Endoscopic dilation of complete oesophageal obstructions with a combined antegrade-retrograde rendezvous technique.

AIM: To investigate the combined antegrade-retrograde endoscopic rendezvous technique for complete oesophageal obstruction and the swallowing outcome. METHODS: This single-centre case series includes consecutive patients who were unable to swallow due to complete oesophageal obstruction and underwent combined antegrade-retrograde endoscopic dilation (CARD) within the last 10 years. The patients' demographic characteristics, clinical parameters, endoscopic therapy, adverse events, and outcomes were obtained retrospectively. Technical success was defined as effective restoration of oesophageal patency. Swallowing success was defined as either percutaneous endoscopic gastrostomy (PEG)-tube independency and/or relevant improvement of oral food intake, as assessed by the functional oral intake scale (FOIS) (≥ level 3). RESULTS: The cohort consisted of six patients [five males; mean age 71 years (range, 54-74)]. All but one patient had undergone radiotherapy for head and neck or oesophageal cancer. Technical success was achieved in five out of six patients. After discharge, repeated dilations were performed in all five patients. During follow-up (median 27 mo, range, 2-115), three patients remained PEG-tube dependent. Three of four patients achieved relevant improvement of swallowing (two patients: FOIS 6, one patient: FOIS 7). One patient developed mediastinal emphysema following CARD, without a need for surgery. CONCLUSION: The CARD technique is safe and a viable alternative to high-risk blind antegrade dilation in patients with complete proximal oesophageal obstruction. Although only half of the patients remained PEG-tube independent, the majority improved their ability to swallow.

18F-RB390: innovative ligand for imaging the T877A androgen receptor mutant in prostate cancer via positron emission tomography (PET).

BACKGROUND: Detecting prostate cancer before spreading or predicting a favorable therapy are challenging issues for impacting patient's survival. Presently, 2-[(18) F]-fluoro-2-deoxy-D-glucose ((18) F-FDG) and/or (18) F-fluorocholine ((18) F-FCH) are the generally used PET-tracers in oncology yet do not emphasize the T877A androgen receptor (AR) mutation being exclusively present in cancerous tissue and escaping androgen deprivation treatment. METHODS: We designed and synthesized fluorinated 5α-dihydrotestosterone (DHT) derivatives to target T877A-AR. We performed binding assays to select suitable candidates using COS-7 cells transfected with wild-type or T877A AR (WT-AR, T877A-AR) expressing plasmids and investigated cellular uptake of candidate (18) F-RB390. Stability, biodistribution analyses and PET-Imaging were assessed by injecting (18) F-RB390 (10MBq), with and without co-injection of an excess of unlabeled DHT in C4-2 and PC-3 tumor bearing male SCID mice (n = 12). RESULTS: RB390 presented a higher relative binding affinity (RBA) (28.1%, IC50 = 32 nM) for T877A-AR than for WT-AR (1.7%, IC50 = 357 nM) related to DHT (RBA = 100%). A small fraction of (18) F-RB390 was metabolized when incubated with murine liver homogenate or human blood for 3 hr. The metabolite of RB390, 3-hydroxysteroid RB448, presented similar binding characteristics as RB390. (18) F-RB390 but not (18) F-FDG or (18) F-FCH accumulated 2.5× more in COS-7 cells transfected with pSG5AR-T877A than with control plasmid. Accumulation was reduced with an excess of DHT. PET/CT imaging and biodistribution studies revealed a significantly higher uptake of (18) F-RB390 in T877A mutation positive xenografts compared to PC-3 control tumors. This effect was blunted with DHT. CONCLUSION: Given the differential binding capacity and the favorable radioactivity pattern, (18) F-RB390 represents the portrayal of the first imaging ligand with predictive potential for mutant T877A-AR in prostate cancer for guiding therapy. Prostate 75:348-359, 2015. © 2014 Wiley Periodicals, Inc.

Detection and functional portrayal of a novel class of dihydrotestosterone derived selective progesterone receptor modulators (SPRM).

In early pregnancy, abortion can be induced by blocking the actions of progesterone receptors (PR). However, the PR antagonist, mifepristone (RU38486), is rather unselective in clinical use because it also cross-reacts with other nuclear receptors. Since the ligand-binding domain of human progesterone receptor (hPR) and androgen receptor (hAR) share 54% identity, we hypothesized that derivatives of dihydrotestosterone (DHT), the cognate ligand for hAR, might also regulate the hPR. Compounds designed and synthesized in our laboratory were investigated for their affinities for hPRB, hAR, glucocorticoid receptor (hGRα) and mineralocorticoid receptor (hMR), using whole cell receptor competitive binding assays. Agonistic and antagonistic activities were characterized by reporter assays. Nuclear translocation was monitored using cherry-hPRB and GFP-hAR chimeric receptors. Cytostatic properties and apoptosis were tested on breast cancer cells (MCF7, T-47D). One compound presented a favorable profile with an apparent neutral hPRB antagonistic function, a selective cherry-hPRB nuclear translocation and a cytostatic effect. 3D models of human PR and AR with this ligand were constructed to investigate the molecular basis of selectivity. Our data suggest that these novel DHT-derivatives provide suitable templates for the development of new selective steroidal hPR antagonists.

