Advancing the Role of Proton Therapy for Spine Metastases Through Diagnostic Scan-Based Planning.

Purpose: Many patients with metastatic cancer live years beyond diagnosis, and there remains a need to improve the therapeutic ratio of metastasis-directed radiation for these patients. This study aimed to assess a process for delivering cost-effective palliative proton therapy to the spine using diagnostic scan-based planning (DSBP) and prefabricated treatment delivery devices. Materials and Methods: We designed and characterized a reusable proton aperture system that adjusts to multiple lengths for spine treatment. Next, we retrospectively identified 10 patients scan treated with thoracic proton therapy who also had a diagnostic computed tomography within 4 months of simulation. We contoured a T6-T9 target volume on both the diagnostic scans (DS) and simulation scans (SS). Using the aperture system, we generated proton plans on the DS using a posterior-anterior beam with no custom range compensator to treat T6-T9 to 8 Gy × 1. Plans were transferred to the SS to compare coverage and normal tissue doses, followed by robustness analysis. Finally, we compared normal tissue doses and costs between proton and photon plans. Results were compared using the Wilcoxon signed-rank test. Results: Median D95% on the DS plans was 101% (range, 100%-102%) of the prescription dose. Median Dmax was 107% (range, 105%-108%). When transferred to SS, coverage and hot spots remained acceptable for all cases. Heart and esophagus doses did not vary between the DS and SS proton plans (P >.2). Robustness analysis with 5 mm X/Y/Z shifts showed acceptable coverage (D95% > 98%) for all cases. Compared with the proton plans, the mean heart dose was higher for both anterior-posterior/posterior-anterior and volumetric modulated arc therapy plans (P < .01). Cost for proton DSBP was comparable to more commonly used photon regimens. Conclusion: Proton DSBP is technically feasible and robust, with superior sparing of the heart compared with photons. Eliminating simulation and custom devices increases the value of this approach in carefully selected patients.

Operational Performance of a Compact Proton Therapy System: A 5-Year Experience.

Purpose: We present an analysis of various operational metrics for a novel compact proton therapy system, including clinical case mix, subsystems utilization, and quality assurance trends in beam delivery parameters over a period of 5 years. Materials and Methods: Patient-specific data from a total of 850 patients (25,567 fractions) have been collected and analyzed. The patient mix include a variety of simple, intermediate, and complex cases. Beam-specific delivery parameters for a total of 3585 beams were analyzed. In-room imaging system usage for off-line adaptive purpose is reported. We also report key machine performances metrics based on routine quality assurance in addition to uptime. Results: Our analysis shows that system subcomponents including gantry and patient positioning system have maintained a tight mechanical tolerance over the 5-year period. Various beam parameters were all within acceptable tolerances with no clear trends. Utilization frequency histograms of gantry and patient positioning system show that only a small fraction of all available angles was used for patient deliveries with cardinal angels as the most usable. Similarly, beam-specific metrics, such as range, modulation, and air gaps, were clustered unevenly over the available range indicating that this compact system was more than capable to treat the complex variety of tumors of our patient mix. Conclusion: Our data show that this compact system is versatile, robust, and capable of delivering complex treatments like a large full-gantry system. Utilization data show that a fraction of all subcomponents range of angular motion has been used. Compilation of beam-specific metrics, such as range and modulation, show uneven distributions with specific clustering over the entire usable range. Our findings could be used to further optimize the performance and cost-effectiveness of future compact proton systems.

LncRNA MST1P2/miR-133b axis affects the chemoresistance of bladder cancer to cisplatin-based therapy via Sirt1/p53 signaling.

