Preparation and optimization of pyrazolo[1,5-a]pyrimidines as new potent PDE4 inhibitors.

A new series of pyrazolo[1,5-a]pyrimidines exemplified by compound 1, has been identified with moderate activity (IC50=165nM), following GSK256066 rescaffolding. Compound 1 optimization at positions 2, 3, 6 and 7 gave compound 10 with high in vitro activity (IC50=0.7nM). Modeling studies based on the PDB structure 3GWT with compound 5 showed the expected overlay with the carboxamide, the aryl moiety and the sulfone. Cyclisation of the primary amide to the 5 position of the pyrazolo[1,5-a]pyrimidines scaffold afforded compounds 15 and 16 with 200-fold enhancement in activity and cellular potency.

The European "clinical trial" regulation; relationship with the Jardé Act: a Giens workshop.

In May 2014, the European Union Parliament and Council published a new regulation on clinical trials on medicinal products for human use, which is designed to replace Directive 2001/20/EC. It will not come into effect until 2016. Nevertheless, it is essential to examine its relationship with national legislation, i.e. the Jardé Act, whose implementation has been delayed pending publication of the European regulation. The Giens workshop identified and examined the various issues that this relationship is bound to raise. In particular, it looked at trial methodology assessment procedures, the working relationship between the French National Agency of Drug Safety and Health Products (Agence Nationale de Sécurité du Médicament et des Produits de Santé, ANSM) and ethics committees during the authorization application evaluation phase, review of post-authorization/registration studies on medicinal products and medical devices, and data transparency.

Clinical performance of serum prostate-specific antigen isoform [-2]proPSA (p2PSA) and its derivatives, %p2PSA and the prostate health index (PHI), in men with a family history of prostate cancer: results from a multicentre European study, the PROMEtheuS project.

OBJECTIVES: To test the sensitivity, specificity and accuracy of serum prostate-specific antigen isoform [-2]proPSA (p2PSA), %p2PSA and the prostate health index (PHI), in men with a family history of prostate cancer (PCa) undergoing prostate biopsy for suspected PCa. To evaluate the potential reduction in unnecessary biopsies and the characteristics of potentially missed cases of PCa that would result from using serum p2PSA, %p2PSA and PHI. PATIENTS AND METHODS: The analysis consisted of a nested case-control study from the PRO-PSA Multicentric European Study, the PROMEtheuS project. All patients had a first-degree relative (father, brother, son) with PCa. Multivariable logistic regression models were complemented by predictive accuracy analysis and decision-curve analysis. RESULTS: Of the 1026 patients included in the PROMEtheuS cohort, 158 (15.4%) had a first-degree relative with PCa. p2PSA, %p2PSA and PHI values were significantly higher (P < 0.001), and free/total PSA (%fPSA) values significantly lower (P < 0.001) in the 71 patients with PCa (44.9%) than in patients without PCa. Univariable accuracy analysis showed %p2PSA (area under the receiver-operating characteristic curve [AUC]: 0.733) and PHI (AUC: 0.733) to be the most accurate predictors of PCa at biopsy, significantly outperforming total PSA ([tPSA] AUC: 0.549), free PSA ([fPSA] AUC: 0.489) and %fPSA (AUC: 0.600) (P ≤ 0.001). For %p2PSA a threshold of 1.66 was found to have the best balance between sensitivity and specificity (70.4 and 70.1%; 95% confidence interval [CI]: 58.4-80.7 and 59.4-79.5 respectively). A PHI threshold of 40 was found to have the best balance between sensitivity and specificity (64.8 and 71.3%, respectively; 95% CI 52.5-75.8 and 60.6-80.5). At 90% sensitivity, the thresholds for %p2PSA and PHI were 1.20 and 25.5, with a specificity of 37.9 and 25.5%, respectively. At a %p2PSA threshold of 1.20, a total of 39 (24.8%) biopsies could have been avoided, but two cancers with a Gleason score (GS) of 7 would have been missed. At a PHI threshold of 25.5 a total of 27 (17.2%) biopsies could have been avoided and two (3.8%) cancers with a GS of 7 would have been missed. In multivariable logistic regression models, %p2PSA and PHI achieved independent predictor status and significantly increased the accuracy of multivariable models including PSA and prostate volume by 8.7 and 10%, respectively (P ≤ 0.001). p2PSA, %p2PSA and PHI were directly correlated with Gleason score (ρ: 0.247, P = 0.038; ρ: 0.366, P = 0.002; ρ: 0.464, P < 0.001, respectively). CONCLUSIONS: %p2PSA and PHI are more accurate than tPSA, fPSA and %fPSA in predicting PCa in men with a family history of PCa. Consideration of %p2PSA and PHI results in the avoidance of several unnecessary biopsies. p2PSA, %p2PSA and PHI correlate with cancer aggressiveness.

Imaging findings of urosymphyseal fistulas.

