Evaluating Proton Dose and Associated Range Uncertainty Using Daily Cone-Beam CT.

Purpose: This study aimed to quantitatively evaluate the range uncertainties that arise from daily cone-beam CT (CBCT) images for proton dose calculation compared to CT using a measurement-based technique. Methods: For head and thorax phantoms, wedge-shaped intensity-modulated proton therapy (IMPT) treatment plans were created such that the gradient of the wedge intersected and was measured with a 2D ion chamber array. The measured 2D dose distributions were compared with 2D dose planes extracted from the dose distributions using the IMPT plan calculated on CT and CBCT. Treatment plans of a thymoma cancer patient treated with breath-hold (BH) IMPT were recalculated on 28 CBCTs and 9 CTs, and the resulting dose distributions were compared. Results: The range uncertainties for the head phantom were determined to be 1.2% with CBCT, compared to 0.5% for CT, whereas the range uncertainties for the thorax phantom were 2.1% with CBCT, compared to 0.8% for CT. The doses calculated on CBCT and CT were similar with similar anatomy changes. For the thymoma patient, the primary source of anatomy change was the BH uncertainty, which could be up to 8 mm in the superior-inferior (SI) direction. Conclusion: We developed a measurement-based range uncertainty evaluation method with high sensitivity and used it to validate the accuracy of CBCT-based range and dose calculation. Our study demonstrated that the CBCT-based dose calculation could be used for daily dose validation in selected proton patients.

Dosimetric evaluation of cone-beam CT-based synthetic CTs in pediatric patients undergoing intensity-modulated proton therapy.

PURPOSE: To evaluate dosimetric changes detected using synthetic computed tomography (sCT) derived from online cone-beam CTs (CBCT) in pediatric patients treated using intensity-modulated proton therapy (IMPT). METHODS: Ten pediatric patients undergoing IMPT and aligned daily using proton gantry-mounted CBCT were identified for retrospective analysis with treated anatomical sites fully encompassed in the CBCT field of view. Dates were identified when the patient received both a CBCT and a quality assurance CT (qCT) for routine dosimetric evaluation. sCTs were generated based on a deformable registration between the initial plan CT (pCT) and CBCT. The clinical IMPT plans were re-computed on the same day qCT and sCT, and dosimetric changes due to tissue change or response from the initial plan were computed using each image. Linear regression analysis was performed to determine the correlation between dosimetric changes detected using the qCT and the sCT. Gamma analysis was also used to compare the dose distributions computed on the qCT and sCT. RESULTS: The correlation coefficients (p-values) between qCTs and sCTs for changes detected in target coverage, overall maximum dose, and organ at risk dose were 0.97 (< .001), 0.84 (.002) and 0.91 (< .001), respectively. Mean ± SD gamma pass rates of the sCT-based dose compared to the qCT-based dose at 3%/3 mm, 3%/2 mm, and 2%/2 mm criteria were 96.5%±4.5%, 93.2%±6.3%, and 91.3%±7.8%, respectively. Pass rates tended to be lower for targets near lung. CONCLUSION: While insufficient for re-planning, sCTs provide approximate dosimetry without administering additional imaging dose in pediatric patients undergoing IMPT. Dosimetric changes detected using sCTs are correlated with changes detected using clinically-standard qCTs; however, residual differences in dosimetry remain a limitation. Further improvements in sCT image quality may both improve online dosimetric evaluation and reduce imaging dose for pediatric patients by reducing the need for routine qCTs.

Diagnostic performance of 18F-FDG PET/CT for the detection of occult primary tumors in squamous cell carcinoma of unknown primary in the head and neck: a single-center retrospective study.

