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Purpose/Objective(s) The responses of human head and neck cancer (HNSCC) cells to photon (XRT) and proton (PRT) radiotherapy can be enhanced by a poly-(ADP-ribose) polymerase (PARP)-1 and PARP-2 inhibitor (PARPi) with undefined underlying mechanisms. We hypothesize that elucidating these mechanisms will facilitate a personalized selection of PARPi in combination with XRT or PRT. Herein, the effects of PARPi on XRT and PRT induced cell death, cell cycle distribution, and related protein expression in HNSCC cells were defined. Materials/Methods Human papillomavirus (HPV)-negative HN5, SqCC/Y1, and HPV-positive UPCI-SCC-154, UM-SCC-47 cell lines were tested. Cells were exposed to a 4 Gy PRT or XRT with or without PARPi (1 µM, 1 hour [h] before radiation). Cell cycle distribution, cell necrosis and apoptosis (staining with Annexin-VFITC) were determined using terminal deoxy-nucleotidyltransferase dUTP nickend labeling assay and were analyzed by flow cytometry. Cell mitotic catastrophe (co-staining for cytoplasm with γ- tubulin for nucleus with Dapi), and senescence (assessed using SA-β-gal) were examined. Protein expressions were determined by western blot or by flow cytometry. Results PARPi significantly increased XRT and PRT induced cellular senescence at 6 days in the two HPV+ cell lines, with higher percentages of senescence in PRT than XRT cells (P all Conclusion In conclusion, PARPi induced higher levels of mitotic catastrophe in combination with PRT versus XRT, promoted XRT and PRT induced senescence, while it led to a trend of increased cell necrosis after PRT and XRT. These upregulating effects of PARPi were cell line dependent. Cell line based delayed DNA damage repair and increase in radiation-induced cell cycle arrest at G2/M phase may have served as parts of the underlying mechanisms. Further studies on personalized therapy of XRT or PRT in combination with PARPi to improve the efficacy of radiotherapy are warranted.

The clinical role of APC promoter methylation in patients with bladder cancer remains to be determined. The relevant databases (PubMed, EMBASE, EBSCO, Wangfang, CNKI and Cochrane Library) were searched to get eligible studies. The overall odds ratios (ORs) and the corresponding 95% confidence intervals (95% CIs) were calculated to assess the effects of APC promoter methylation on bladder cancer risk and clinicopathological features. 2214 patients with bladder cancer and 665 controls were identified. APC promoter methylation was significantly higher in bladder cancer than in nonmalignant tissue and urine samples (tissue: OR = 11.14, 95% CI = 4.29-28.91, P0.001; urine: OR = 24.31, 95% CI = 6.26-94.38, P0.001), but not in blood samples (P = 0.242). The relationship was observed between APC promoter methylation and gender (male vs. female: OR = 1.46, 95% CI = 0.96-2.22, P = 0.074), tumor stage (stage T2-T4 vs. Ta-T1: OR = 3.00, 95% CI = 1.66-5.42, P0.001), and tumor grade (grade 3-4 vs. grade 1-2: OR = 1.99, 95% CI = 1.15-3.42, P = 0.013). But no correlation was found between APC promoter methylation and age, lymph node status, and tumor number (P0.1). APC gene was not associated with overall survival of bladder cancer. Our findings indicate that APC promoter methylation may be associated with the development and progression of bladder cancer and may serve as a promising noninvasive biomarker using urine samples for the detection of bladder cancer.