Although bladder cancer is commonly chemosensitive to standard first-line therapy, the acquisition of the resistance to cisplatin (DDP)-based therapeutic regimens remains a huge challenge. Noncoding RNAs (ncRNAs), including long noncoding RNAs (lncRNAs) and microRNAs, have been reported to play a critical role in cancer resistance to DDP. Here, we attempted to provide a novel mechanism by which the resistance of bladder cancer to DDP treatment could be modulated from the perspective of ncRNA regulation. We demonstrated that lncRNA MST1P2 (lnc-MST1P2) expression was dramatically upregulated, whereas miR-133b expression was downregulated in DDP-resistant bladder cancer cell lines, SW 780/DDP and RT4/DDP. Lnc-MST1P2 and miR-133b negatively regulated each other via targeting miR-133b. Both lnc-MST1P2 silence and miR-133b overexpression could resensitize DDP-resistant bladder cancer cells to DDP treatment. More important, miR-133b could directly target the Sirt1 3'-untranslated region to inhibit its expression. Inc-MST1P2/miR-133b axis affected the resistance of bladder cancer cells to DDP via Sirt1/p53 signaling. In conclusion, MST1P2 serves as a competing endogenous RNA for miR-133b to counteract miR-133b-induced suppression on Sirt1, therefore enhancing the resistance of bladder cancer cells to DDP. MST1P2/miR-133b axis affects the resistance of bladder cancer cells to DDP via downstream Sirt1/p53 signaling.

An optimized approach for robust spot placement in proton pencil beam scanning.

Maintaining a sharp lateral dose falloff in pencil beam scanning (PBS) proton therapy is crucial for sparing organs at risk (OARs), especially when they are in close proximity to the target volume. The most common approach to improve lateral dose falloff is through the use of physical beam shaping devices, such as brass apertures or collimator based systems. A recently proposed approach focuses on proton beam spot placements, moving away from traditional grid-based placements to concentric-contours based schemes. This improves lateral dose falloff in two ways: (1) by better conforming all spots to the tumor boundary and (2) allowing for 'edge enhancement', where boundary spots deliver higher fluence than more central spots, thereby creating a steeper lateral dose falloff. However, these benefits come at the expense of maintaining uniformity of spot distribution inside the target volume. In this work we have developed a new optimized spot placement scheme that provides robust spot distributions inside the target. This approach achieves the boundary conformity of a concentric-contours based approach and uses a fast-iterative method to distribute the interior spots in a highly uniform fashion in an attempt to improve both the lateral dose falloff and uniformity. Furthermore, we quantified the impact of this new approach through direct comparison with grid, contour, and hybrid spot placements schemes, showing improvements for this new approach. The results were validated in homogeneous medium for two different target shapes having concave and convex geometry.

SIRT1 promotes GLUT1 expression and bladder cancer progression via regulation of glucose uptake.

Bladder cancer (BC) is one of the most common tumors. Metabolic reprogramming is a feature of neoplasia and tumor growth. Understanding the metabolic alterations in bladder cancer may provide new directions for bladder cancer treatment. Sirtuin 1 (SIRT1) is a lysine deacetylase of multiple targets including metabolic regulators. In pancreatic cancer, the loss of SIRT1 is accompanied by a decreased expression of proteins in the glycolysis pathway, such as GLUT1, and cancer cell proliferation. Thus, we hypothesize that SIRT1 may interact with GLUT1 to modulate the proliferation and glycolysis phenotype in bladder cancer. In the present study, the expression of SIRT1 and GLUT1 was upregulated in BC tissues and cell lines and positively correlated in tissue samples. SIRT1 overexpression or GLUT1 overexpression alone was sufficient to promote cell proliferation and glucose uptake in BC cells. EX527, a specific inhibitor of SIRT1, exerted an opposing effect on bladder cancer proliferation and glucose uptake. The effect of EX527 could be partially reversed by GLUT1 overexpression. More importantly, SIRT1 overexpression significantly promoted the transcriptional activity and expression of GLUT1, indicating that SIRT1 increases the transcription activity and expression of GLUT1, therefore, promoting the cell proliferation and glycolysis in BC cells. Our study first reported that SIRT1/GLUT1 axis promotes bladder cancer progression via regulation of glucose uptake.