OBJECTIVE: To investigate the diagnostic performance of 18F-FDG PET/computed tomography (CT) for the detection of occult primary tumors in patients with squamous cell carcinoma of unknown primary (SCCUP) in the head and neck. PATIENTS: From March 2016 to January 2020, 37 patients diagnosed as SCCUP before PET/CT were retrospectively reviewed. The diagnosis of SCCUP was made when an overt primary tumor location could not be found for histologically proven squamous cell cervical lymphadenopathy after a complete diagnostic workup which includes full medical history, physical examinations, flexible rhinolaryngoscopy and CT or MRI. The PET/CT images were visually assessed by two nuclear medicine radiologists. Histopathological investigations after the PET scan served as the reference standard. RESULTS: The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of PET/CT for SCCUP were 71.4, 43.8, 62.5, 53.9 and 59.5%, respectively. PET/CT allowed identification of previously undetected lesions in 40.5% of the SCCUP patients. A total of 24 PET/CT scans indicated a positive result. Among them, nine were categorized into false-positive because of negative results from subsequent targeted and random biopsies. There were 13 PET/CT scans with a negative result, six of which, however, were revealed to have a primary site by subsequent random biopsies. CONCLUSION: 18F-FDG PET/CT was shown to be useful in detecting a primary tumor for SCCUP, but had limitations in terms of both false-positive cases and false-negative cases. Therefore, histopathological investigations such as targeted and random biopsy should be viewed as necessary practice irrespective of PET/CT results.

Erratum: Role of macrophage migration inhibitory factor in mesenchymal epithelial transition of cervical carcinoma cells.

[This corrects the article on p. 9621 in vol. 10, PMID: 31966840.].

MiR-338 suppresses cell proliferation and invasion by targeting CTBP2 in glioma.

BACKGROUND: Previous studies indicated that microRNA-338-5p (miR-338-5p) functions as tumor suppressor in some cancer types including glioma. However, the clinical significance and biological function of miR-338-5p in glioma still need to be explored. METHODS: We used quantitative real time PCR (qRT-PCR) to detect the miR-338-5p expression in the 44 cases of glioma tissues and adjacent normal tissues. In vitro, CCK8 cell proliferation, cell colony formation, transwell invasion assay and flow cytometry analysis were performed to explore the effects of miR-338-5p on cell proliferation, cell invasion and cell cycle distribution. Dual luciferase assay, qRT-PCR and western blot analysis were applied to validate CTBP2 was a direct target of miR-338-5p in glioma cells. RESULTS: we demonstrated that miR-338-5p was significantly lower expression in 44 glioma patients, compared with adjacent normal tissues. MiR-338-5p expression was significantly correlated with glioma grades and Karnofsky Performance Status in patients. We then validated that increased miR-338-5p significantly inhibited the cell proliferation, cell invasion and epithelial-mesenchymal transition (EMT) in vitro. Moreover, Dual luciferase assay results indicated that CTBP2 was direct target of miR-338-5p in glioma cells. Meanwhile, CTBP2 silencing can rescued the phenotype changes induced by miR-338-5p inhibitor on cell proliferation and invasion in glioma. CONCLUSION: Our results suggested that miR-338-5p acts as tumor suppressor and could be a potential therapeutic target for glioma.

Role of macrophage migration inhibitory factor in mesenchymal epithelial transition of cervical carcinoma cells.

Cervical cancer is a kind of female malignant tumor with increasing incidence recently. Macrophage migration inhibitory factor (MIF) is a major tumor facilitating factor. The previous study suggests that there was a correlation between MIF and migration or invasion of tumors. Epithelial mesenchymal transition (EMT) is the basis for tumor invasion and migration. Therefore, this study utilized MFI to treat cervical carcinoma Hela cells, and the mechanism of EMT was also further analyzed. Cervical carcinoma Hela cells were transfected with pFenesil MIF siRNA plasmids, following by real-time fluorescent quantitative PCR to detect MIF levels. MTT assay was then utilized for evaluate the proliferative activity of Hela cells after transfection. The cell invasion and migration were examined. The expression of E-cadherin and Vimentin were also detected. The results indicated that the MIF was positively expressed in Hela cells, whose MIF mRNA level was increased after the transfection (P<0.05). Compared to the control or blank group, the transfected group had elevated proliferative activity with elongated incubation time (P<0.05). Both invasion and migration functions of transfected cells were significantly potentiated (P<0.05) compared to the control or blank group. E-cadherin expression level was also decreased in experimental group. MIF was also expressed in cervical carcinoma Hela cells. Elevated MIF level could facilitate the cell invasion and migration, and elevate the Vimentin and decrease E-cadherin expression, thus facilitating EMT.

