Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Superparamagnetic iron oxide nanoparticles coated with dextran derivative as new MRI contrast agents

Celem pracy było otrzymanie stabilnych superparamagnetycznych nanocząstek tlenku żelaza (SPIONy) pokrytych kationowo modyfikowaną pochodną dekstranu i ich charakterystyka pod kątem zastosowania jako kontrastów w obrazowaniu przy użyciu magnetycznego rezonansu jądrowego (MRI). Nanocząstki otrzymano metodą współstrącania soli żelaza(II) i żelaza(III) w środowisku zasadowym. Rozmiar zsyntetyzowanych cząstek wyznaczono metodą Dynamicznego Rozpraszania Światła, natomiast stabilność koloidalną określono na podstawie elektroforetycznego pomiaru potencjału Zeta. By zbadać efektywność otrzymanych nanocząstek jako kontrastów MRI, zmierzono czasy relaksacji T2 dla kilku próbek SPIONów o różnych stężeniach żelaza i wyznaczono relaksacyjność r2, której wartość okazała się być wysoka. Uzyskane wyniki sugerują, że otrzymane superparamagnetyczne nanoczastki tlenku żelaza pokrywane pochodną dekstranu mogłyby być efektywnymi środkami kontrastowymi w obrazowaniu metoda magnetycznego rezonansu jądrowego.The aim of the research was to obtain stable superparamagnetic iron oxide nanoparticles (SPIONs) coated with cationic derivative of dextran and to characterize them as potential MRI contrast agents. Nanoparticles were synthesized by co-precipitation of ferrous and ferric salt solutions in basic environment. Size of particles was measured using Dynamic Light Scattering technique whereas electrophoretic measurement of Zeta potential gave the information about their colloidal stability. To determine the efficacy of obtained nanoparticles as MRI contrast agents, T2 relaxation times for several samples with different iron concentration were measured. SPIONs coated with cationic derivative of dextran were found to exhibit a high relaxivity r2 value, what suggests that they could be an effective contrast agent in magnetic resonance imaging

Generowanie reaktywnych form tlenu na powierzchni nanokrystalicznych materiałów konwertujących energię "w górę" : potencjalne zastosowanie w fototerapii

Nanocząstki konwertujące energię "w górę" są nową klasą materiałów, które mogą emitować promieniowanie z zakresu widzialnego i ultrafioletu o wzbudzeniu światłem podczerwonym. Światło z zakresu bliskiej podczerwieni charakteryzuje się dużą głębokością penetracji tkanek i jego zastosowanie mogłoby potencjalnie poszerzyć zastosowanie fototerapii, w tym terapii fotodynamicznej.W ramach tej pracy zsyntetyzowano materiały na bazie nanocząstek domieszkowanych lantanowcami, mogących konwertować światło "w górę" i pokryto je warstwą tlenku tytanu, który generuje reaktywne formy tlenu po wzbudzeniu światłem ultrafiolwtowym. Dodatkowo, powierzchnię TiO2 zmodyfikowano kompleksami rutyny - sensibilizując go na światło widzialne. Otrzymane nanocząstki lantanowców wykazały silną emisję promieniwoania z zakresu UV i Vis pod wpływem wzbudzenia długością fali 980 nm. Badania XRD, EDX i pomiary absorpcyjne potwierdziły utworzenie warstwy tlenku tytanu oraz modyfikację jego powierzchni rutyną. Generowanie wolnych rodników przez tak utworzone kompozyty zostało zbadane przy pomocy kwasu tereftalowego, który w reakcji z rodnikami OH tworzy fluoryzujący produkt.Upconverting nanoparticles (UCNPs), capable of emitting visible and ultraviolet light under NIR irradiation, are the new class materials with a great potential for application in biology and medicine. Radiation from near-infrared region, with a large tissue penetration depth and minimal photodamage, would expand the use of therapies activated with light such as photodynamic therapy. In this work, attempts to obtain UCNPs-based materials with ability to generate reactive oxygen species under NIR-irradiation, were made. Therefore, small, water-dispersible core-shell lanthanide-doped upconverting nanoparticles were synthesised via the high-temperature coprecipitation method. They exhibited strong upconversion photoluminescence in the UV and visible region at 980 nm excitation wavelength. The as prepared nanoparticles were coated with a titania layer in the reaction of TiCl4 hydrolysis and then further modified with rutin to sensitise TiO2 for visible light. The XRD and EDX analyses confirmed the formation of the titanium dioxide and the UV/Vis spectrometry showed that the rutin-modified materials absorb light for wavelengths shorter than c.a. 500 nm. The generation of hydroxyl radicals by the NIR-irradiated UCNPs@TiO2 nanocomposites was assessed using terephthalic acid as the OH radical scavenger

Enhanced UV light emission by core-shell upconverting particles powering up TiO2TiO_2 photocatalysis in near-infrared light

The core-shell NaYb0.99F4:Tm0.01@NaYF4 upconverting particles (UCPs) with a high UV emission to apply in NIR-driven photocatalysis were synthesized. The influence of the Yb3+ doping concentration in NaYxF4:Yb0.99−xTm0.01 core particles, and the role of the NaYF4 shell on the upconversion emission intensity of the UCPs were studied. The absorption of NIR light by the obtained UCPs was maximized by increasing the Yb3+ concentration in the core, reaching the maximum for Y3+-free particles (NaYb0.99F4:Tm0.01). Additionally, covering the NaYb0.99F4:Tm0.01 core with a protective layer of NaYF4 minimized the surface luminescence quenching, which significantly improved the efficiency of upconversion emission. The high intensity of the UV light emitted by the NaYb0.99F4:Tm0.01@NaYF4 under NIR irradiation resulted in a high photocatalytic activity of TiO2 (P25) mixed with the synthesized material

Activation of human pro-urokinase by unrelated proteases secreted by Pseudomonas aeruginosa.

Contains fulltext : 87870.pdf (publisher's version ) (Closed access)Pathogenic bacteria, including Pseudomonas aeruginosa, interact with and engage the host plasminogen (Plg) activation system, which encompasses the urokinase (uPA)-type Plg activator, and is involved in extracellular proteolysis, including matrilysis and fibrinolysis. We hypothesized that secreted bacterial proteases might contribute to the activation of this major extracellular proteolytic system, thereby participating in bacterial dissemination. We report that LasB, a thermolysin-like metalloprotease secreted by Ps. aeruginosa, converts the human uPA zymogen into its active form (kcat=4.9 s-1, Km=8.9 microM). Accordingly, whereas the extracellular secretome from the LasB-expressing pseudomonal strain PAO1 efficiently activates pro-uPA, the secretome from the isogenic LasB-deficient strain PDO240 is markedly less potent in pro-uPA activation. Still, both secretomes induce some metalloprotease-independent activation of the human zymogen. The latter involves a serine protease, which we identified via both recombinant protein expression in Escherichia coli and purification from pseudomonal cultures as protease IV (PIV; kcat=0.73 s-1, Km=6.2 microM). In contrast, neither secretomes nor the pure proteases activate Plg. Along with this, LasB converts Plg into mini-Plg and angiostatin, whereas, as reported previously, it processes the uPA receptor, inactivates the plasminogen activator inhibitor 1, and activates pro-matrix metalloproteinase 2. PIV does not target these factors at all. To conclude, LasB and PIV, although belonging to different protease families and displaying quite different substrate specificities, both activate the urokinase-type precursor of the Plg activation cascade. Direct pro-uPA activation, as also reported for other bacterial proteases, might be a frequent phenomenon that contributes to bacterial virulence