Multipurpose use of the over-the-scope-clip system ("Bear claw") in the gastrointestinal tract: Swiss experience in a tertiary center.

AIM: To evaluate the outcome of over-the-scope-clip system (OTSC) for endoscopic treatment of various indications in daily clinical practice in Switzerland. METHODS: This prospective, consecutive case series was conducted at a tertiary care hospital from September 2010 to January 2014. Indications for OTSC application were fistulae, anastomotic leakage, perforation, unroofed submucosal lesion for biopsy, refractory bleeding, and stent fixation in the gastrointestinal (GI) tract. Primary technical success was defined as the adequate deployment of the OTSC on the target lesion. Clinical success was defined as resolution of the problem; for instance, no requirement for surgery or further endoscopic intervention. In cases of recurrence, retreatment of a lesion with a second intervention was possible. Complications were classified into those related to sedation, endoscopy, or deployment of the clip. RESULTS: A total of 28 OTSC system applications were carried out in 21 patients [median age 64 years (range 42-85), 33% females]. The main indications were fistulae (52%), mostly after percutaneous endoscopic gastrostomy tube removal, and anastomotic leakage after GI surgery (29%). Further indications were unroofed submucosal lesions after biopsy, upper gastrointestinal bleeding, or esophageal stent fixation. The OTSC treatments were applied either in the upper (48%) or lower (52%) GI tract. The mean lesion size was 8 mm (range: 2-20 mm). Primary technical success and clinical success rates were 85% and 67%, respectively. In 53% of cases, the suction method was used without accessories (e.g., twin grasper or tissue anchor). No endoscopy-related or OTSC-related complications were observed. CONCLUSION: OTSC is a useful tool for endoscopic closure of various GI lesions, including fistulae and leakages. Future randomized prospective multicenter trials are warranted.

First report of colonoscopic closure of a gastrocolocutaneous PEG migration with over-the-scope-clip-system.

Percutaneous endoscopic gastrostomy (PEG) is a common practice for long-term nutrition of patients who are unable to take oral food. We report of an 85-year old man with a history of recurrent larynx carcinoma and hemicolectomy many years ago due to unknown reason. Laryngectomy was indicated. Preoperatively a PEG was inserted endoscopically after an abdominal ultrasonography without abnormal findings. Few months after PEG insertion, the patient was evaluated for diarrhea and insufficient feeding without signs of infection or peritonism. An upper endoscopy and computed tomography scan confirmed a buried bumper syndrome with migration of the PEG tube into the colon as a rare complication. He underwent successful colonoscopic removal of the internal bumper and closure of the colonic orifice of the fistula with the over-the-scope-clip system (OTSC). OTSC is an endoscopic device for treatment of bleeding, perforation, leak and fistula in the gastrointestinal tract. To the best of our knowledge, this is the first report of the use of OTSC for colonoscopic closure of a gastrocolocutaneous fistula due to a buried bumper syndrome with transcolonic PEG tube migration.

A novel steroidal antiandrogen targeting wild type and mutant androgen receptors.

Prostate cancer (PCa) progression is enhanced by androgen and treatment with antiandrogens represents an alternative to castration. While patients initially respond favorably to androgen ablation therapy, most experience a relapse of the disease within 1-2 years by expressing androgen receptor (AR) mutants. Such mutations, indeed, promote unfavorable agonistic behavior from classical antagonists. Here, we have synthesized and screened 37 novel compounds derived from dihydrotestosterone (DHT), cyanolutamide and hydroxyflutamide. These derivatives were tested for their potential antagonistic activity using a luciferase reporter gene assay and binding properties were determined for wild type (WT) and mutant ARs (T877A, W741C, W741L, H874Y). In the absence and presence of antiandrogens, androgen dependent cellular proliferation and prostate specific antigen (PSA) expression were assayed in the prostate cancer cell line LNCaP by crystal violet, real time PCR and by Western blots. Also, cellular proliferation and PSA expression were assayed in 22Rv1. A novel compound RB346, derived from DHT, was found to be an antagonist for all tested AR forms, preventing DHT induced proliferation and PSA expression in LNCaP and 22Rv1 cells. RB346 displayed no agonistic activity, in contrast to the non-steroidal antiandrogen bicalutamide (Casodex) with unfavorable agonistic activity for W741L-AR. Additionally, RB346 has a slightly higher binding affinity for WT-AR, T877A-AR and H874Y-AR than bicalutamide. Thus, RB346 is the first potent steroidal antiandrogen with efficacy for WT and various AR mutants.