Engineered sTRAIL-armed MSCs overcome STING deficiency to enhance the therapeutic efficacy of radiotherapy for immune checkpoint blockade.

Radiotherapy (RT) mainly elicits antitumor immunity via the cGAS/STING axis for type I interferon (IFN) production. However, dysregulation of cGAS/STING constrains radiotherapy-induced antitumor immunity and type I IFN-dependent cell death and is associated with shorter survival of patients with colorectal cancer (CRC). Due to their tumor tropism, mesenchymal stem cells (MSCs) have shown the potential to deliver therapeutic genes for cancer therapy. Here, we showed that MSCs enhance the sensitivity to RT by inducing TRAIL-dependent cell death and remodel the tumor microenvironment by recruiting CD8+ immune cells to upregulate PD-L1 in the tumor. By engineering MSCs to express CRC-specific soluble TRAIL via adenovirus-associated virus 2 (AAV2), we found that the therapeutic activity of MSC-sTRAIL was superior to that of MSCs alone when combined with RT. Combined treatment with MSC-sTRAIL and RT significantly reduced cell viability and increased apoptosis by inducing TRAIL-dependent cell death in STING-deficient colorectal cancer cells. MSC-sTRAIL directly triggered TRAIL-dependent cell death to overcome the deficiency of the cGAS/STING axis. Moreover, these combination treatments of MSC-sTRAIL and RT significantly remodeled the tumor microenvironment, which was more suitable for anti-PD-L1 immunotherapy. Taken together, this therapeutic strategy represents a novel targeted treatment option for patients with colorectal cancer, especially cGAS/STING-deficient patients.

The cost-effectiveness of surgical resection and cesium-131 intraoperative brachytherapy versus surgical resection and stereotactic radiosurgery in the treatment of metastatic brain tumors.

This study aims to evaluate the cost-effectiveness of surgical resection (S) and Cesium-131 (Cs-131) [S + Cs-131] intraoperative brachytherapy versus S and stereotactic radiosurgery (SRS) [S + SRS] for the treatment of brain metastases. Treatment records as well as hospital and outpatient charts of 49 patients with brain metastases between 2008 and 2012 who underwent S + Cs-131 (n = 24) and S + SRS (n = 25) were retrospectively reviewed. Hospital charges were compared for the single treatment in question. Means and curves of survival time were defined by the Kaplan-Meier estimator, with the cost analysis focusing on the time period of the relevant treatment. Quality adjusted life years (QALY) and Incremental cost-effectiveness ratios (ICER) were calculated for each treatment option as a measure of cost-effectiveness. The direct hospital costs of treatments per patient were: S + Cs131 = $19,271 and S + SRS = $44,219. The median survival times of S + Cs-131 and S + SRS were 15.5 and 11.3 months, and the 12 month survival rates were 61 % and 49 % (P = 0.137). The QALY for S + SRS when compared to S + Cs-131 yielded a p < 0.0001, making it significantly more cost-effective. The ICER also revealed that when compared to S + Cs-131, S + SRS was significantly inferior (p < 0.0001). S + Cs-131 is more cost-effective compared with S + SRS based on hospital charges as well as QALYs and ICER. Cost effectiveness, in addition to efficacy and risk, should factor into the comparison between these two treatment modalities for patients with surgically resectable brain metastases.

Higher locoregional recurrence rate for triple-negative breast cancer following neoadjuvant chemotherapy, surgery and radiotherapy.

