Investigation of four-dimensional (4D) Monte Carlo dose calculation in real-time tumor tracking stereotatic body radiotherapy for lung cancers.

PURPOSE: To investigate the dosimetric variations and radiobiological impacts as a consequence of delivering treatment plans of 3D nature in 4D manner based on the 4D Monte Carlo treatment planning framework implemented on Cyberknife. METHODS AND MATERIALS: Dose distributions were optimized on reference 3D images at end of exhale phase of a 4DCT dataset for twenty-five lung cancer patients treated with 60 Gy / 3Fx or 48 Gy / 4Fx. Deformable image registrations (DIR) between individual 3DCT images to the reference 3DCT image in the 4DCT study were performed to interpolate doses calculated on multiple anatomical geometries back on to the reference geometry to compose a 4D dose distribution that included the tracking beam motion and organ deformation. The 3D and 4D dose distributions that were initially calculated with the equivalent path-length (EPL) algorithm (3DEPL dose and 4DEPL dose) were recalculated with the Monte Carlo algorithm (3DMC dose and 4DMC dose). Dosimetric variations of V60Gy / 48Gy and D99 of GTV, mean doses to the lung and the heart and maximum dose (D1 ) of the spinal cord as a consequence of tracking beam motion in deforming anatomy, dose calculation algorithm, and both were quantified by the relative change from 4DMC to 3DMC doses, from 4DMC to 4DEPL doses, and from 4DMC to 3DEPL doses, respectively. RESULTS: Comparing 4DMC to 3DEPL plans, V60Gy / 48Gy and D99 of GTV decreased considerably by 13 ± 22% (mean ± 1SD) and 9.2 ± 5.5 Gy but changes of normal tissue doses were not more than 0.5 Gy on average. The generalized equivalent uniform dose (gEUD) and tumor control probability (TCP) were reduced by 14.3 ± 8.8 Gy and 7.5 ± 5.2%, and normal tissue complication probability (NTCP) for myelopathy and pericarditis were close to zero and NTCP for radiation pneumonitis was reduced by 2.5 ± 4.1%. Comparing 4DMC to 4DEPL plans found decreased V60Gy / 48Gy and D99 by 12.3 ± 21.6% and 7.3 ± 5.3 Gy, the normal tissues doses by 0.5 Gy on average, gEUD and TCP by 13.0 ± 8.6 Gy and 7.1 ± 5.1%. Comparing 4DMC to 3DMC doses, V60Gy / 48Gy and D99 of GTV was reduced by 5.2 ± 8.8 %and 2.6 ± 3.3 Gy, and normal tissues hardly changed from 4DMC to 3DMC doses. The corresponding decreases of gEUD and TCP were 2.8 ± 4.0 Gy and 1.6 ± 2.4%. CONCLUSION: The large discrepancy between original 3DEPL plan and benchmarking 4DMC plan is predominately due to dose calculation algorithms as the tracking beam motion and organ deformation hardly influenced doses of normal tissues and moderately decreased V60Gy / 48Gy and D99 of GTV. It is worth to make a thoughtful weight of the benefits of full 4D MC dose calculation and consider 3D MC dose calculation as a compromise of 4D MC dose calculation considering the multifold computation time. This article is protected by copyright. All rights reserved.

3-Deazaneplanocin A and neplanocin A analogues and their effects on apoptotic cell death.

3-Deazaneplanocin A (DzNep) is a potential epigenetic drug for the treatment of various cancers. DzNep has been reported to deplete histone methylations, including oncogenic EZH2 complex, giving rise to epigenetic modifications that reactivate many silenced tumor suppressors in cancer cells. Despite its promise as an anticancer drug, little is known about the structure-activity relationships of DzNep in the context of epigenetic modifications and apoptosis induction. In this study, a number of analogues of DzNep were examined for DzNep-like ability to induce synergistic apoptosis in cancer cells in combination with trichostatin A, a known histone deacetylase (HDAC) inhibitor. The structure-activity relationship data thus obtained provide valuable information on the structural requirements for biological activity. The studies identified three compounds that show similar activities to DzNep. Two of these compounds show good pharmacokinetics and safety profiles. Attempts to correlate the observed synergistic apoptotic activities with measured S-adenosylhomocysteine hydrolase (SAHH) inhibitory activities suggest that the apoptotic activity of DzNep might not be directly due to its inhibition of SAHH.

A new route to bicyclo[1.1.1]pentan-1-amine from 1-azido-3-iodobicyclo[1.1.1]pentane.

From a medicinal chemistry perspective, bicyclo[1.1.1]pentan-1-amine (1) has served as a unique and important moiety. Synthetically, however, this compound has received little attention, and only one scalable route to this amine has been demonstrated. Reduction of an easily available and potentially versatile intermediate, 1-azido-3-iodobicyclo[1.1.1]pentane (2), can offer both a flexible and scalable alternative to this target. Herein, we describe our scrutiny of this reportedly elusive transformation and report our ensuing success with this endeavor.