Ubiquitin-specific Protease 15 Negatively Regulates Virus-induced Type I Interferon Signaling via Catalytically-dependent and -independent Mechanisms.

Viral infection triggers a series of signaling cascades, which converge to activate the transcription factors nuclear factor-κB (NF-κB) and interferon regulatory factor 3 (IRF3), thereby inducing the transcription of type I interferons (IFNs). Although not fully characterized, these innate antiviral responses are fine-tuned by dynamic ubiquitination and deubiquitination processes. In this study, we report ubiquitin-specific protease (USP) 15 is involved in regulation of the retinoic acid-inducible gene I (RIG-I)-dependent type I IFN induction pathway. Knockdown of endogenous USP15 augmented cellular antiviral responses. Overexpression of USP15 inhibited the transcription of IFN-ß. Further analyses identified histidine 862 as a critical residue for USP15's catalytic activity. Interestingly, USP15 specifically removed lysine 63-linked polyubiquitin chains from RIG-I among the essential components in RIG-I-like receptor-dependent pathway. In addition, we demonstrated that in contrast to USP15 de-ubiquitinating (DUB) activity, USP15-mediated inhibition of IFN signaling was not abolished by mutations eliminating the catalytic activity, indicating that a fraction of USP15-mediated IFN antagonism was independent of the DUB activity. Catalytically inactive USP15 mutants, as did the wild-type protein, disrupted virus-induced interaction of RIG-I and IFN-ß promoter stimulator 1. Taken together, our data demonstrate that USP15 acts as a negative regulator of RIG-I signaling via DUB-dependent and independent mechanisms.

Downregulation of the expression of B­cell lymphoma-extra large by RNA interference induces apoptosis and enhances the radiosensitivity of non­small cell lung cancer cells.

B-cell lymphoma-extra large (Bcl-xL), an important member of anti-apoptotic Bcl-2 family, is involved in tumor progression and development. The overexpression of Bcl-xL is associated with radioresistance of human malignancies. The present study aimed to investigate the inhibitory effect of small interfering RNA (siRNA) on the expression of Bcl-xL in the A549 non-small lung cancer (NSCLC) cell line, and its role in inducing the apoptosis and increasing the radiosensitivity of A549 cells. An siRNA expression vector, pSilencer4-CMVneo-short hairpin (sh)RNA, was constructed and stably transfected into A549 cells. The effects of Bcl-xL-shRNA on cell proliferation, apoptosis and the protein expression levels of associated proteins were assessed in vitro in the A549 cells. The radiosensitivity of the A549 cells was evaluated using a clonogenic cell survival assay. The results demonstrated that the sequence-specific siRNA targeting Bcl-xL efficiently and specifically downregulated the mRNA and protein expression levels of Bcl-xL. The RNA interference-mediated downregulation in the expression of Bcl-xL inhibited cell proliferation, induced apoptosis and reduced the radioresistance of the NSCLC cells. These findings suggested that Bcl-xL may be a promising therapeutic approach for the treatment of NSCLC.

Genistein enhances the effect of cisplatin on the inhibition of non-small cell lung cancer A549 cell growth in vitro and in vivo.

