Rosuvastatin and cardiovascular events in patients undergoing hemodialysis

Statins reduce the incidence of cardiovascular events in patients at high cardiovascular risk. However, a benefit of statins in such patients who are undergoing hemodialysis has not been proved.

Effect of precursor on the performance of alumina for the dehydration of methanol to dimethyl ether

Dimethyl ether (DME) is amongst one of the most promising alternative, renewable and clean fuels being considered as a future energy carrier. In this study, the comparative catalytic performance of γ-Al2O3 prepared from two common precursors (aluminum nitrate (AN) and aluminum chloride (AC)) is presented. The impact of calcination temperature was evaluated in order to optimize both the precursor and pre-treatment conditions for the production of DME from methanol in a fixed bed reactor. The catalysts were characterized by TGA, XRD, BET and TPD-pyridine. Under reaction conditions where the temperature ranged from 180 °C to 300 °C with a WHSV = 12.1 h−1 it was found that all the catalysts prepared from AN(η-Al2O3) showed higher activity, at all calcination temperatures, than those prepared from AC(γ-Al2O3). In this study the optimum catalyst was produced from AN and calcined at 550 °C. This catalyst showed a high degree of stability and had double the activity of the commercial γ-Al2O3 or 87% of the activity of commercial ZSM-5(80) at 250 °C.

Impact of geometric variations on delivered dose in highly focused single vocal cord IMRT

Purpose. To investigate the robustness of single vocal cord intensity modulated radiation therapy (IMRT) treatment plans for set-up errors, respiration, and deformation. Material and methods. Four-dimensional computed tomography (4D-CT) scans of 10 early glottic carcinoma patients, previously treated with conventional techniques, were used in this simulation study. For each patient a pre-treatment 4D-CT was used for IMRT planning, generating a reference dose distribution. Prescribed PTV dose was 66 Gy. The impact of systematic set-up errors was simulated by applying shifts of ± 2 mm to the planning CT scans, followed by dose re-calculation with original beam segments, MUs, etc. Effects of respiration and deformation were determined utilizing extreme inhale and exhale CT scans, and repeat scans acquired after 22 Gy, 44 Gy, and 66 Gy, respectively. All doses were calculated using Monte Carlo dose simulations. Results. Considering all investigated geometrical perturbations, reductions in the clinical target volume (CTV) V95%, D98%, D2%, and generalized equivalent uniform dose (gEUD) were limited to 1.2 ± 2.2%, 2.4 ± 2.9%, 0.2 ± 1.8%, and 0.6 ± 1.1 Gy, respectively. The near minimum dose, D98%, was always higher than 89%, and gEUD always remained higher than 66 Gy. Planned contra-lateral (CL) vocal cord DMean, gEUD, and V40 Gy were 38.2 ± 6.0 Gy, 43.4 ± 5.6 Gy, and 42.7 ± 14.9%. With perturbations these values changed by -0.1 ± 4.3 Gy, 0.1 ± 4.0 Gy, and -1.0 ± 9.6%, respectively. Conclusions. On average, CTV dose reductions due to geometrical perturbations were very low, and sparing of the CL vocal cord was maintained. In a few observations (6 of 103 simulated situations), the near-minimum CTV-dose was around 90%, requiring attention in deciding on a future clinical protocol. 

Volumetric modulated arc therapy and breath-hold in image-guided locoregional left-sided breast irradiation

PURPOSE: To investigate the effects of using volumetric modulated arc therapy (VMAT) and/or voluntary moderate deep inspiration breath-hold (vmDIBH) in the radiation therapy (RT) of left-sided breast cancer including the regional lymph nodes.

MATERIALS AND METHODS: For 13 patients, four treatment combinations were compared; 3D-conformal RT (i.e., forward IMRT) in free-breathing 3D-CRT(FB), 3D-CRT(vmDIBH), 2 partial arcs VMAT(FB), and VMAT(vmDIBH). Prescribed dose was 42.56 Gy in 16 fractions. For 10 additional patients, 3D-CRT and VMAT in vmDIBH only were also compared.

RESULTS: Dose conformity, PTV coverage, ipsilateral and total lung doses were significantly better for VMAT plans compared to 3D-CRT. Mean heart dose (D(mean,heart)) reduction in 3D-CRT(vmDIBH) was between 0.9 and 8.6 Gy, depending on initial D(mean,heart) (in 3D-CRT(FB) plans). VMAT(vmDIBH) reduced the D(mean,heart) further when D(mean,heart) was still >3.2 Gy in 3D-CRT(vmDIBH). Mean contralateral breast dose was higher for VMAT plans (2.7 Gy) compared to 3DCRT plans (0.7 Gy).