Prostate cancer accounts for 13% of all new cancer diagnoses in the UK. Urosymphyseal fistulas are a rare complication that can occur post-radiotherapy and surgery for prostate cancer. Patients often present with non-specific symptoms such as suprapubic tenderness, poor mobility, recurrent urinary infections, and difficulty passing urine. These can be difficult to diagnose clinically and extremely problematic and debilitating for patients. The management of these patients is often complex and requires input from urology, orthopaedics, and microbiology. At present, there are no clear guidelines for diagnosing these conditions. Recommended investigations include blood tests, urine culture, and imaging. The preferred imaging modality is pelvic MRI. This article explores three rare cases of such complications and the classic imaging findings on CT and MRI to aid the diagnosis of urosymphyseal fistula.

A Rare Case of Prostatic Stromal Tumour of Uncertain Malignant Potential Surrounding Ejaculatory Ducts in a Patient With Concurrent Prostate Adenocarcinoma.

Stromal tumour of uncertain malignant potential (STUMP) is exceedingly rare. Diagnosis and management of STUMP present a challenge to the urologist due to the absence of specific clinical findings and its unpredictable clinical course. Thus, radical resection is often recommended. Here, we present a case of a 64-year-old male, who presented with mild obstructive voiding symptoms with a raised age-specific prostate-specific antigen (PSA) of 3.1. Magnetic resonance imaging (MRI) showed an area of suspicion, in an area thought to be the left seminal vesicle, containing a malignant lesion within it. Biopsy of this area and the prostate confirmed concurrent prostatic STUMP and Gleason 3+3=6 adenocarcinoma of the prostate, managed with robotic-assisted laparoscopic radical prostatectomy with wide local excision.

Multicentre clinical evaluation of the safety and performance of a simple transperineal access system for prostate biopsies for suspected prostate cancer: The CAMbridge PROstate Biopsy DevicE (CamPROBE) study.

OBJECTIVES: To report the prospective multicentre clinical evaluation of a first-in-man disposable device, Cambridge Prostate Biopsy Device, to undertake local anaesthetic outpatient transperineal prostate biopsies. MATERIAL AND METHODS: Disposable single-use Cambridge Prostate Biopsy devices were manufactured based on a previous prototype. The lead site developed a user training course and disseminated the method to other sites. The Cambridge Prostate Biopsy Device (CamPROBE) was offered as an alternative to transrectal ultrasound guided biopsy to men due for a biopsy as part of their clinical management. Data on safety (infections and device performance), clinical utility, patient reported experience, biopsy quality and cancer detection were collected. Procedure time and local anaesthetic use was recorded in the lead site. The study was funded by a United Kingdom National Institute for Health Research (NIHR) i4i product development award. RESULTS: A total of 40 patients were recruited (median age 69 y) across six sites; five sites were new to the procedure. Overall, 19/40 were first prostate biopsies and 21/40 repeat procedures. Both image-targeted and systematic biopsy cores taken. There were no infections, device deficiencies or safety issues reported. The procedure was well tolerated with excellent patient-reported perception and low pain scores (median of 3, scale 0-10). Histopathology quality was good and the overall cancer diagnosis rate (first diagnostic procedures) was 68% (13/19) and for significant cancers (⩾ histological Grade Group 2), 47% (9/19). In the lead centre (most experienced), median procedure time was 25 minutes, and median local anaesthetic use 11 ml (n=17). CONCLUSIONS: Data from this device evaluation study demonstrate that the United Kingdom-developed Cambridge Prostate Biopsy Device/method for transperineal biopsies is safe, transferable and maintains high diagnostic yields. The procedure is well tolerated by patients, suited to the local anaesthetic outpatient setting and could directly replace transrectal ultrasound guided biopsy. LEVEL OF EVIDENCE: Level III.

Discovery of 6-(2,4-Dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (SAR439859), a Potent and Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen-Receptor-Positive Breast Cancer.

More than 75% of breast cancers are estrogen receptor alpha (ERα) positive (ER+), and resistance to current hormone therapies occurs in one-third of ER+ patients. Tumor resistance is still ERα-dependent, but mutations usually confer constitutive activation to the hormone receptor, rendering ERα modulator drugs such as tamoxifen and aromatase inhibitors ineffective. Fulvestrant is a potent selective estrogen receptor degrader (SERD), which degrades the ERα receptor in drug-resistant tumors and has been approved for the treatment of hormone-receptor-positive metastatic breast cancer following antiestrogen therapy. However, fulvestrant shows poor pharmacokinetic properties in human, low solubility, weak permeation, and high metabolism, limiting its administration to inconvenient intramuscular injections. This Drug Annotation describes the identification and optimization of a new series of potent orally available SERDs, which led to the discovery of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (43d), showing promising antitumor activity in breast cancer mice xenograft models and whose properties warranted clinical evaluation.

Duodenal volvulus: report of a case.

A duodenal volvulus is a hitherto unreported condition caused by an abnormal mobility of the third and fourth parts of the duodenum. We herein report the first such case, including its presentation, management, and possible etiology.

Structural and electronic evolution of the As(OH)3 molecule in high temperature aqueous solutions: an x-ray absorption investigation.

The geometrical and electronic structure of the arsenious acid molecule As(OH)(3) in aqueous solutions has been investigated by x-ray absorption spectroscopy (XAS) within extended x-ray absorption spectroscopy (EXAFS) and x-ray absorption near edge structure (XANES), using realistic first-principle calculations in the latter case. This investigation was performed on aqueous solutions of arsenious acid from ambient to supercritical conditions (P = 250 and 600 bars, T