Background Recurrent gene fusions resulting from chromosome translocations are critical genetic aberrations causing cancer. In our previous study, we identified recurrent rearrangements between ESR1 and its neighbor, CCDC170, in 6-8% of luminal B tumors. Luminal B subtype is a more aggressive ER+ breast cancer, with a higher risk of early relapse after endocrine therapy. These rearrangements enable the expression of N-terminally truncated CCDC170 (ΔCCDC170) under ESR1 promoter. Consistent with the behavior of luminal B tumors, ectopic ΔCCDC170 expression in ER+ breast cancer cells, led to markedly increased cell motility, invasion, anchorage-independent growth, and reduced endocrine sensitivity in vitro, as well as enhanced xenograft growth in vivo. In the present study, we studied the role of ESR1-CCDC170 in breast cancer endocrine resistance in vivo and explored the potential mechanism. Methods To study endocrine resistance in vivo, we transplanted T47D cells stably overexpressing (OE) control (empty) construct or 2 ΔCCDC170 fusion variants (E2-E7 and E2-E10) bilaterally to 4-6 week old female athymic nude mice (supplemented with 17β-estradiol pellets). The tumor growth was monitored biweekly and tumor volume was measured by the formula 1/2(length × width2). When the tumors reach 150–200 mm3, mice were randomly allocated to vehicle or tamoxifen (tam) treatment groups. For ERE luciferase assay, cells were co-transfected with ERE luciferase reporter (ERE-TK-Luc) and pCMV β-galactosidase. The luciferase levels were measured and normalized to β-gal activity. For immunoblot analysis, T47D OE cells were estrogen-deprived, serum-starved, and treated with vehicle, estrogen (E2) or tam. Reverse Phase Protein Array (RPPA) analysis was performed using ∼200 validated antibodies against an array of key signaling molecules in cancer. Results Our in vivo endocrine sensitivity study showed that, while T47D vector control tumors mostly regressed after tam treatment, the regression of E2-E7 tumors was significantly slower. Moreover, E2-E10 tumors continued to grow despite tam treatment. These observations suggest that ΔCCDC170 may render the T47D xenografts less sensitive to tam in vivo. Kaplan–Meier analysis revealed a significantly worse progression-free survival (defined by tumor doubling time) for E2-E7 (p Conclusion These data suggest a potential role of ESR1-CCDC170 in mediating breast cancer endocrine resistance, presumably due to hyperactive growth factor signaling endowed by this fusion. Further studies are required to elucidate the role of endogenous ESR1-CCDC170 in breast cancer endocrine resistance, and discover the precise engaged mechanisms. Citation Format: Hu Y, Veeraraghavan J, Wang X, Tan Y, Kim J, Schiff R, Wang X-S. Evaluating the role of recurrent ESR1-CCDC170 in breast cancer endocrine resistance. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD2-05.

Background: Repair and reconstruction of the medial patellofemoral ligament (MPFL) has been undertaken for the treatment of patellar instability. For successful surgery detailed knowledge of the anatomy of the ligament is required. The aim of this study was to describe the origin, structure and insertion of the MPFL. Materials and methods: We studied cadaveric knees from 30 Chinese adults. We studied the origin, course and insertion of the MPFL. Results: We found that the MPFL was composed of two main strands, superficial and deep. We also found that the insertion of the MPFL into the femur had three common patterns. All three were located between the adductor tubercle and the proximal part of superficial medial collateral ligament. Conclusions: We have added to the anatomical knowledge of the structure of the MPFL. Our study has implications for guiding bone tunnel positioning during MPFL reconstruction surgery. (Folia Morphol 2018; 77, 2: 356–361)

Purpose To evaluate the patient setup accuracy and effectiveness using ExacTrac and CT_on_rails systems. Methods We used Brainlab's Exactrac system and Varian/GE's CT_on_rails for spine radiosurgery patient setup. Once the patient was setup using the ExacTrac and couch position was recorded, fiducially markers were placed on stable surfaces based on the room laser to indicate the linac iso for the CT images. CT images were acquired using the on-rail CT with the couch rotated 180 degrees. The couch was returned to 0 degree position, and verification X-ray images were taken and corrections were made by ExacTrac. The treatment CT images were registered with the planning CT using the in-house CAT software and it displays the correct couch position based on CT which can be compared with ExacTrac setup. The corrected couch positions from CT registration are compared to those from ExacTrac. The translational discrepancies needed to be within 2 mm for confirmation. If a discrepancy was greater than 2 mm, investigation or re-setup was required. The rotation deviations were also evaluated by ExacTrac and confirmed by the treatment CT images. We would also re-setup patient if Exactrac detected more than 3 degree rotation, or treatment CT images showed significant target rotation compared to planning CT. The use of the CTonrails took little extra time, but make the overall evaluation process easier, faster and with more confidence. Results for 171 treatment sessions using this approach, the mean discrepancies between CTonrails and ExacTrac setup is: x=0.0±1.0 mm, y=-0. 1±0.9 mm, z=0.2±0.9 mm; for rotations, about 3% of the cases required re-setup patient due to significant rotation displayed by the treatment CT on the CAT system. Conclusions The combined use of ExacTrac and CT_on_Rails systems can improve the overall setup accuracy and increase the confidence in setup for spine radiosurgery treatments.