Cell-based proteome profiling using an affinity-based probe (AfBP) derived from 3-deazaneplanocin A (DzNep).

3-Deazaneplanocin A (DzNep), a global histone methylation inhibitor, has attracted significant interest in epigenetic research in recent years. The molecular mechanism of action and the cellular off-targets of DzNep, however, are still not well-understood. Our aim was to develop novel DzNep-derived small-molecule probes suitable to be used in live mammalian cells for identification of potential cellular targets of DzNep under physiologically relevant settings. In the current study, we have successfully designed, synthesized, and tested one such probe, called DZ-1. DZ-1 is a 'clickable' affinity-based probe (AfBP) derived from DzNep with minimal structural modifications. The probe was found to be highly cell-permeable, and possessed similar anti-apoptotic activities as DzNep in MCF-7 mammalian cells. Two additional control probes were made as negative labeling/pull-down probes in order to minimize false identification of background proteins due to unavoidable, intrinsic nonspecific photo-crosslinking reactions. All three probes were subsequently used for in-situ proteome profiling in live mammalian cells, followed by large-scale pull-down/LC-MS/MS analysis for identification of potential cellular protein targets that might interact with DzNep in native cellular environments. Our LC-MS/MS results revealed some highly enriched proteins that had not been reported as potential DzNep targets. These proteins might constitute unknown cellular off-targets of DzNep. Though further validation experiments are needed in order to unequivocally confirm these off-targets, our findings shed new light on the future use of DzNep as a validated chemical probe for epigenetic research and as a potential drug candidate for cancer therapy.

Experimental evaluations of the accuracy of 3D and 4D planning in robotic tracking stereotactic body radiotherapy for lung cancers.

PURPOSE: Due to the complexity of 4D target tracking radiotherapy, the accuracy of this treatment strategy should be experimentally validated against established standard 3D technique. This work compared the accuracy of 3D and 4D dose calculations in respiration tracking stereotactic body radiotherapy (SBRT). METHODS: Using the 4D planning module of the CyberKnife treatment planning system, treatment plans for a moving target and a static off-target cord structure were created on different four-dimensional computed tomography (4D-CT) datasets of a thorax phantom moving in different ranges. The 4D planning system used B-splines deformable image registrations (DIR) to accumulate dose distributions calculated on different breathing geometries, each corresponding to a static 3D-CT image of the 4D-CT dataset, onto a reference image to compose a 4D dose distribution. For each motion, 4D optimization was performed to generate a 4D treatment plan of the moving target. For comparison with standard 3D planning, each 4D plan was copied to the reference end-exhale images and a standard 3D dose calculation was followed. Treatment plans of the off-target structure were first obtained by standard 3D optimization on the end-exhale images. Subsequently, they were applied to recalculate the 4D dose distributions using DIRs. All dose distributions that were initially obtained using the ray-tracing algorithm with equivalent path-length heterogeneity correction (3D EPL and 4D EPL) were recalculated by a Monte Carlo algorithm (3D MC and 4D MC) to further investigate the effects of dose calculation algorithms. The calculated 3D EPL, 3D MC, 4D EPL, and 4D MC dose distributions were compared to measurements by Gafchromic EBT2 films in the axial and coronal planes of the moving target object, and the coronal plane for the static off-target object based on the γ metric at 5%/3mm criteria (γ5%/3mm). Treatment plans were considered acceptable if the percentage of pixels passing γ5%/3mm (Pγ<1) ≥ 90%. RESULTS: The averaged Pγ<1 values of the 3D EPL, 3D MC, 4D EPL, and 4D MC dose calculation methods for the moving target plans are 95%, 95%, 94%, and 95% for reproducible motion, and 95%, 96%, 94%, and 93% for nonreproducible motion during actual treatment delivery. The overall measured target dose distributions are in better agreement with the 3DMC dose distributions than the 4DMC dose distributions. Conversely, measured dose distributions agree much better with the 4D EPL/MC than the 3D EPL/MC dose distributions in the static off-target structure, resulting in higher Pγ<1 values with 4D EPL/MC (91%) vs 3D EPL (24%) and 3D MC (25%). Systematic changes of target motion reduced the averaged Pγ<1 to 47% and 53% for 4D EPL and 4D MC dose calculations, and 22% for 3D EPL/MC dose calculations in the off-target films. CONCLUSIONS: In robotic tracking SBRT, 4D treatment planning was found to yield better prediction of the dose distributions in the off-target structure, but not necessarily in the moving target, compared to standard 3D treatment planning, for reproducible and nonreproducible target motion. It is important to ensure on a patient-by-patient basis that the cumulative uncertainty associated with the 4D-CT artifacts, deformable image registration, and motion variability is significantly smaller than the cumulative uncertainty occurred in standard 3D planning in order to make 4D planning a justified option.

