total of 120,481 patients with CP met eligibility criteria, with 58% receiving an opioid in 2012. The adjusted prevalence of receiving an opioid was highest for back/cervical pain (71%). The odds of receiving an opioid increased linearly with the number of CP conditions per patient (OR, 1.29; 95% CI, 1.25-1.33; P <.001). Men were generally more likely to receive an opioid than women, as were patients with noncommercial insurance, especially Medicaid (OR, 2.77; 95% CI, 2.56-3.01; P <.001) versus commercial. CONCLUSIONS: In an ambulatory healthcare setting, opioid prescribing to patients with CP varied by type and number of pain conditions. Opioid prescriptions to men, those with back/cervical pain, and Medicaid beneficiaries were particularly prevalent. The identification of populations more likely to receive an opioid in the treatment of CP should be of interest to healthcare systems to ensure these drugs are being used appropriately and safely.

Orienting hypnosis.

This article presents a new frame for understanding hypnosis and its clinical applications. Despite great potential to transform health and care, hypnosis research and clinical integration is impaired in part by centuries of misrepresentation and ignorance about its demonstrated efficacy. The authors contend that advances in the field are primarily encumbered by the lack of distinct boundaries and definitions. Here, hypnosis, trance, and mind are all redefined and grounded in biological, neurological, and psychological phenomena. Solutions are proposed for boundary and language problems associated with hypnosis. The biological role of novelty stimulating an orienting response that, in turn, potentiates systemic plasticity forms the basis for trance. Hypnosis is merely the skill set that perpetuates and influences trance. This formulation meshes with many aspects of Milton Erickson's legacy and Ernest Rossi's recent theory of mind and health. Implications of this hypothesis for clinical skills, professional training, and research are discussed.

Symptoms as solutions: hypnosis and biofeedback for autonomic regulation in autism spectrum disorders.

The Autonomic Dysregulation Theory of autism posits that a phylogenetically early autonomic defect leads to overarousal and impairments in language and social engagement. Cognitive rigidity and repetitive behaviors manifest as mitigating efforts. Focusing on the implications of this premise may provide more productive therapeutic approaches than existing methods. It suggests that self-regulation therapy using hypnosis and biofeedback should be highly effective, especially for young people. Hypnotic strategies can utilize restrictive repetitive behaviors in trance as resources for comfort and control. Biofeedback training can be tailored to focus on autonomic regulation. The authors develop this theory and describe methods of integrating hypnosis and biofeedback that have been therapeutic for people with autism. Directions for future research to validate this approach are discussed.

V/Q SPECT imaging of acute pulmonary embolus - a practical perspective.

The following article is intended to illustrate the place of scintigraphy and computed tomography pulmonary angiography (CTPA) in the investigation of acute PE in current practice, and to guide non-radionuclide radiologists and other medical professionals to the best test for patients. We share our early experiences with ventilation-perfusion (V/Q) single-photon-emission computed tomography (SPECT) including image acquisition and interpretation. A comparison of the two techniques is given, along with practical considerations in a variety of clinical scenarios.

Is there a role for free breathing non-contrast steady-state free precession renal MRA imaging for assessing live donors? A preliminary study.

OBJECTIVE: Accurate pre-operative evaluation of renal vascular anatomy is essential for successful renal harvest in live donor transplantation. Non-contrast renal MR angiographic (MRA) techniques are potentially well suited to the screening of donors; however, their restricted imaging field of view (FOV) has previously been an important limitation. We sought to assess whether the addition of a large FOV balanced fast field echo (BFFE) steady-state free precession (SSFP) sequence to non-contrast SSFP MRA could overcome this problem. Comparison with contrast-enhanced MRA (CE MRA) and findings at surgery were performed. METHODS: 22 potential renal donors each underwent SSFP and CE MRA. 11 out of 22 potential donors subsequently underwent a donor nephrectomy. RESULTS: All images were diagnostic. Both SSFP MRA and CE MRA identified an equal number of arteries. Surgery confirmed two accessory renal arteries, both demonstrated with both imaging techniques. A third accessory vessel was identified with both techniques on a kidney contralateral to the donated organ. 6 out of 11 procured kidneys demonstrated early branch arteries at surgery, 5 out of 6 of which had been depicted on both SSFP and CE MRA. The median grading of image quality for main renal arteries was slightly better for CE MRA (p=0.048), but for accessory vessels it was better for SSFP MRA. CONCLUSION: This pilot study indicates that by combining free-breathing SSFP MRA with large-FOV bFFE images, an accurate depiction of renal vascular anatomy without the need for intravenous contrast administration can be obtained, as compared with surgical findings and CE MRA.

Unusual manifestations of astroblastoma: a radiologic-pathologic analysis.

Astroblastoma is a very rare primary glial tumor occurring in children and young adults that is almost exclusively supratentorial in location. We report an extremely unusual presentation of a densely calcified posterior fossa astroblastoma with disseminated spinal and supratentorial metastasis. The mass exhibited neoplastic bone formation, which has not been reported, although calcifications are commonly seen in astroblastomas. A companion case of a low-grade astroblastoma that demonstrated classic histologic features but nonspecific and atypical imaging findings is also included. These cases expand the imaging and pathologic spectrum of this controversial tumor that shows highly variable biologic behavior and is difficult to distinguish from ependymoma.

Intradural capillary hemangioma of the cauda equina.

Hemangiomas, which are usually found in the skin, are extremely rare in an intradural location. An unusual case of capillary hemangioma intimate to the cauda equina is discussed. This entity has not previously been reported in the pediatric or adolescent population to the best of our knowledge, although it has been reported in adults.