Purpose: To compare gamma knife treatment plans that use skull scaling instrument measurements for skull definition vs. CT based skull definition. Methods: Eight previously treated patients who had head CT scans were randomly selected. Their CTimages were imported into Leksell GammaPlan. For each patient, three dose plans were developed: 1. the reference plan. It was planned based on the standard clinical treatment planning guidelines. Measurements were used for skull definition and TMR10 for dose calculation algorithm. 2. CT TMR10 plan, a recalculation of the reference plan with CTimages used for skull definition 3. CT Convolution plan, a recalculation of the TMR10 plan using convolution algorithm. The treatment times for CT TMR10 plan and CT convolution plan were set to be the same as the reference plan by adjusting the prescription dose level. Prescription dose and shots were left unchanged. Plan comparisons were carried out using minimum dose, target coverage, gradient index and selectivity. Results: On average, the minimum dose for CT TMR10 and CT Convolution plans are 1.8% and 6.5% lower than that of the reference plan. The target coverage, gradient index are comparable for these three plans. The selectivity indices for CT TMR10 and CT Convolution plans were found to be 3.1% and 9.8% higher than that of reference plan. Conclusions: This work indicates the measurement based skull definition could Result in inaccurate calculation in minimum dose to the target. The target coverage and gradient index are however uncompromised. The selectivity index was actually underestimated.

Cachexia is a frequent manifestation of pancreatic cancer, can limit a patient’s ability to take chemotherapy, and is associated with shortened survival. We developed a model to predict the early onset of cachexia in advanced pancreatic cancer patients. Patients with newly diagnosed, untreated metastatic or locally advanced pancreatic cancer were included. Serum cytokines were drawn prior to therapy. Patient symptoms were recorded using the M.D. Anderson Symptom Inventory (MDASI). Our primary endpoint was either 10% weight loss or death within 60 days of the start of therapy. Twenty-seven of 89 patients met the primary endpoint (either having lost 10% of body weight or having died within 60 days of the start of treatment). In a univariate analysis, smoking, history symptoms of pain and difficulty swallowing, high levels of MK, CXCL-16, IL-6, TNF-a, and low IL-1b all correlated with this endpoint. We used recursive partition to fit a regression tree model, selecting four of 26 variables (CXCL-16, IL-1b, pain, swallowing difficulty) as important in predicting cachexia. From these, a model of two cytokines (CXCL-16 > 5.135 ng/ml and IL-1b

Summary Background There are ethnic differences in the prevalence and types of androgenetic alopecia (AGA). Although there have been several reports on the prevalence and types of AGA in caucasian and Asian populations, there are very few data on a Chinese population that have been derived from a sufficient number of samples. Objectives To estimate the prevalence and types of AGA in a Chinese population, and to compare the results with those in caucasians and Koreans reported previously in the literature. Methods A population-based cross-sectional study was carried out in 7056 subjects (3519 men and 3537 women) from May 2006 to December 2006 in a community of Shanghai. Questionnaires were completed during face-to-face interviews at the subjects’ homes. The degree of AGA was classified according to the Norwood and Ludwig classifications. Results The prevalence of AGA in Chinese men was 19·9%, and the prevalence of female pattern AGA in men was 0·1%. The most common type in men was type III vertex (3·5%). The prevalence of AGA in women was 3·1%, while male pattern AGA was found in those aged over 50 years (0·4%), and the most common type was type I (Ludwig classification) (1·4%). A family history of AGA was present in 55·8% of men and 32·4% of women with AGA. Conclusions The prevalence of AGA in Chinese men was lower than in caucasian men but was similar to that in Korean men; however, over the age of 60 years it was approaching that in caucasian men but was higher than that in Korean men. The most common type in Chinese men with AGA was type III vertex. Interestingly, the prevalence of AGA in Chinese women was lower than that in Korean women and caucasian women, and type I was the most common type (Ludwig classification).