Although cisplatin (DDP) has been reported to be a promising antitumor therapy for non-small cell lung cancer (NSCLC), the effectiveness of the treatment remains limited due to an inherent tumor resistance to DDP. Genistein (GEN) is an abundant, naturally occurring isoflavonoid found in soy products that has been demonstrated to increase the anti-neoplastic activity of certain chemotherapy drugs in multiple tumor types. In the present study, DDP in combination with GEN was selected as a potential treatment to suppress tumor growth and simultaneously reduce the doses of the two drugs required for the treatment of NSCLC. Cell growth inhibition, apoptosis, cell cycle distribution and receptor signaling assays were conducted. In the in vivo study, DDP and GEN, either alone or in combination, were used to treat a xenograft model of the A549 cells. It was found that the combination of low concentrations of DDP and GEN induced significantly greater growth inhibition (P<0.01) and increased apoptosis in the A549 cells compared with either agent alone. In addition, DDP in combination with GEN could significantly suppress tumor growth in vivo compared with either agent alone. Combination treatment significantly suppresses constitutive phosphorylation of AKT and phosphoinositide-3 kinase, which may contribute to the inhibition of tumor growth. Overall, the present data suggested that GEN can increase the anti-neoplastic activity of DDP and that a combination of GEN and DDP is a potential drug candidate for the treatment of NSCLC.

Correlation of dose computed using different algorithms with local control following stereotactic ablative radiotherapy (SABR)-based treatment of non-small-cell lung cancer.

PURPOSE: To retrospectively compute dose distributions for lung cancer patients treated with SABR, and to correlate dose distributions with outcome using a tumor control probability (TCP) model. METHODS: Treatment plans for 133 NSCLC patients treated using 12 Gy/fxn × 4 (BED=106 Gy), and planned using a pencil-beam (1D-equivalent-path-length, EPL-1D) algorithm were retrospectively re-calculated using model-based algorithms (including convolution/superposition, Monte Carlo). 4D imaging was performed to manage motion. TCP was computed using the Marsden model and associations between dose and outcome were inferred. RESULTS: Mean D95 reductions of 20% (max.=33%) were noted with model-based algorithms (relative to EPL-1D) for the smallest tumors (PTV<20 cm(3)), corresponding to actual delivered D95 BEDs of ≈ 60-85 Gy. For larger tumors (PTV>100 cm(3)), D95 reductions were ≈ 10% (BED>100 Gy). Mean lung doses (MLDs) were 15% lower for model-based algorithms for PTVs<20 cm(3). No correlation between tumor size and 2-year local control rate was observed clinically, consistent with TCP calculations, both of which were ≈ 90% across all PTV bins. CONCLUSION: Results suggest that similar control rates might be achieved for smaller tumors using lower BEDs relative to larger tumors. However, more studies with larger patient cohorts are necessary to confirm this possible finding.

An assessment of PTV margin based on actual accumulated dose for prostate cancer radiotherapy.

The purpose of this work is to present the results of a margin reduction study involving dosimetric and radiobiologic assessment of cumulative dose distributions, computed using an image guided adaptive radiotherapy based framework. Eight prostate cancer patients, treated with 7-9, 6 MV, intensity modulated radiation therapy (IMRT) fields, were included in this study. The workflow consists of cone beam CT (CBCT) based localization, deformable image registration of the CBCT to simulation CT image datasets (SIM-CT), dose reconstruction and dose accumulation on the SIM-CT, and plan evaluation using radiobiological models. For each patient, three IMRT plans were generated with different margins applied to the CTV. The PTV margin for the original plan was 10 mm and 6 mm at the prostate/anterior rectal wall interface (10/6 mm) and was reduced to: (a) 5/3 mm, and (b) 3 mm uniformly. The average percent reductions in predicted tumor control probability (TCP) in the accumulated (actual) plans in comparison to the original plans over eight patients were 0.4%, 0.7% and 11.0% with 10/6 mm, 5/3 mm and 3 mm uniform margin respectively. The mean increase in predicted normal tissue complication probability (NTCP) for grades 2/3 rectal bleeding for the actual plans in comparison to the static plans with margins of 10/6, 5/3 and 3 mm uniformly was 3.5%, 2.8% and 2.4% respectively. For the actual dose distributions, predicted NTCP for late rectal bleeding was reduced by 3.6% on average when the margin was reduced from 10/6 mm to 5/3 mm, and further reduced by 1.0% on average when the margin was reduced to 3 mm. The average reduction in complication free tumor control probability (P+) in the actual plans in comparison to the original plans with margins of 10/6, 5/3 and 3 mm was 3.7%, 2.4% and 13.6% correspondingly. The significant reduction of TCP and P+ in the actual plan with 3 mm margin came from one outlier, where individualizing patient treatment plans through margin adaptation based on biological models, might yield higher quality treatments.