BACKGROUND: Breast cancer subtype, determined by expression of estrogen/progesterone receptor (ER/PR) and human epidermal growth factor receptor (HER)-2, is predictive for prognosis. The importance of subtype to locoregional recurrence (LRR) following neoadjuvant chemotherapy (NAC) is unknown, particularly after adjuvant radiotherapy (RT). METHODS: We retrospectively identified 160-breast cancer patients registered at Columbia University Medical Center from 1999 to 2012 treated with NAC, surgery and adjuvant RT. RESULTS: Patients were grouped by receptor status: hormone receptor positive (HR+) [(ER or PR+)/HER2-; n = 75], HER2+ (n = 46), or triple-negative (TNBC) [ER (-) PR (-) HER2 (-); n = 36]. The median follow-up was 28 months. 92.0% received an anthracycline-taxane based NAC and 80.4% of HER2+ patients received trastuzumab. All underwent surgical resection followed by RT. 15.6% had a pathologic complete response (pCR): 26% of HER2+, 5% of HR+, and 25% of TN. The actuarial rate of DM was 13.8% for the entire cohort, with equivalent rates by subtypes in non-pCR patients. The overall rate of LRR was 8%. However, the LRR rate was significantly higher for TNBC patients (22.2%) than HER2+ (5.6%) (p = 0.025) or HR+ (3.0%) (p = 0.037) in non-pCR group. In the pCR group, two patients had recurrence; one LRR and one a DM, both had TNBC. All LRR occurred in or near the radiation field. CONCLUSIONS: TNBC patients with < pCR to NAC have a significantly higher LRR rate as compared to other subtypes even with surgery and adjuvant RT. Our data support a need to further intensify local therapy in TNBC patients.

Comparison of primary radiation versus robotic surgery plus adjuvant radiation in high-risk prostate cancer: a single center experience.

OBJECTIVE: The objective of this study was to compare robotic-prostatectomy plus adjuvant radiation therapy (RPRAT) versus primary RT for high-risk prostate cancer (HRPCa). MATERIALS AND METHODS: A retrospective chart review was performed for the HRPCa patients treated in our institution between 2000 and 2010. One hundred and twenty-three patients with high-risk disease were identified. The Chi-square test and Fisher's exact test were used to compare local control and distant failure rates between the two treatment modalities. For prostate-specific antigen comparisons between groups, Wilcoxon rank-sum test was used. RESULTS: The median follow-up was 49 months (range: 3-138 months). Local control, biochemical recurrence rate, distant metastasis, toxicity, and disease-free survival were similar in the two groups. CONCLUSIONS: Primary RT is an excellent treatment option in patients with HRPCa, is equally effective and less expensive treatment compared with RPRAT. A prospective randomized study is required to guide treatment for patients with HRPCa.

Outcomes of gamma knife radiosurgery, bi-modality & tri-modality treatment regimens for patients with one or multiple brain metastases: the Columbia University Medical Center experience.

Optimal treatment of brain metastases (BMs) is debatable. However, surgery or gamma knife radiosurgery (GKRS) improves survival when combined with whole brain radiotherapy (WBRT) versus WBRT alone. We retrospectively reviewed an institutional database of patients treated with GKRS for BMs from 1998 to 2013 to explore effects of single or multi-modality therapies on survival. There were 528 patients with median age 62 years. Histologies included 257 lung, 102 breast, 62 melanoma, 40 renal cell, 29 gastrointestinal, and 38 other primary cancers. Treatments included: 206 GKRS alone, 111 GKRS plus WBRT, 109 GKRS plus neurosurgical resection (NSG), and 102 all three modalities. Median overall survival (mOS) was 16.6 months. mOS among patients with one versus multiple metastasis was 17.2 versus 16.0 months respectively (p = 0.825). For patients with one BM, mOS following GKRS alone, GKRS plus WBRT, GKRS plus NSG, and all three modalities was 9.0, 19.1, 25.5, and 25.0 months, respectively, and for patients with multiple BMs, mOS was 8.6, 20.4, 20.7, 24.5 months for the respective groups. Among all patients, multivariate analysis confirmed that tri-modality group had the longest survival (HR 0.467; 95 % CI 0.350-0.623; p < 0.001) compared to GKRS alone; however, this was not significantly different than bi-modality approaches. Uncontrolled primary extra-CNS disease, age and KPS were also independent predictors of survival. Patients treated with GKRS plus NSG, GKRS plus WBRT, or all three modalities had improved OS versus GKRS alone. In our analysis, resection and GKRS allowed avoidance of WBRT without shortening survival.

Phase I/II study of resection and intraoperative cesium-131 radioisotope brachytherapy in patients with newly diagnosed brain metastases.