Purpose: To assess quantitatively the impact of incorporating functional lung imaging into intensity-modulated radiation therapy planning for locally advanced non-small cell lung cancer (NSCLC). Methods and Materials: Sixteen patients with advanced-stage NSCLC who underwent radiotherapy were included in this study. Before radiotherapy, each patient underwent lung perfusion imaging with single-photon-emission computed tomography and X-ray computed tomography (SPECT-CT). The SPECT-CT was registered with simulation CT and was used to segment the 50- and 90-percentile hyperperfusion lung (F50 lung and F90 lung). Two IMRT plans were designed and compared in each patient: an anatomic plan using simulation CT alone and a functional plan using SPECT-CT in addition to the simulation CT. Dosimetric parameters of the two types of plans were compared in terms of tumor coverage and avoidance of normal tissues. Results: In incorporating perfusion information in IMRT planning, the median reductions in the mean doses to the F50 and F90 lung in the functional plan were 2.2 and 4.2 Gy, respectively, compared with those in the anatomic plans. The median reductions in the percentage of volume irradiated with >5 Gy, >10 Gy, and >20 Gy in the functional plans were 7.1%, 6.0%, and 5.1%, respectively, for F50 lung, and 11.7%, 12.0%,more » and 6.8%, respectively, for F90 lung. A greater degree of sparing of the functional lung was achieved for patients with large perfusion defects compared with those with relatively uniform perfusion distribution. Conclusion: Function-guided IMRT planning appears to be effective in preserving functional lung in locally advanced-stage NSCLC patients.« less

Background: Aspirin causes bronchospasm in patients with aspirin exacerbated respiratory disease (AERD). The contribution of mast cells to the increased cysteinyl-leucotrienes (cys-LTs) detected in AERD patients is however not defined. Aims of the study: Effects of prostaglandin (PG) E2 and inhibitors of cyclooxygenase (COX) and lipoxygenase (LO) pathways on mediator release from cultured mast cells of normal subjects, aspirin tolerant asthma (ATA) and AERD patients were compared to better define the role of mast cells in AERD. Methods: Mast cells were cultured from peripheral blood progenitors and were activated by anti-IgE. Histamine, PGD2 and cys-LTs released were then determined. Results: Basal release of all three mediators was similar in all subjects. Although the release of all three mediators was increased by anti-IgE, mast cells from AERD patients produced significantly more cys-LTs (6.9 ± 2.0 ng/106 cells) than normal and ATA subjects (2.3 ± 0.8 and 1.7 ± 0.5 ng/106 cells, respectively). While COX and LO pathway inhibitors did not affect anti-IgE induced histamine release, they significantly suppressed the production of PGD2 and cys-LTs, respectively, in all patients. PGE2 significantly enhanced anti-IgE induced histamine and PGD2 release from mast cells of normal subjects but not those of ATA and AERD patients. In contrast, PGE2 suppressed only anti-IgE induced cys-LTs release from mast cells of AERD patients. Conclusion: We speculate that overproduction of cys-LTs is unique to mast cells of AERD patients and is particularly sensitive to suppression by PGE2. Consequently reduction of PGE2 production by aspirin removes this endogenous control of cys-LTs overproduction, resulting in asthma attack.