Expression of AFP and STAT3 is involved in arsenic trioxide-induced apoptosis and inhibition of proliferation in AFP-producing gastric cancer cells.

Alpha-fetoprotein (AFP)-producing gastric cancer (AFPGC), represented by the production of AFP, has a more aggressive behavior than common gastric cancer. The underlying mechanisms are not well understood. Arsenic trioxide (As(2)O(3)) is used clinically to treat acute promyelocytic leukemia(APL) and has activity in vitro against several solid tumor cell lines, with induction of apoptosis and inhibition of proliferation the prime effects. Signal transducer and activator of transcription 3 (STAT3) has an important role in tumorigenesis of various primary cancers and cancer cell by upregulating cell-survival and downregulating tumor suppressor proteins. Here, we found decreased expression of AFP and STAT3 after induction of apoptosis by As(2)O(3) in the AFPGC FU97 cells. Also, the level of the STAT3 target oncogene Bcl-2 was decreased with As(2)O(3), and that of the tumor suppressor Bax was increased. Furthermore, STAT3 expression and depth of invasion and lymph node metastasis were associated. Survival of patients with gastric cancer was lower with AFP and STAT3 double overexpression than with overexpression of either alone. Downregulation of AFP and STAT3 expression plays an important role in As(2)O(3)-induced apoptosis of AFPGC cells, which suggests a new mechanism of As(2)O(3)-induced cell apoptosis. As(2)O(3) may be a possible agent for AFPGC treatment.

Practical methods for improving dose distributions in Monte Carlo-based IMRT planning of lung wall-seated tumors treated with SBRT.

Current commercially available planning systems with Monte Carlo (MC)-based final dose calculation in IMRT planning employ pencil-beam (PB) algorithms in the optimization process. Consequently, dose coverage for SBRT lung plans can feature cold-spots at the interface between lung and tumor tissue. For lung wall (LW)-seated tumors, there can also be hot spots within nearby normal organs (example: ribs). This study evaluated two different practical approaches to limiting cold spots within the target and reducing high doses to surrounding normal organs in MC-based IMRT planning of LW-seated tumors. First, "iterative reoptimization", where the MC calculation (with PB-based optimization) is initially performed. The resultant cold spot is then contoured and used as a simultaneous boost volume. The MC-based dose is then recomputed. The second technique uses noncoplanar beam angles with limited path through lung tissue. Both techniques were evaluated against a conventional coplanar beam approach with a single MC calculation. In all techniques the prescription dose was normalized to cover 95% of the PTV. Fifteen SBRT lung cases with LW-seated tumors were planned. The results from iterative reoptimization showed that conformity index (CI) and/or PTV dose uniformity (UPTV) improved in 12/15 plans. Average improvement was 13%, and 24%, respectively. Nonimproved plans had PTVs near the skin, trachea, and/or very small lung involvement. The maximum dose to 1cc volume (D1cc) of surrounding OARs decreased in 14/15 plans (average 10%). Using noncoplanar beams showed an average improvement of 7% in 10/15 cases and 11% in 5/15 cases for CI and UPTV, respectively. The D1cc was reduced by an average of 6% in 10/15 cases to surrounding OARs. Choice of treatment planning technique did not statistically significantly change lung V5. The results showed that the proposed practical approaches enhance dose conformity in MC-based IMRT planning of lung tumors treated with SBRT, improving target dose coverage and potentially reducing toxicities to surrounding normal organs.

Evaluation of the deformation and corresponding dosimetric implications in prostate cancer treatment.