OBJECT: Resected brain metastases have a high rate of local recurrence without adjuvant therapy. Adjuvant whole-brain radiotherapy (WBRT) remains the standard of care with a local control rate > 90%. However, WBRT is delivered over 10-15 days, which can delay other therapy and is associated with acute and long-term toxicities. Permanent cesium-131 ((131)Cs) implants can be used at the time of metastatic resection, thereby avoiding the need for any additional therapy. The authors evaluated the safety, feasibility, and efficacy of a novel therapeutic approach with permanent (131)Cs brachytherapy at the resection for brain metastases. METHODS: After institutional review board approval was obtained, 24 patients with a newly diagnosed metastasis to the brain were accrued to a prospective protocol between 2010 and 2012. There were 10 frontal, 7 parietal, 4 cerebellar, 2 occipital, and 1 temporal metastases. Histology included lung cancer (16), breast cancer (2), kidney cancer (2), melanoma (2), colon cancer (1), and cervical cancer (1). Stranded (131)Cs seeds were placed as permanent volume implants. The prescription dose was 80 Gy at a 5-mm depth from the resection cavity surface. Distant metastases were treated with stereotactic radiosurgery (SRS) or WBRT, depending on the number of lesions. The primary end point was local (resection cavity) freedom from progression (FFP). Secondary end points included regional FFP, distant FFP, median survival, overall survival (OS), and toxicity. RESULTS: The median follow-up was 19.3 months (range 12.89-29.57 months). The median age was 65 years (range 45-84 years). The median size of resected tumor was 2.7 cm (range 1.5-5.5 cm), and the median volume of resected tumor was 10.31 cm(3) (range 1.77-87.11 cm(3)). The median number of seeds used was 12 (range 4-35), with a median activity of 3.82 mCi per seed (range 3.31-4.83 mCi) and total activity of 46.91 mCi (range 15.31-130.70 mCi). Local FFP was 100%. There was 1 adjacent leptomeningeal recurrence, resulting in a 1-year regional FFP of 93.8% (95% CI 63.2%-99.1%). One-year distant FFP was 48.4% (95% CI 26.3%-67.4%). Median OS was 9.9 months (95% CI 4.8 months, upper limit not estimated) and 1-year OS was 50.0% (95% CI 29.1%-67.8%). Complications included CSF leak (1), seizure (1), and infection (1). There was no radiation necrosis. CONCLUSIONS: The use of postresection permanent (131)Cs brachytherapy implants resulted in no local recurrences and no radiation necrosis. This treatment was safe, well tolerated, and convenient for patients, resulting in a short radiation treatment course, high response rate, and minimal toxicity. These findings merit further study with a multicenter trial.

Surveillance, epidemiology, and end results-based analysis of the impact of preoperative or postoperative radiotherapy on survival outcomes for T3N0 rectal cancer.

PURPOSE: Preoperative chemoradiation has been established as standard of care for T3/T4 node-positive rectal cancer. Recent work, however, has called into question the overall benefit of radiation for tumors with lower risk characteristics, particularly T3N0 rectal cancers. We retrospectively analyzed T3N0 rectal cancer patients and examined how outcomes differed according to the sequence of treatment received. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to analyze T3N0 rectal cancer cases diagnosed between 1998 and 2008. Treatment consisted of surgery alone (No RT), preoperative radiation followed by surgery (Neo-Adjuvant RT), or surgery followed by postoperative radiation (Adjuvant RT). Demographic and tumor characteristics of the three groups were compared using t-tests for the comparison of means. Survival information from the SEER database was utilized to estimate cause-specific survival (CSS) and to generate Kaplan-Meier survival curves. Multivariate analysis (MVA) of features associated with outcomes was conducted using Cox proportional hazards regression models with Adjuvant RT, Neo-Adjuvant RT, No RT, histological grade, tumor size, year of diagnosis, and demographic characteristics as covariates. RESULTS: 10-Year CSS estimates were 66.1% (95% CI 62.3-69.6%; P=0.02), 73.5% (95% CI 68.9-77.5%; P=0.02), and 76.1% (95% CI 72.4-79.4%; P=0.02), for No RT, Neo-Adjuvant RT, and Adjuvant RT, respectively. On MVA, Adjuvant RT (HR=0.688; 95% CI, 0.578-0.819; P<0.001) was associated with significantly decreased risk for cancer death. By contrast, Neo-Adjuvant RT was not significantly associated with improved cancer survival (HR=0.863; 95% CI, 0.715-1.043; P=0.127). CONCLUSION: Adjuvant RT was associated with significantly higher CSS when compared with surgery alone, while the benefit of Neo-Adjuvant RT was not significant. This indicates that surgery followed by Adjuvant RT may still be an important treatment plan for T3N0 rectal cancer with potentially significant survival advantages over other treatment sequences.