The incidence of bladder cancer is closely associated with exposure to aromatic amines, that can cause cancer only after metabolic activation regulated by N-acetyl transferase 1 and 2 (NAT1 and NAT2). Many studies have indicated that slow acetylation of NAT2 increases the risk of bladder cancer. The major risk factor is tobacco smoke; however, some studies have failed to prove this. This study attempted to explore the correlation between NAT2 slow acetylation and bladder cancer risk through a meta-analysis of published case-control studies. Studies detecting NAT2 gene status in bladder cancer patients and healthy controls were retrieved from PubMed, Cochrane, EMchrane, CBM, and CNKI. We retrieved the data of cited articles and publications to identify and compare NAT2 gene in bladder cancer patients and healthy controls. The variables within and between the studies were also considered. The META module in the Stata v.6.0 software was used for data analysis. Twenty independent studies were enrolled in our meta-analysis according to the inclusion and exclusion criteria. Individual differences in the bladder cancer susceptibility were, in part, attributed to the effect of carcinogens. The merged odds ratio of the effect of slow acetylation on bladder cancer was 1.31 (95% confidence interval = 1.11-1.55). In conclusion, NAT2 slow acetylation state was associated with bladder cancer risk, and was shown to modestly increase the risk of bladder cancer.

This study proposed to retrospectively analyze the efficacy of radiotherapy on brain/bone metastases in patients with stage IV lung adenocarcinoma and to evaluate the correlation between overall survival after radiotherapy and other factors including metastatic sites and EGFR mutation status. 115 patients with Stage IV lung adenocarcinoma admitted to our center from March, 2011 to December, 2013 were enrolled. They presented with metastases to no other solid organs except the bone or brain and had received no prior treatment. 50 patients received EGFR mutation test with 32 detected as EGFR mutant and 18 wild-type. Patients with brain metastases were treated with 40 Gy whole brain irradiation (WBI) in 2 Gy fractions; patients with bone metastases were treated with 30 Gy local irradiation in 3 Gy fractions or 40 Gy in 2 Gy fractions. All the patients received systemic therapy during or after radiotherapy and 68 received targeted therapy.The median overall survival of patients with solitary brain metastases, solitary bone metastases or combined brain and bone metastases were 8.50 months, 8.50 months and 9.50 months respectively, revealing no significant difference (p=0.57). The median overall survival of patients with EGFR mutations was 10.25 months, longer than the 8.75 months of patients without EGFR mutations, revealing no significant difference (p=0.57). The median overall survival of EGFR mutant patients with solitary bone metastases, solitary brain metastases or combined brain and bone metastases were 7.50 months, 10.50 months and 11.50 months respectively, revealing no significant difference (p=0.91). 36 patients with untested EGFR mutation status received EGFR-TKI. Among EGFR mutant patients, 10 didn't receive targeted therapy; 8 were administered Erlotinib and 14 Gefitinib with median overall survival of 10.25 months and 14.5 months, showing no significant difference (p=0.11) between the two drugs. When patients with stage IV lung adenocarcinoma have been treated by early radiotherapy, the overall survival doesn't correlate with metastatic sites. Radiotherapy could extend survival for EGFR mutant patients with stage IV lung adenocarcinoma. EGFR mutation test should be performed before treatment of the disease.