The cone-beam computed tomography (CBCT) imaging modality is an integral component of image-guided adaptive radiation therapy (IGART), which uses patient-specific dynamic/temporal information for potential treatment plan modification. In this study, an offline process for the integral component IGART framework has been implemented that consists of deformable image registration (DIR) and its validation, dose reconstruction, dose accumulation and dose verification. This study compares the differences between planned and estimated delivered doses under an IGART framework of five patients undergoing prostate cancer radiation therapy. The dose calculation accuracy on CBCT was verified by measurements made in a Rando pelvic phantom. The accuracy of DIR on patient image sets was evaluated in three ways: landmark matching with fiducial markers, visual image evaluation and unbalanced energy (UE); UE has been previously demonstrated to be a feasible method for the validation of DIR accuracy at a voxel level. The dose calculated on each CBCT image set was reconstructed and accumulated over all fractions to reflect the 'actual dose' delivered to the patient. The deformably accumulated (delivered) plans were then compared to the original (static) plans to evaluate tumor and normal tissue dose discrepancies. The results support the utility of adaptive planning, which can be used to fully elucidate the dosimetric impact based on the simulated delivered dose to achieve the desired tumor control and normal tissue sparing, which may be of particular importance in the context of hypofractionated radiotherapy regimens.

Initial validation and clinical experience with 3D optical-surface-guided whole breast irradiation of breast cancer.

We had introduced 3D optical surface-guided radiotherapy (SGRT) of the breast cancer (BC). We then initiated the feasibility, accuracy, and precision studies of stereovision in detection of any breast displacement through the course of treatment for total thirty breasts undertaken whole breast irradiation (WBI). In the SGRT, CT-based plan data were parsed into an in-house computer program through which the reference surfaces were generated in 3D video format. When patients were positioned on treatment Tables, real-time stereovisions were rapidly acquired while the live surface tracking shown steady thorax motion. The real-time surface images were automatically aligned with the reference surface and detected shape and location changes of the breast were online corrected through the Table and beam adjustments. Accumulated dose to each patient was computed according to the frequency distribution of the measured breast locations during beam on time. Application of SGRT had diminished large skin-marking errors of > 5-mm and daily breast-setup errors of >10-mm that occurred on half of cases. Accuracy (mean) and precision (two standard deviations) of the breast displacements across the tangential field edges in the (U, V) directions were improved from (-0.5 ± 8.8, 2.2 ± 10.8) mm in conventional setup to (0.4 ± 4.6, 0.7 ± 4.4) mm in the final position while intra-fractional motion contributed only (0.1 ± 2.8, 0.0 ± 2.2) mm in free breathing. Dose uniformity and coverage to targets had both been increased by up to 10% and the lung or heart intersections have been decreased by half of those volumes if they were irradiated at the initial positions. SGRT of BC appears to be feasible regardless of skin tones, as fast as a snapshot for 3D imaging, and very accurate and precise for daily setup of flexible breast targets. Importantly, the technique allows us to verify the breast shape and position during beam-on time.

A TCP model incorporating setup uncertainty and tumor cell density variation in microscopic extension to guide treatment planning.