Fast polyenergetic forward projection for image formation using OpenCL on a heterogeneous parallel computing platform.

PURPOSE: Simulated projection images of digital phantoms constructed from CT scans have been widely used for clinical and research applications but their quality and computation speed are not optimal for real-time comparison with the radiography acquired with an x-ray source of different energies. In this paper, the authors performed polyenergetic forward projections using open computing language (OpenCL) in a parallel computing ecosystem consisting of CPU and general purpose graphics processing unit (GPGPU) for fast and realistic image formation. METHODS: The proposed polyenergetic forward projection uses a lookup table containing the NIST published mass attenuation coefficients (µ∕ρ) for different tissue types and photon energies ranging from 1 keV to 20 MeV. The CT images of interested sites are first segmented into different tissue types based on the CT numbers and converted to a three-dimensional attenuation phantom by linking each voxel to the corresponding tissue type in the lookup table. The x-ray source can be a radioisotope or an x-ray generator with a known spectrum described as weight w(n) for energy bin E(n). The Siddon method is used to compute the x-ray transmission line integral for E(n) and the x-ray fluence is the weighted sum of the exponential of line integral for all energy bins with added Poisson noise. To validate this method, a digital head and neck phantom constructed from the CT scan of a Rando head phantom was segmented into three (air, gray∕white matter, and bone) regions for calculating the polyenergetic projection images for the Mohan 4 MV energy spectrum. To accelerate the calculation, the authors partitioned the workloads using the task parallelism and data parallelism and scheduled them in a parallel computing ecosystem consisting of CPU and GPGPU (NVIDIA Tesla C2050) using OpenCL only. The authors explored the task overlapping strategy and the sequential method for generating the first and subsequent DRRs. A dispatcher was designed to drive the high-degree parallelism of the task overlapping strategy. Numerical experiments were conducted to compare the performance of the OpenCL∕GPGPU-based implementation with the CPU-based implementation. RESULTS: The projection images were similar to typical portal images obtained with a 4 or 6 MV x-ray source. For a phantom size of 512 × 512 × 223, the time for calculating the line integrals for a 512 × 512 image panel was 16.2 ms on GPGPU for one energy bin in comparison to 8.83 s on CPU. The total computation time for generating one polyenergetic projection image of 512 × 512 was 0.3 s (141 s for CPU). The relative difference between the projection images obtained with the CPU-based and OpenCL∕GPGPU-based implementations was on the order of 10(-6) and was virtually indistinguishable. The task overlapping strategy was 5.84 and 1.16 times faster than the sequential method for the first and the subsequent digitally reconstruction radiographies, respectively. CONCLUSIONS: The authors have successfully built digital phantoms using anatomic CT images and NIST µ∕ρ tables for simulating realistic polyenergetic projection images and optimized the processing speed with parallel computing using GPGPU∕OpenCL-based implementation. The computation time was fast (0.3 s per projection image) enough for real-time IGRT (image-guided radiotherapy) applications.

Panoramic cone beam computed tomography.