Calibration of a detector array through beam profile reconstruction with error-locking.

An iterative method is proposed to calibrate radiation sensitivities of an arbitrary two-dimensional (2D) array of detectors. The array is irradiated with a wide open- field beam at the central position, as well as at laterally and longitudinal shifted positions; the 2D beam profile of the wide field is reconstructed iteratively from the ratios of shifted images to the central image. The propagation errors due to output variation and inaccurate array positioning are estimated and removed from the reconstructed beam profile by an error-locking scheme with narrow open-field irradiations. The beam profile is interpolated when necessary and then compared to raw detector responses to determine sensitivities. Two additional methods were implemented for comparison: 1) the commercial iterative calibration method for MapCHECK2 with translation and rotation operations; 2) a labor-intensive noniterative method without the issue of error propagation. A MapCHECK2 2D detector array was used to validate the proposed method with the 6 MV photon beam from a Varian iX linear accelerator. All calibration methods were repeated three times. A total of 5, 9, and 29 irradiations were required to implement the commercial method, the proposed method and the noniterative method respec- tively. Moreover, a 5 mm positioning error was intentionally introduced into the calibration procedures of the commercial and the proposed method to test their robustness. Under the normal operation condition of the linear accelerator and with careful alignment of the MapCHECK2, the deviations of the calibrated sensitivities of the proposed method and commercial method with respect to the noniterative method were 0.30% ± 0.29% and 0.92% ± 0.63% respectively; when the 5 mm positioning error was presented, these two methods resulted in deviations of 0.40% ± 0.36% and 3.58% ± 1.94%, respectively. A patient study suggested that, due to this 5 mm positioning error, the mean DTA (dose to agreement) passing rate by the commercial method was 2.7% lower than that by the noniterative method, whereas the proposed method led to a comparable passing rate. It is evident from this study that the proposed iterative method leads to within 1% mean calibration results to established methods. It requires much fewer number of measurements than noniterative method and is more robust against the positioning error than the commercial iterative method. The method also eliminates the need of rotation operations and, therefore, is applicable to inline detector arrays without rotation function, such as electronic portal imager device (EPID). 

Rapid magnetic resonance-guided near-infrared mapping to image pulsatile hemoglobin in the breast.

A near-IR (NIR) tomography system with spectral-encoded sources was built to quantify the temporal contrast in human breast tissue using guidance from magnetic resonance imaging. The systems were integrated with a custom breast coil interface to provide simultaneous acquisition. The NIR signal was synchronized to simultaneous finger pulse oximeter plethysmogram, which offered a frequency reference. A 0.1 s temporal delay of the absorption pulse within adipose tissue relative to fibroglandular tissue was found, in an initial human study, showing the potential for novel contrast imaging of fast flow signals in deep tissue.

Video-rate near infrared tomography to image pulsatile absorption properties in thick tissue.

A high frame-rate near-infrared (NIR) tomography system was created to allow transmission imaging of thick tissues with spectral encoding for parallel source implementation. The design was created to maximize tissue penetration through up to 10 cm of tissue, allowing eventual use in human imaging. Eight temperature-controlled laser diodes (LD) are used in parallel with 1.5 nm shifts in their lasing wavelengths. Simultaneous detection is achieved with eight high-resolution, CCD-based spectrometers that were synchronized to detect the intensities and decode their source locations from the spectrum. Static and dynamic imaging is demonstrated through a 64 mm tissue-equivalent phantom, with acquisition rates up to 20 frames per second. Imaging of pulsatile absorption changes through a 72 mm phantom was demonstrated with a 0.5 Hz varying object having only 1% effect upon the transmitted signal. This subtle signal change was used to show that while reconstructing the signal changes in a tissue may not be possible, image-guided recovery of the pulsatile change in broad regions of tissue was possible. The ability to image thick tissue and the capacity to image periodic changes in absorption makes this design well suited for tracking thick tissue hemodynamics in vivo during MR or CT imaging.