PURPOSE: Tumor control probability (TCP) models have been proposed to evaluate and guide treatment planning. However, they are usually based on the dose volume histograms (DVHs) of the planning target volume (PTV) and may not properly reflect the substantial variation in tumor burden from the gross tumor volume (GTV) to the microscopic extension (ME) and to the margin of PTV. In this study, the authors propose a TCP model that can account for the effects of setup uncertainties and tumor cell density decay in the ME region. METHODS: The proposed TCP model is based on the total surviving clonogenic tumor cells (CTCs) after irradiation of a known dose distribution to a region with a CTC distribution. The CTC density was considered to be homogeneous within the GTV, while decreasing exponentially in the ME region. The effect of random setup uncertainty was modeled by convolving the dose distribution with a Gaussian probability density function, represented by a standard deviation, sigma. The effect of systematic setup uncertainty was modeled by summing each calculated TCP for all potential offsets in a Gaussian probability, represented by sigma. The model was then applied to simplified cases to demonstrate the concept. TCP dose responses were calculated for various GTV volumes, DVH shapes, CTC density decay coefficients, probabilities of lymph node metastasis, and random and systematic errors. The slopes of the dose falloff to cover the CTC density decay in the ME region and the margins to compensate setup errors were also analyzed in generalized cases. RESULTS: The sigmoid TCP dose response curve shifted to the right substantially for a larger GTV, while modestly for cold spots in DVH. A dose distribution with a uniform dose within the GTV, and a linear dose falloff in the ME region, tended to cause a minimal TCP deterioration if a proper dose falloff slope was used. When the dose falloff slope was less steep than a critical slope represented by kT, the D50, which is the prescription dose at TCP=50%, and gamma50, which is the TCP slope at TCP=50%, varied little with different dose falloff slopes. However, both D50 and gamma50 deteriorated fast when the slopes were steeper than kT. The random setup error tended to shift the TCP curve to the right, while the systematic error tended to compress the curve downward. For combined random and systematic errors, we demonstrated that based on the model, a margin of mean square root of (0.75 sigma)2 + (1.15 sigma)2 added to the GTV was found to cause a TCP change corresponding to 2% drop at TCP=90%, or 0.5 Gy shift in D50. CONCLUSIONS: This study conceptually demonstrated that a TCP model incorporating the effects of tumor cell density variation and setup uncertainty may be used to guide radiation treatment planning.

Dosimetric verification and clinical evaluation of a new commercially available Monte Carlo-based dose algorithm for application in stereotactic body radiation therapy (SBRT) treatment planning.

Modern cancer treatment techniques, such as intensity-modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT), have greatly increased the demand for more accurate treatment planning (structure definition, dose calculation, etc) and dose delivery. The ability to use fast and accurate Monte Carlo (MC)-based dose calculations within a commercial treatment planning system (TPS) in the clinical setting is now becoming more of a reality. This study describes the dosimetric verification and initial clinical evaluation of a new commercial MC-based photon beam dose calculation algorithm, within the iPlan v.4.1 TPS (BrainLAB AG, Feldkirchen, Germany). Experimental verification of the MC photon beam model was performed with film and ionization chambers in water phantoms and in heterogeneous solid-water slabs containing bone and lung-equivalent materials for a 6 MV photon beam from a Novalis (BrainLAB) linear accelerator (linac) with a micro-multileaf collimator (m(3) MLC). The agreement between calculated and measured dose distributions in the water phantom verification tests was, on average, within 2%/1 mm (high dose/high gradient) and was within +/-4%/2 mm in the heterogeneous slab geometries. Example treatment plans in the lung show significant differences between the MC and one-dimensional pencil beam (PB) algorithms within iPlan, especially for small lesions in the lung, where electronic disequilibrium effects are emphasized. Other user-specific features in the iPlan system, such as options to select dose to water or dose to medium, and the mean variance level, have been investigated. Timing results for typical lung treatment plans show the total computation time (including that for processing and I/O) to be less than 10 min for 1-2% mean variance (running on a single PC with 8 Intel Xeon X5355 CPUs, 2.66 GHz). Overall, the iPlan MC algorithm is demonstrated to be an accurate and efficient dose algorithm, incorporating robust tools for MC-based SBRT treatment planning in the routine clinical setting.

Montelukast inhibits matrix metalloproteinases expression in atherosclerotic rabbits.