PURPOSE: Cone-beam computed tomography (CBCT) is the main imaging tool for image-guided radiotherapy but its functionality is limited by a small imaging volume and restricted image position (imaged at the central instead of the treatment position for peripheral lesions to avoid collisions). In this paper, the authors present the concept of "panoramic CBCT," which can image patients at the treatment position with an imaging volume as large as practically needed. METHODS: In this novel panoramic CBCT technique, the target is scanned sequentially from multiple view angles. For each view angle, a half scan (180° + θ(cone) where θ(cone) is the cone angle) is performed with the imaging panel positioned in any location along the beam path. The panoramic projection images of all views for the same gantry angle are then stitched together with the direct image stitching method (i.e., according to the reported imaging position) and full-fan, half-scan CBCT reconstruction is performed using the stitched projection images. To validate this imaging technique, the authors simulated cone-beam projection images of the Mathematical Cardiac Torso (MCAT) thorax phantom for three panoramic views. Gaps, repeated/missing columns, and different exposure levels were introduced between adjacent views to simulate imperfect image stitching due to uncertainties in imaging position or output fluctuation. A modified simultaneous algebraic reconstruction technique (modified SART) was developed to reconstruct CBCT images directly from the stitched projection images. As a gold standard, full-fan, full-scan (360° gantry rotation) CBCT reconstructions were also performed using projection images of one imaging panel large enough to encompass the target. Contrast-to-noise ratio (CNR) and geometric distortion were evaluated to quantify the quality of reconstructed images. Monte Carlo simulations were performed to evaluate the effect of scattering on the image quality and imaging dose for both standard and panoramic CBCT. RESULTS: Truncated images with artifacts were observed for the CBCT reconstruction using projection images of the central view only. When the image stitching was perfect, complete reconstruction was obtained for the panoramic CBCT using the modified SART with the image quality similar to the gold standard (full-scan, full-fan CBCT using one large imaging panel). Imperfect image stitching, on the other hand, lead to (streak, line, or ring) reconstruction artifacts, reduced CNR, and/or distorted geometry. Results from Monte Carlo simulations showed that, for identical imaging quality, the imaging dose was lower for the panoramic CBCT than that acquired with one large imaging panel. For the same imaging dose, the CNR of the three-view panoramic CBCT was 50% higher than that of the regular CBCT using one big panel. CONCLUSIONS: The authors have developed a panoramic CBCT technique and demonstrated with simulation data that it can image tumors of any location for patients of any size at the treatment position with comparable or less imaging dose and time. However, the image quality of this CBCT technique is sensitive to the reconstruction artifacts caused by imperfect image stitching. Better algorithms are therefore needed to improve the accuracy of image stitching for panoramic CBCT.

Predicting the risk of secondary lung malignancies associated with whole-breast radiation therapy.

PURPOSE: The risk of secondary lung malignancy (SLM) is a significant concern for women treated with whole-breast radiation therapy after breast-conserving surgery for early-stage breast cancer. In this study, a biologically based secondary malignancy model was used to quantify the risk of secondary lung malignancies (SLMs) associated with several common methods of delivering whole-breast radiation therapy (RT). METHODS AND MATERIALS: Both supine and prone computed tomography simulations of 15 women with early breast cancer were used to generate standard fractionated and hypofractionated whole-breast RT treatment plans for each patient. Dose-volume histograms (DVHs) of the ipsilateral breast and lung were calculated for each patient on each plan. A model of spontaneous and radiation-induced carcinogenesis was used to determine the relative risks of SLMs for the different treatment techniques. RESULTS: A higher risk of SLMs was predicted for supine breast irradiation when compared with prone breast irradiation for both the standard fractionation and hypofractionation schedules (relative risk [RR] = 2.59, 95% confidence interval (CI) = 2.30-2.88, and RR = 2.68, 95% CI = 2.39-2.98, respectively). No difference in risk of SLMs was noted between standard fractionation and hypofractionation schedules in either the supine position (RR = 1.05, 95% CI = 0.97-1.14) or the prone position (RR = 1.01, 95% CI = 0.88-1.15). CONCLUSIONS: Compared with supine whole-breast irradiation, prone breast irradiation is associated with a significantly lower predicted risk of secondary lung malignancy. In this modeling study, fractionation schedule did not have an impact on the risk of SLMs in women treated with whole-breast RT for early breast cancer.