1. Mast cells cultured from human peripheral blood have been used as a cell model for functional studies of human mast cells, particularly human lung mast cells. However, the beta-adrenoceptor subtype expressed by these cultured cells has not been identified. The aim of the present study was to characterize pharmacologically the beta-adrenoceptors involved in the suppression of IgE-mediated release of mediators, including histamine, prostaglandin (PG) D2 and leukotriene (LT) C4 from cultured mast cells. 2. Mast cells were cultured from mast cell progenitors isolated from peripheral blood in the presence of 200 ng/mL stem cell factor and 50 ng/mL interleukin-6. Mast cells were sensitized with human myeloma IgE, treated with beta-adrenoceptor agonists or antagonist and then challenged with anti-human IgE. The release of histamine, PGD2 and LTC4 from mast cells was determined. 3. Both isoprenaline and salbutamol inhibited anti-IgE-induced release of histamine, PGD2 and LTC4 from cultured mast cells in a dose-dependent manner. Isoprenaline was a more potent inhibitor than salbutamol. The pD2 values for the inhibition of the release of histamine, PGD2 and LTC4 were 7.37 +/- 0.12, 8.38 +/- 0.23, 8.85 +/- 0.23, respectively, for isoprenaline and 6.96 +/- 0.12, 7.65 +/- 0.36, 7.91 +/- 0.64, respectively, for salbutamol. The selective beta3-adrenoceptor agonist BRL-37344 failed to affect anti-IgE-induced histamine release from cultured mast cells. 4. The selective beta2-adrenoceptor antagonist ICI 118 551 (108 mol/L) strongly reversed the concentration-dependent suppression of histamine release by isoprenaline and salbutamol; however, the selective beta1-adrenoceptor antagonist atenolol (106 mol/L) did not have any effect. 5. These results indicate that both isoprenaline and salbutamol act at beta2-adrenoceptors to suppress IgE-mediated mediator release from cultured human mast cells.

Background: Mast cells cultured from human peripheral blood have been widely used to study human mast cell function. Prostanoids are the important regulators of mast cell activity, however, there were no reports about the class of prostanoid receptors expressed on such cultured cells. Aims: The present study was to characterize pharmacologically the prostanoid receptors by investigating the effects of prostanoid receptor agonists on the immunoglobulin E (IgE)-mediated histamine release from the cultured mast cells. Methods: Mast cells cultured from human progenitor cells in peripheral blood were sensitized with human myeloma IgE, and then challenged with anti-human IgE following pretreatment with diverse prostanoid receptor agonists. The histamine content in supernatants and cell pellets were measured by histamine autoanalyzer. Results: Of the prostanoid receptor agonists tested, the prostaglandin E 2 (PGE 2 ) receptor (EP receptor) agonist PGE 2 (10 -7 to 10 -11 M) produced concentration-related potentiation of IgE-mediated histamine release from the cultured mast cells. Sulprostone, an EP 1 /EP 3 agonist, SC-46275, a selective EP 3 agonist, and 11-deoxy-PGE 1 , a selective EP 2 /EP 3 /EP 4 agonist also caused a significant increase in histamine release induced by anti-IgE. BW245C, fluprostone, cicaprost and U46619 for the prostaglandin D 2 , F 2α , I 2 , and thromboxane A 2 receptors respectively, and the EP 2 /EP 4 receptor agonist butaprost had little effect on anti-IgE stimulated histamine release from mast cells. Conclusions: The present results suggest that PGE 2 potentiates the IgE-mediated histamine release from the cultured mast cell via EP 3 and/or EP 1 receptors.

We have studied by immunocytochemistry, the distribution of DMT-1, a cellular iron transporter responsible for transport of metal irons from the plasma membrane to endosomes, in the normal monkey cerebral neocortex and hippocampus. Light to moderate DMT-1 staining was observed in glial cell bodies in the neocortex, the subcortical white matter, and the hippocampus. Despite light labeling of cell bodies, glial end feet around cortical and subcortical blood vessels were heavily labeled. In the neocortex, the glial cell bodies displayed the morphological features of protoplasmic astrocytes. Labeled glial cells in the subcortical white matter contained dense bundles of glial filaments and were identified as fibrous astrocytes. The observation that DMT-1 was present on astrocytic endfeet suggests that these cells are involved in uptake of iron from endothelial cells. It is possible that the iron could then be redistributed into the extracellular space in the brain parenchyma.