CONCLUSIONS: VMAT and 3D-CRT(vmDIBH) significantly reduced heart dose for patients treated with locoregional RT of left-sided breast cancer. When Dmean,heart exceeded 3.2 Gy in 3D-CRT(vmDIBH) plans, VMAT(vmDIBH) resulted in a cumulative heart dose reduction. VMAT also provided better target coverage and reduced ipsilateral lung dose, at the expense of a small increase in the dose to the contralateral breast.

Single vocal cord irradiation:a competitive treatment strategy in early glottic cancer

INTRODUCTION: The treatment of choice for early glottic cancer is still being debated; ultimately it relies on the functional outcome. This paper reports on a novel sparing 4D conformal technique for single vocal cord irradiation (SVCI).

MATERIAL AND METHODS: The records of 164 T1a patients with SCC of the vocal cord, irradiated in the Erasmus MC between 2000 and 2008, were analyzed for local control and overall survival. The quality of life was determined by EORTC H&N35 questionnaires. Also the VHI (voice handicap index), and the TSH (thyroid stimulating hormone) blood levels, were established. On-line image guided SVCI, using cone beam CT or stereotactic radiation therapy (SRT) techniques, were developed.

RESULTS: A LC rate at five-years of 93% and a VHI of 12.7 (0-63) was determined. It appeared feasible to irradiate one vocal cord within 1-2mm accuracy. This way sparing of the contralateral (CL) vocal cord and CL normal tissues, could be achieved.

CONCLUSIONS: Given the accuracy (1-2mm) and small volume disease (CTV limited to one vocal cord), for the use of stereotactic RT techniques SVCI with large fraction sizes is currently being investigated in clinic. It is argued that hypofractionated SVCI can be a competitive alternative to laser surgery.

Accelerated partial breast irradiation (APBI): Are breath-hold and volumetric radiation therapy techniques useful?

Background: In a selective group of patients accelerated partial breast irradiation (APBI) might be applied after conservative breast surgery to reduce the amount of irradiated healthy tissue. The role of volumetric modulated arc therapy (VMAT) and voluntary moderately deep inspiration breath-hold (vmDIBH) techniques in further reducing irradiated healthy – especially heart – tissue is investigated.

Material and methods: For 37 partial breast planning target volumes (PTVs), three-dimensional conformal radiotherapy (3D-CRT) (3 – 5 coplanar or non-coplanar 6 and/or 10 MV beams) and VMAT (two partial 6 MV arcs) plans were made on CTs acquired in free-breathing (FB) and/or in vmDIBH. Dose-volume parameters for the PTV, heart, lungs, and breasts were compared. 

Results: Better dose conformity was achieved with VMAT compared to 3D-CRT (conformity index 1.24 0.09 vs. 1.49 0.20). Non-PTV ipsilateral breast receiving 50% of the prescribed dose was on average reduced by 28% in VMAT plans compared to 3D-CRT plans. Mean heart dose (MHD) reduced from 2.0 (0.1 – 5.1) Gy in 3D-CRT(FB) to 0.6 (0.1 – 1.6) Gy in VMAT(vmDIBH). VMAT is benefi cial for MHD reduction if MHD with 3D-CRT exceeds 0.5Gy. Cardiac dose reduction as a result of VMAT increases with increasing initial MHD, and adding vmDIBH reduces the cardiac dose further. Mean dose to the ipsilateral lung decreased from 3.7 (0.7 – 8.7) to 1.8 (0.5 – 4.0) Gy with VMAT(vmDIBH) compared to 3D-CRT(FB). VMAT resulted in a slight increase in the contralateral breast dose (DMean ) always remaining 1.9 Gy). 

Conclusions: For APBI patients, VMAT improves PTV dose conformity and delivers lower doses to the ipsilateral breast and lung compared to 3D-CRT. This goes at the cost of a slight but acceptable increase of the contralateral breast dose. VMAT reduces cardiac dose if MHD exceeds 0.5 Gy for 3D-CRT. Adding vmDIBH results in a further reduction of heart and ipsilateral lung dose. 

IMRT for image-guided single vocal cord irradiation

PURPOSE: We have been developing an image-guided single vocal cord irradiation technique to treat patients with stage T1a glottic carcinoma. In the present study, we compared the dose coverage to the affected vocal cord and the dose delivered to the organs at risk using conventional, intensity-modulated radiotherapy (IMRT) coplanar, and IMRT non-coplanar techniques.