Oral small-molecule tyrosine kinase inhibitor midostaurin (PKC412) inhibits growth and induces megakaryocytic differentiation in human leukemia cells.

Midostaurin (PKC412), a small-molecule multiple tyrosine kinase inhibitor, has been shown to suppress the growth of various tumor cells. Since kinases inhibited by midostaurin are involved in megakaryocytic differentiation, we hypothesized that this novel target therapeutic might have a role in the treatment of human leukemia cells. Hence, we examined the effect of midostaurin on human erythroleukemia cells and evaluated potential mechanisms. Midostaurin inhibited the growth of both K562 and HEL cells in dose- and time-dependent manner. Morphological changes such as enlarged contours, multipolarity of mitotic spindles, and multinucleation of megakaryocytes were noted in both cell lines treated by midostaurin. A smaller population of apoptotic cells was also observed. DNA histogram revealed polyploid and hypoploid populations of midostaurin-treated cells. Midostaurin treatment enhanced the surface expression of the megakaryocytic marker CD61; in contrast, the erythroid marker glycophorin A expression was decreased. At optimal conditions for inducing megakaryocytic differentiation, midostaurin upregulated the expression and signaling of c-Mpl, a thrombopoietin receptor-encoding gene, in HEL cells. These results indicate that midostaurin can inhibit growth; induce megakaryocytic differentiation; and to a lesser extent, cause apoptosis in HEL cells. This effect might involve the expression and signaling of c-Mpl.

Cervical tumor control evaluated with ICRU 38 reference volumes and integrated reference air kerma.

PURPOSE: The purpose of this investigation was to evaluate the relationship of ICRU 38 reference volumes and integrated reference air kerma to primary cervical tumor control. MATERIALS AND METHODS: This retrospective study includes 1253 women with carcinoma of the uterine cervix treated with radiotherapy. Patients were treated from 1959 to 1993 at the Mallinckrodt Institute of Radiology. There were 39 women with stage Ia disease, 211 with stage Ib1, 88 with stage Ib2, 580 with stage 2, and 335 with stage 3 disease. Most patients with stage Ia disease were treated with low dose rate brachytherapy alone. All other patients were treated with external irradiation and low dose rate brachytherapy. External irradiation doses ranged from 8.2-63.8 Gy to the whole pelvis and an additional parametrial boost to deliver a total of 65-75 Gy to Point P depending on tumor stage. Low dose rate brachytherapy was delivered to the primary tumor with doses ranging from 40x10(4)-60x10(4) Gy cm(2) (integrated reference air kerma; IRAK). Isodose reference volumes (60-160 Gy) and point A doses were determined for all patients. Tumor control was defined as control of the primary cervical cancer with or without failure at other pelvic or distant sites. RESULTS: The mean 60 Gy volume was calculated to be 139.5 cm(3) for stage Ia, 200.4 cm(3) for stage Ib1, 270.9 cm(3) for stage Ib2, 235 cm(3) for stage 2, and 293.4 cm(3) for stage 3. No patient with stage Ia disease had a failure in the cervix. For stage Ib1 tumors the mean 60 Gy volume was 219.1 cm(3) for those who failed in the cervix and 199.9 cm(3) for those who did not fail (P=0.73). For stage Ib2 tumors the mean 60 Gy volume was 354.4 cm(3) for those who failed and 260.2 cm(3) for those who did not fail (P=0.004). The mean 60 Gy volume was 249.3 cm(3) for those with stage 2 disease who failed and 233.8 cm(3) for those who did not fail (P=0.02). For patients with stage 3 cancer the mean 60 Gy volume was 321.6 cm(3) for those who failed and 287.3 cm(3) for those who did not fail (P=0.20). Reference volumes from 70-160 Gy were not statistically different within each stage for those who failed in the cervix compared to those who did not fail. Cervical recurrences by clinical stage did not have statistically significant differences for mean IRAK except for stage II disease (P=0.001). CONCLUSION: Analysis of the 60-160 Gy reference volumes and IRAK failed to demonstrate a consistent positive increasing correlation of these values to primary cervical tumor control.