Discovery and preclinical studies of (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5- methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan- 2-ol (BMS-540215), an in vivo active potent VEGFR-2 inhibitor.

A series of substituted 4-(4-fluoro-1H-indol-5-yloxy)pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of vascular endothelial growth factor receptor-2 kinase is reported. Structure-activity relationship studies revealed that a methyl group at the 5-position and a substituted alkoxy group at the 6-position of the pyrrolo[2,1-f][1,2,4]triazine core gave potent compounds. Biochemical potency, kinase selectivity, and pharmacokinetics of the series were optimized and in vitro safety liabilities were minimized to afford BMS-540215 (12), which demonstrated robust preclinical in vivo activity in human tumor xenograft models. The l-alanine prodrug of 12, BMS-582664 (21), is currently under evaluation in clinical trials for the treatment of solid tumors.

Molecular and biochemical characterization of the selenocysteine Se-methyltransferase gene and Se-methylselenocysteine synthesis in broccoli.

Selenium (Se) plays an indispensable role in human nutrition and has been implicated to have important health benefits, including being a cancer preventative agent. While different forms of Se vary in their anticarcinogenic efficacy, Se-methylselenocysteine (SeMSC) has been demonstrated to be one of the most effective chemopreventative compounds. Broccoli (Brassica oleracea var. italica) is known for its ability to accumulate high levels of Se with the majority of the selenoamino acids in the form of Se-methylselenocysteine. Therefore, it serves as a good model to study the regulation of SeMSC accumulation in plants. A cDNA encoding selenocysteine Se-methyltransferase, the key enzyme responsible for SeMSC formation, was cloned from broccoli using a homocysteine S-methyltransferase gene probe from Arabidopsis (Arabidopsis thaliana). This clone, designated as BoSMT, was functionally expressed in Escherichia coli, and its identity was confirmed by its substrate specificity in the methylation of selenocysteine. The BoSMT gene represents a single copy sequence in the broccoli genome. Examination of BoSMT gene expression and SeMSC accumulation in response to selenate, selenite, and sulfate treatments showed that the BoSMT transcript and SeMSC synthesis were significantly up-regulated in plants exposed to selenate but were low in plants supplied with selenite. Simultaneous treatment of selenate with selenite significantly reduced SeMSC production. In addition, high levels of sulfate suppressed selenate uptake, resulting in a dramatic reduction of BoSMT mRNA level and SeMSC accumulation. Our results reveal that SeMSC accumulation closely correlated with the BoSMT gene expression and the total Se status in tissues and provide important information for maximizing the SeMSC production in this beneficial vegetable plant.

Design, synthesis, and structure-activity relationships of tetrahydroquinoline-based farnesyltransferase inhibitors.

Tetrahydroquinoline-based small molecule inhibitors of farnesyltransferase (FT) have been identified. Lead compounds were shown to have nanomolar to sub-nanomolar activity in biochemical assays with excellent potency in a Ras-mutated cellular reversion assay. BMS-316810 (9e), a 0.7 nM FT inhibitor, was orally-active in a nude mouse tumor allograft efficacy study.

Rates of discontinuation and change of glaucoma therapy in a managed care setting.

BACKGROUND: Comparing discontinuation and change rates of glaucoma pharmacotherapies provides insight as to which agents perform more effectively. OBJECTIVE: To quantify the rates of discontinuation and change of different glaucoma therapies. METHODS: This retrospective, observational study using managed care administrative claims data included patients who were between 20 and 64 years of age and received at least 1 prescription for 1 of the following glaucoma agents as monotherapy: betaxolol, brimonidine, latanoprost, or timolol. Patients receiving any glaucoma medication during the 180 days prior to their index prescription were excluded, as were those who did not have continuous plan enrollment during this period. The primary outcome measures were the discontinuation and change (switching/adding on) of the index glaucoma medication. Rates of discontinuation and change were compared using a proportional hazard model. RESULTS: A total of 1006 patients comprised the final study population. Approximately 62% of patients discontinued their index glaucoma medication, and 18% of patients changed to a different therapy within 18 months of starting therapy. Among those discontinuing therapy, latanoprost patients remained on therapy the longest (mean: 217 days) compared to other study cohorts (range: 182 to 184 days). Compared with latanoprost, patients initiated on any of the other agents were more likely to discontinue or change therapy. CONCLUSIONS: This study indicates that latanoprost therapy results in a lower rate of discontinuation or change compared to patients started on betaxolol, brimonidine, or timolol.

Reversed-phase liquid chromatographic determination of phytometallophores from Strategy II Fe-uptake species by 9-fluorenylmethyl chloroformate fluorescence.

An HPLC method to quantitate phytometallophores (phytosiderophores) exuded from roots of barley (Hordeum vulgare L.) growing in nutrient solution culture was developed. 9-Fluorenylmethyl chloroformate (FMOC) derivatives of phytometallophores were separated on a C18 reverse-phase column using a sodium acetate (pH 7.2) and acetonitrile-methanol gradient over 20 min followed by fluorescence detection. Detection limits ranged from 15 to 370 pmol depending on the particular phytometallophore. The effectiveness of this method was demonstrated using the response of barley seedlings to Fe-sufficient and Fe-deficient nutrient solution conditions. Phytometallophores collected in root washings of Fe-deficient barley seedlings increased with plant age while phytometallophore release from Fe-adequate roots was negligible.

The Origin of Pharyngeal Obstruction during Sleep.

This paper traces the development of the adult human pharynx through evolution, comparative anatomy, and development from infant to adult. Based on phylogeny and otogeny, an hypothesis for the occurrence of obstructive sleep apnea in the mature human is presented.