METHODS AND MATERIALS: For 10 patients, conventional treatment plans using two laterally opposed wedged 6-MV photon beams were calculated in XiO (Elekta-CMS treatment planning system). An in-house IMRT/beam angle optimization algorithm was used to obtain the coplanar and non-coplanar optimized beam angles. Using these angles, the IMRT plans were generated in Monaco (IMRT treatment planning system, Elekta-CMS) with the implemented Monte Carlo dose calculation algorithm. The organs at risk included the contralateral vocal cord, arytenoids, swallowing muscles, carotid arteries, and spinal cord. The prescription dose was 66 Gy in 33 fractions.

RESULTS: For the conventional plans and coplanar and non-coplanar IMRT plans, the population-averaged mean dose ± standard deviation to the planning target volume was 67 ± 1 Gy. The contralateral vocal cord dose was reduced from 66 ± 1 Gy in the conventional plans to 39 ± 8 Gy and 36 ± 6 Gy in the coplanar and non-coplanar IMRT plans, respectively. IMRT consistently reduced the doses to the other organs at risk.

CONCLUSIONS: Single vocal cord irradiation with IMRT resulted in good target coverage and provided significant sparing of the critical structures. This has the potential to improve the quality-of-life outcomes after RT and maintain the same local control rates.

On-line cone beam CT image guidance for vocal cord tumor targeting

Background and purpose: We are developing a technique for highly focused vocal cord irradiation in early glottic carcinoma to optimally treat a target volume confined to a single cord. This technique, in contrast with the conventional methods, aims at sparing the healthy vocal cord. As such a technique requires sub-mm daily targeting accuracy to be effective, we investigate the accuracy achievable with on-line kV-cone beam CT (CBCT) corrections. Materials and methods: CBCT scans were obtained in 10 early glottic cancer patients in each treatment fraction. The grey value registration available in X-ray volume imaging (XVI) software (Elekta, Synergy) was applied to a volume of interest encompassing the thyroid cartilage. After application of the thus derived corrections, residue displacements with respect to the planning CT scan were measured at clearly identifiable relevant landmarks. The intra- and inter-observer variations were also measured. Results: While before correction the systematic displacements of the vocal cords were as large as 2.4 ± 3.3 mm (cranial-caudal population mean ± SD Σ), daily CBCT registration and correction reduced these values to less than 0.2 ± 0.5 mm in all directions. Random positioning errors (SD σ) were reduced to less than 1 mm. Correcting only for translations and not for rotations did not appreciably affect this accuracy. The residue random displacements partly stem from intra-observer variations (SD = 0.2-0.6 mm). Conclusion: The use of CBCT for daily image guidance in combination with standard mask fixation reduced systematic and random set-up errors of the vocal cords to <1 mm prior to the delivery of each fraction dose. Thus, this facilitates the high targeting precision required for a single vocal cord irradiation. © 2009 Elsevier Ireland Ltd. All rights reserved.

Four-dimensional CT analysis of vocal cords mobility for highly focused single vocal cord irradiation

Background and Purpose: To quantify respiratory motion of the vocal cords during normal respiration using 4D-CT. The final goal is to develop a technique for single vocal cord irradiation (SVCI) in early glottic carcinoma. Sparing the non-involved cord and surrounding structures has the potential to preserve voice quality and allow re-irradiation of recurrent and second primary tumors. Material and methods: Four-dimensional CTs of 1 mm slice thickness from 10 early glottic carcinoma patients were acquired. The lateral dimensions of the air gap separating the vocal cords were measured anteriorly, at mid-level and posteriorly at each phase of the 4D-CTs. The corresponding anterior-posterior gaps were similarly measured. Cranio-caudal vocal cords movements during breathing were derived from the shifts of the arythenoids. Results: The population-averaged mean gap size ± the corresponding standard deviation due to breathing (SD_B) for the lateral gaps was 5.8 ± 0.7 mm anteriorly, 8.7 ± 0.9 mm at mid-level, and 11.0 ± 1.3 mm posteriorly. Anterior-posterior gap values were 21.7 ± 0.7 mm, while cranio-caudal shift SD_B was 0.8 mm. Conclusion: Vocal cords breathing motions were found to be small relative to their separation. Hence, breathing motion does not seem to be a limiting factor for SVCI. © 2008 Elsevier Ireland Ltd. All rights reserved.

