Purpose: To evaluate gross tumor volume (GTV) changes for non-small cell lung cancer (NSCLC) patients using daily megavoltage CT (MVCT) studies acquired before each treatment fraction on helical tomotherapy, and to relate the potential benefit of adaptive image-guided radiotherapy to changes in GTV. Methods: 17 patients were prescribed 30 fractions of radiotherapy on helical tomotherapy for NSCLC at London Regional Cancer Program from December 2005 to March 2007. The GTV was contoured on the daily MVCT studies of each patient. Adapted plans were created using merged MVCT-kVCT image sets to investigate the advantages of replanning for patients with differing GTV regression characteristics. Results: The average GTV change observed over 30 fractions was −38%, ranging from −12 to −87%. No significant correlation was observed between GTV change and patient's physical or tumor features. The pattern of GTV changes of the 17 patients could be broadly divided into 3 groups with distinctive potential for benefit from adaptive planning. Conclusions: GTV changes are difficult to predict quantitatively based on patient or tumor characteristics. If changes do occur, there are points in time during the treatment course when it may be appropriate to adapt the plan to improve sparing of normal tissues. If the GTV decreases by greater than 30% at any point in the first twenty fractions of treatment, adaptive planning is appropriate to further improve the therapeutic ratio.
Abstract The generation of pancreatic endocrine progenitor cells is an important step in the differentiation of beta cells from human pluripotent stem cells (hPSC). This stage is marked by the expression of Nkx6.1, a transcription factor with well understood downstream targets but with unclear upstream regulators. In hPSC differentiation, Nkx6.1 is strongly induced by nicotinamide, a derivative of vitamin B3, which has three known functions within a cell. Nicotinamide inhibits two classes of enzymes known as poly-ADP-ribose polymerases (PARPs) and sirtuins. It also contributes to the cellular pool of nicotinamide adenosine deoxynucleotide (NAD + ) after conversion in the nicotinamide salvage pathway. Induction of Nkx6.1 expression in pancreatic endocrine progenitors by nicotinamide was mimicked by 3 PARP inhibitors (PJ34, olaparib, NU1025). Small molecule inhibition of the nicotinamide salvage pathway reduced Nkx6.1 expression but not Pdx1 expression and caused alteration in NAD + /NADH ratio. Nkx6.1 expression was not affected by sirtuin inhibition. Metabolic profiling of differentiating pancreatic and endocrine progenitors showed that oxygen consumption increases as differentiation progresses, and that nicotinamide reduces oxygen consumption rate. Expression of Nkx6.1 and other beta cell related genes, including Ins2 and Pdx1 increased in mouse islets after exposure to nicotinamide. In summary, nicotinamide induced Nkx6.1 expression in differentiating human pancreatic endocrine progenitors through inhibition of the PARP family of enzymes. Nicotinamide administration was also associated with increased NAD+/NADH ratio, without affecting Nkx6.1 expression. Similarly, the association between nicotinamide and Nkx6.1 expression was also seen in isolated mouse islets. These observations show a link between the regulation of beta cell identity and the effectors of NAD + metabolism, suggesting possible therapeutic targets in the field of diabetes.
This study aims to determine the settings that provide the optimal clinical accuracy and consistency for the registration of megavoltage CT (MVCT) with planning kilovoltage CT image sets on the Hi-ART tomotherapy system. The systematic offset between the MVCT and the planning kVCT was determined by registration of multiple MVCT scans of a head phantom aligned with the planning isocentre. Residual error vector lengths and components were used to quantify the alignment quality for the phantom shifted by 5 mm in different directions obtained by all 27 possible combinations of MVCT inter-slice spacing, registration techniques and resolution. MVCT scans with normal slices are superior to coarse slices for registration of shifts in the superior–inferior, lateral and anterior–posterior directions. Decreasing the scan length has no detrimental effect on registration accuracy as long as the scan lengths are larger than 24 mm. In the case of bone technique and fine resolution, normal and fine MVCT scan slice spacing options give similar accuracy, so normal mode is preferable due to shorter procedure and less delivered dose required for patient set-up. A superior–inferior field length of 24–30 mm, normal slice spacing, bone technique, and fine resolution is the optimum set of registration settings for MVCT scans of a Rando head phantom acquired with the Hi-ART tomotherapy system, provided the registration shifts are less than 5 mm.
This study aims to investigate the settings that provide optimum registration accuracy when registering megavoltage CT (MVCT) studies acquired on tomotherapy with planning kilovoltage CT (kVCT) studies of patients with lung cancer. For each experiment, the systematic difference between the actual and planned positions of the thorax phantom was determined by setting the phantom up at the planning isocenter, generating and registering an MVCT study. The phantom was translated by 5 or 10 mm, MVCT scanned, and registration was performed again. A root-mean-square equation that calculated the residual error of the registration based on the known shift and systematic difference was used to assess the accuracy of the registration process. The phantom study results for 18 combinations of different MVCT/kVCT registration options are presented and compared to clinical registration data from 17 lung cancer patients. MVCT studies acquired with coarse (6 mm), normal (4 mm) and fine (2 mm) slice spacings could all be registered with similar residual errors. No specific combination of resolution and fusion selection technique resulted in a lower residual error. A scan length of 6 cm with any slice spacing registered with the full image fusion selection technique and fine resolution will result in a low residual error most of the time. On average, large corrections made manually by clinicians to the automatic registration values are infrequent. Small manual corrections within the residual error averages of the registration process occur, but their impact on the average patient position is small. Registrations using the full image fusion selection technique and fine resolution of 6 cm MVCT scans with coarse slices have a low residual error, and this strategy can be clinically used for lung cancer patients treated on tomotherapy. Automatic registration values are accurate on average, and a quick verification on a sagittal MVCT slice should be enough to detect registration outliers.