BACKGROUND: Matrix metalloproteinases (MMPs) play important roles in the development and destabilization of atherosclerotic plaques. It is known that montelukast inhibits neointimal hyperplasia. However, the underlying mechanisms for the inhibitory effects of montelukast on neointimal formation have been poorly defined. METHODS: Thirty-six male New Zealand White rabbits were randomized as normal control, placebo (0.9% NaCl, 1.5 ml/kg/day, via intraperitoneal injection), atorvastatin (atorvastatin, 1.5 mg/kg/day, orally) and montelukast groups (montelukast, 1.5 mg/kg/day, via intraperitoneal injection). Atherosclerosis was induced by balloon-injury and high-cholesterol (HC) diet. Serum lipids were measured at 0, 8 and 12 weeks. After 12 weeks, the rabbits were sacrificed and histopathological changes examined. Immunohistochemistry and reverse transcription-polymerase chain reaction were used to measure the expression of MMP-2 and MMP-9 in the plaques. RESULTS: It was found that montelukast reduced neointimal formation, decreased macrophage accumulation, and increased smooth muscle cells. It also attenuated the expression of MMP-2 and MMP-9 in atherosclerotic plaques, but it had no effect on plasma lipid levels. CONCLUSION: These data indicate that montelukast inhibits neointimal hyperplasia in association with decreased expression of MMP-2 and MMP-9 independent of plasma lipid levels in atherosclerotic plaques after vascular injury in hyperlipidemic rabbits.

[Effects of montelukast on atherosclerosis and monocyte chemoattractant protein-1 expression in ahypercholesterolemic rabbit model.].

OBJECTIVE: To investigate the effects of montelukast on atherosclerosis and monocyte chemoattractant protein-1 expression in a hypercholesterolemic rabbit model. METHODS: Thirty four male New Zealand white rabbits were randomized into four groups including normal control group (n = 6), placebo group (n = 8), atorvastatin group (1.5 mgxkg(-1)xd(-1), beginning at 8(th) weeks for 4 weeks, n = 10) and montelukast group (1 mgxkg(-1)xd(-1), beginning at 8(th) weeks for 4 weeks, n = 10). Rabbits except those in normal control group were fed a high cholesterol diet for 12 weeks. Serum lipids were measured at 0, 8 and 12 weeks after intervention. The intima/media ratio, percentages of macrophages or smooth muscle cells in intima and the expression of MCP-1 mRNA were examined. RESULTS: Atherosclerosis was evidenced in placebo group and atorvastatin or montelukast treatment significantly reduced neointima (0.32 +/- 0.12 and 0.34 +/- 0.10 vs. 1.12 +/- 0.36, P < 0.05) and macrophage content [(9.8 +/- 4.6)% and (11.2 +/- 3.7)% vs. (34.6 +/- 8.8)%, P < 0.05], increased SMC content [(18.6 +/- 6.9)% and (19.2 +/- 8.6)% vs. (5.2 +/- 2.3)%, P < 0.05] and inhibited expression of MCP-1 mRNA (0.42 +/- 0.08 and 0.40 +/- 0.06 vs. 2.36 +/- 0.48, P < 0.01). Montelukast had similar anti-atherogenetic effects as atorvastatin but had no influence on plasma lipids. CONCLUSIONS: Montelukast could attenuate atherosclerosis in this hypercholesterolemic rabbit model which might be attributed to its anti-inflammatory effects.

IL-18 accelerates the cell apoptosis by up-regulating cysteinyl leukotriene 2 receptor expression in human umbilical vein endothelial cells at the early stage of administration.

The purpose of the present study is to identify whether interleukin (IL)-18 can modulate cysteinyl leukotriene 2 receptor (CysLT2R) expression in Human Umbilical Vein Endothelial Cells (HUVECs) and how it influences the cell death. According to the results from real-time reverse transcription PCR, confocal laser scanning microscopy, and western blotting, a dose-dependent augmentation of CysLT2R protein expression in HUVECs was triggered by IL-18 for the first 2 h followed by down-regulation within the next 22 h after IL-18 administration. The flow cytometry showed that non-selective CysLT1R and CysLT2R antagonist BAY-u9773 could attenuate the early stage apoptosis mediated by IL-18 whereas CysLT1R antagonist Montelukast couldn't. Also, pretreatment with BAY-u9773 suppressed calcium influx of HUVECs induced by IL-18 whereas Montelukast didn't work. The observation that progression of cell death aggravated by IL-18 could be attenuated by BAY-u9773 may offer a chance to develop a novel way to treat arteriosclerosis.