Fluence dependence of the surface roughness of InP after N2 + bombardment

InP(1 0 0) surfaces were sputtered under ultrahigh vacuum conditions by 5 keV N2+ ions at an angle of incidence of 41° to the sample normal. The fluence, φ, used in this study, varied from 1 × 10¹⁴ to 5 × 10¹⁸ N2+ cm^-2. The surface topography was investigated using field emission scanning electron microscopy (FE-SEM) and atomic force microscopy (AFM). At the lower fluences (φ ≤ 5 × 10¹⁶ N2+ cm^-2) only conelike features appeared, similar in shape as was found for noble gas ion bombardment of InP. At the higher fluences, ripples also appeared on the surface. The bombardment-induced topography was quantified using the rms roughness. This parameter showed a linear relationship with the logarithm of the fluence. A model is presented to explain this relationship. The ripple wavelength was also determined using a Fourier transform method. These measurements as a function of fluence do not agree with the predictions of the Bradley-Harper theory. © 2004 Elsevier B.V. All rights reserved.

Inter- and Intrafraction Target Motion in Highly Focused Single Vocal Cord Irradiation of T1a Larynx Cancer Patients

PURPOSE: The purpose of this study was to verify clinical target volume-planning target volume (CTV-PTV) margins in single vocal cord irradiation (SVCI) of T1a larynx tumors and characterize inter- and intrafraction target motion.

METHODS AND MATERIALS: For 42 patients, a single vocal cord was irradiated using intensity modulated radiation therapy at a total dose of 58.1 Gy (16 fractions × 3.63 Gy). A daily cone beam computed tomography (CBCT) scan was performed to online correct the setup of the thyroid cartilage after patient positioning with in-room lasers (interfraction motion correction). To monitor intrafraction motion, CBCT scans were also acquired just after patient repositioning and after dose delivery. A mixed online-offline setup correction protocol ("O2 protocol") was designed to compensate for both inter- and intrafraction motion.

RESULTS: Observed interfraction, systematic (Σ), and random (σ) setup errors in left-right (LR), craniocaudal (CC), and anteroposterior (AP) directions were 0.9, 2.0, and 1.1 mm and 1.0, 1.6, and 1.0 mm, respectively. After correction of these errors, the following intrafraction movements derived from the CBCT acquired after dose delivery were: Σ = 0.4, 1.3, and 0.7 mm, and σ = 0.8, 1.4, and 0.8 mm. More than half of the patients showed a systematic non-zero intrafraction shift in target position, (ie, the mean intrafraction displacement over the treatment fractions was statistically significantly different from zero; P<.05). With the applied CTV-PTV margins (for most patients 3, 5, and 3 mm in LR, CC, and AP directions, respectively), the minimum CTV dose, estimated from the target displacements observed in the last CBCT, was at least 94% of the prescribed dose for all patients and more than 98% for most patients (37 of 42). The proposed O2 protocol could effectively reduce the systematic intrafraction errors observed after dose delivery to almost zero (Σ = 0.1, 0.2, 0.2 mm).

CONCLUSIONS: With adequate image guidance and CTV-PTV margins in LR, CC, and AP directions of 3, 5, and 3 mm, respectively, excellent target coverage in SVCI could be ensured.

STAT3 regulated ARF expression suppresses prostate cancer metastasis

Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19(ARF) as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF-Mdm2-p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14(ARF) expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.

Phenotype-Based Discovery of 2-[(E)-2-(Quinolin-2-yl)vinyl]phenol as a Novel Regulator of Ocular Angiogenesis

Retinal angiogenesis is tightly regulated to meet oxygenation and nutritional requirements. In diseases such as proliferative diabetic retinopathy and neovascular age-related macular degeneration, uncontrolled angiogenesis can lead to blindness. Our goal is to better understand the molecular processes controlling retinal angiogenesis and discover novel drugs that inhibit retinal neovascularization. Phenotype-based chemical screens were performed using the ChemBridge Diverset^TM library and inhibition of hyaloid vessel angiogenesis in Tg(fli1:EGFP) zebrafish. 2-[(E)-2-(Quinolin-2-yl)vinyl]phenol, (quininib) robustly inhibits developmental angiogenesis at 4–10 μM in zebrafish and significantly inhibits angiogenic tubule formation in HMEC-1 cells, angiogenic sprouting in aortic ring explants, and retinal revascularization in oxygen-induced retinopathy mice. Quininib is well tolerated in zebrafish, human cell lines, and murine eyes. Profiling screens of 153 angiogenic and inflammatory targets revealed that quininib does not directly target VEGF receptors but antagonizes cysteinyl leukotriene receptors 1 and 2 (CysLT_1–2) at micromolar IC₅₀ values. In summary, quininib is a novel anti-angiogenic small-molecule CysLT receptor antagonist. Quininib inhibits angiogenesis in a range of cell and tissue systems, revealing novel physiological roles for CysLT signaling. Quininib has potential as a novel therapeutic agent to treat ocular neovascular pathologies and may complement current anti-VEGF biological agents.