The present study aimed to elucidate the distribution of the GABA transporter GAT-3 in the monkey basal ganglia and brainstem. Very dense GAT-3 immunoreactivity was observed in the medial septum, diagonal band, basal nucleus of Meynert, thalamus, globus pallidus, and substantia nigra. Moderate levels were observed in the subthalamic nucleus, periaqueductal grey, spinal trigeminal and vestibular nuclei. A general light level of staining was observed in the remainder of the brainstem regions, and very light staining was observed in the caudate nucleus and putamen. Electron microscopy showed that GAT-3 immunoreactivity was present in cell bodies with light cytoplasm and dense bundles of glial filaments, and features of astrocytes. Large numbers of astrocytic processes were also labeled in the neuropil. The cell bodies and processes of neurons were unlabeled. Further study is necessary to elucidate GAT-3 expression in neurological conditions, including hyperalgesia and Parkinson's disease.

The distribution of glutamate receptors in the monkey subthalamic nucleus was studied using affinity purified polyclonal antibodies to GluR1, phosphorylated GluR1, GluR2/3, NMDAR1, mGluR1a and mGluR5. Intense staining for both the unphosphorylated and the phosphorylated forms of the AMPA receptor subunit GluR1 was observed in the cell bodies and proximal dendrites of neurons in this nucleus. In comparison to GluR1, less intense staining for GluR2/3 was observed in the cell bodies and processes. NMDAR1 immunoreactivity was present in cell bodies and large numbers of small diameter dendrites. Light staining was observed in cell bodies with mGluR1a and no staining was observed on cell bodies with mGluR5. The neuropil, however, contained many processes that were labeled for mGluR1a or mGluR5. Electron microscopy showed that label was present in cytoplasmic locations in cell bodies and dendrites, in addition to components of the synaptic region, in sections stained for GluR1, GluR2/3 and NMDAR1. In contrast, very lightly labeled or unlabeled cell bodies but labeled dendrites and axon terminals, was observed in sections stained for mGluR1a and mGluR5. In addition to neural processes, occasional astrocytic processes were also labeled for mGluR5. Of the immunogold particles that were associated with components of the synaptic region, label for ionotropic glutamate receptors was mostly present on postsynaptic densities, whilst that for metabotropic glutamate receptors was mostly present in a perisynaptic location. The ratio of GluR1/GluR2 messenger RNAs has been reported to increase in the aged hippocampus (PAGLIUSI, S. R., GERRARD, P., ABDALLAH, M., TALABOT, D. & CATSICAS, S. (1994) Neuroscience 61, 429–433.), and it is possible that a similar change in the ratio of GluR1 and GluR2 may occur in neurons of the subthalamic nucleus with age. It is postulated that this could result an increase in calcium permeability via AMPA receptors, and an enhancement of excitatory transmission in this nucleus.

Purpose: To develop the first 4D robust optimization (RO) method accounting for respiratory motion and evaluate its potential to improve plan robustness and optimality compared to 3D RO and PTV-based optimization. Methods: A set of 4D CT images are used to track respiratory motion and deformation of tumors and organs. For each of 10 respiration phases, dose distributions for nine different uncertainty scenarios including the nominal one, those incorporating ±5mm setup uncertainties long x, y and z directions and ±3.5% range uncertainties are calculated. All 90 dose distributions are simultaneously optimized to achieve full dose coverage of 10 CTVs and sparing of normal structures. ITV-based 3D RO and PTV-based optimization based on the average CT are also carried for the same patient using same dose volume constrains. After optimization, 4D robustness evaluation was performed for all resulting plans. The CTV coverage and the sparing of normal tissue in 10 phases are evaluated and compared among the three methods. The widths of DVH bands represent the robustness of dose distributions in the structures. Results: For one patient studied so far, the worst case CTV coverage by the prescription dose among all 90 scenarios is: 99% for 4D RO; 88.9% for 3D RO, and 85.2% for PTV based optimization. 4D RO also results in best robustness with the narrowest DVH’ bandwidths for the CTV. 4D and 3D RO have similar organ sparing while PTV based optimization results in worst organ sparing. Conclusion: 4D robust optimization which accounts for anatomy motion and deformation in the optimization process, significantly improves plan robustness and achieves higher quality treatment plans for lung cancer patients. The method is being evaluated for multiple patients with different tumor and motion characteristics. Acknowledge the grant U19, the grant number is 2U19CA021239-35