Accuracy and sensitivity of four-dimensional dose calculation to systematic motion variability in stereotatic body radiotherapy (SBRT) for lung cancer.

The dynamic movement of radiation beam in real-time tumor tracking may cause overdosing to critical organs surrounding the target. The primary objective of this study was to verify the accuracy of the 4D planning module incorporated in CyberKnife treatment planning system. The secondary objective was to evaluate the error that may occur in the case of a systematic change of motion pattern. Measurements were made using a rigid thorax phantom. Target motion was simulated with two waveforms (sin and cos4) of different amplitude and frequency. Inversely optimized dose distributions were calculated in the CyberKnife treatment planning system using the 4D Monte Carlo dose calculation algorithm. Each plan was delivered to the phantom assuming (1) reproducible target motion,and (2) systematic change of target motion pattern. The accuracy of 4D dose calculation algorithm was assessed using GAFCHROMIC EBT2 films based on 5%/3 mm γ criteria. Treatment plans were considered acceptable if the percentage of pixels passing the 5%/3 mm γ criteria was greater than 90%. The mean percentages of pixels passing were 95% for the target and 91% for the static off-target structure, respectively, with reproducible target motion. When systematic changes of the motion pattern were introduced during treatment delivery, the mean percentages of pixels passing decreased significantly in the off-target films (48%; p < 0.05), but did not change significantly in the target films (92%; p = 0.324) compared to results of reproducible target motion. These results suggest that the accuracy of 4D dose calculation, particularly in off-target stationary structure, is strongly tied to the reproducibility of target motion and that the solutions of 4D planning do not reflect the clinical nature of nonreproducible target motion generally.

Investigation of four-dimensional (4D) Monte Carlo dose calculation in real-time tumor tracking stereotatic body radiotherapy for lung cancers.

PURPOSE: To investigate the dosimetric variations and radiobiological impacts as a consequence of delivering treatment plans of 3D nature in 4D manner based on the 4D Monte Carlo treatment planning framework implemented on Cyberknife. METHODS: Dose distributions were optimized on reference 3D images at end of exhale phase of a 4DCT dataset for 25 lung cancer patients treated with 60 Gy∕3Fx or 48 Gy∕4Fx. Deformable image registrations between individual 3DCT images to the reference 3DCT image in the 4DCT study were performed to interpolate doses calculated on multiple anatomical geometries back on to the reference geometry to compose a 4D dose distribution that included the tracking beam motion and organ deformation. The 3D and 4D dose distributions that were initially calculated with the equivalent path-length (EPL) algorithm (3D(EPL) dose and 4D(EPL) dose) were recalculated with the Monte Carlo algorithm (3D(MC) dose and 4D(MC) dose). Dosimetric variations of V(60Gy∕48Gy) and D(99) of GTV, mean doses to the lung and the heart and maximum dose (D(1)) of the spinal cord as a consequence of tracking beam motion in deforming anatomy, dose calculation algorithm, and both were quantified by the relative change from 4D(MC) to 3D(MC) doses, from 4D(MC) to 4D(EPL) doses, and from 4D(MC) to 3D(EPL) doses, respectively. RESULTS: Comparing 4D(MC) to 3D(EPL) plans, V(60Gy ∕ 48Gy) and D(99) of GTV decreased considerably by 13 ± 22% (mean ± 1SD) and 9.2 ± 5.5 Gy but changes of normal tissue doses were not more than 0.5 Gy on average. The generalized equivalent uniform dose (gEUD) and tumor control probability (TCP) were reduced by 14.3 ± 8.8 Gy and 7.5 ± 5.2%, and normal tissue complication probability (NTCP) for myelopathy and pericarditis were close to zero and NTCP for radiation pneumonitis was reduced by 2.5% ± 4.1%. Comparing 4D(MC) to 4D(EPL) plans found decreased V(60Gy∕48Gy) and D(99) by 12.3% ± 21.6% and 7.3 ± 5.3 Gy, the normal tissues doses by 0.5 Gy on average, gEUD and TCP by 13.0 ± 8.6 Gy and 7.1% ± 5.1%. Comparing 4D(MC) to 3D(MC) doses, V(60Gy∕48Gy) and D(99) of GTV was reduced by 5.2% ± 8.8% and 2.6 ± 3.3 Gy, and normal tissues hardly changed from 4D(MC) to 3D(MC) doses. The corresponding decreases of gEUD and TCP were 2.8 ± 4.0 Gy and 1.6 ± 2.4%. CONCLUSIONS: The large discrepancy between original 3D(EPL) plan and benchmarking 4D(MC) plan is predominately due to dose calculation algorithms as the tracking beam motion and organ deformation hardly influenced doses of normal tissues and moderately decreased V(60Gy∕48Gy) and D(99) of GTV. It is worth to make a thoughtful weight of the benefits of full 4D(MC) dose calculation and consider 3D(MC) dose calculation as a compromise of 4D(MC) dose calculation considering the multifold computation time.