Purpose: To develop and validate a prediction model using radiomics features extracted from MR images to distinguish radiation necrosis from tumor progression for brain metastases treated with Gamma knife radiosurgery. Methods: The images used to develop the model were T1 post-contrast MR scans from 71 patients who had had pathologic confirmation of necrosis or progression; 1 lesion was identified per patient (17 necrosis and 54 progression). Radiomics features were extracted from 2 images at 2 time points per patient, both obtained prior to resection. Each lesion was manually contoured on each image, and 282 radiomics features were calculated for each lesion. The correlation for each radiomics feature between two time points was calculated within each group to identify a subset of features with distinct values between two groups. The delta of this subset of radiomics features, characterizing changes from the earlier time to the later one, was included as a covariate to build a prediction model using support vector machines with a cubic polynomial kernel function. The model was evaluated with a 10-fold cross-validation. Results: Forty radiomics features were selected based on consistent correlation values of approximately 0 for the necrosis group and >0.2 for the progression group. In performing the 10-fold cross-validation, we narrowed this number down to 11 delta radiomics features for the model. This 11-delta-feature model showed an overall prediction accuracy of 83.1%, with a true positive rate of 58.8% in predicting necrosis and 90.7% for predicting tumor progression. The area under the curve for the prediction model was 0.79. Conclusion: These delta radiomics features extracted from MR scans showed potential for distinguishing radiation necrosis from tumor progression. This tool may be a useful, noninvasive means of determining the status of an enlarging lesion after radiosurgery, aiding decision-making regarding surgical resection versus conservative medical management.

Purpose: To evaluate correlation between the reproducibility of tumor position under feedback guided voluntary deep inspiration breath hold gating at simulation and at treatment. Methods: All patients treated with breath hold (BH) have 3-6 BH CTs taken at simulation (sim). In addition, if the relationship between the tumor and nearby bony anatomy on treatment BH CT(or CBCT) is found to be greater than 5 mm different at treatment than it was at sim, a repeat BH CT is taken before treatment. We retrospectively analyzed the sim CTs for 19 patients who received BH SBRT lung treatments and had repeat BH CT on treatment. We evaluated the reproducibility of the tumor position during the simulation CTs and compared this to the reproducibility of the tumor position on the repeat treatment CT with our in-house CT alignment software (CT-Assisted Targeting for Radiotherapy). Results: Comparing the tumor position for multiple simulation BH CTs, we calculated: maximum difference (max) = 0.69cm; average difference (x) = 0.28cm; standard deviation (σ) = 0.18cm. Comparing the repeat BH CBCTs on treatment days we calculated: max = 0.44cm; x = 0.16cm; σ = 0.22cm. We also found that for 95% of our BH cases, the absolute variation in tumor position within the same imaging day was within 5mm of the range at the time of simulation and treatment. We found that 75% of the BH cases had less residual tumor motion on treatment days than at simulation. Conclusion: This suggests that a GTV contour based upon the residual tumor motion in multiple BH datasets plus 2 mm margin should be sufficient to cover the full range of residual tumor motion on treatment days.

progression was 12.5 months (range, 2.1-41.9 months), and the median time from this local failure to salvage SBRT was 1.2 months (range, 0.425.6 months). At the time of salvage (2 SBRT course), 41% (24/58) were treated following surgery (post-operative SBRT), 5% (3/58) had high grade epidural disease, 78% (45/58) had paraspinal tumor extension, and 57% (33/58) had a baseline vertebral compression fracture (VCF). Specific to salvage SBRT, the median total dose/fx was 30 Gy/4 fx (range, 20-35 Gy/2-5 fx). The median follow-up following salvage SBRT was 6.2 months (range 0.2-39.1 months). The median OS following salvage SBRT was 10.0 months (range, 0.9-39.1 months). Thirteen of 40 (33%) patients were alive at the time of analysis and the median follow-up for these patients was 7.1 months. Local control was achieved in 78% (45/58) of spinal segments at last follow-up, and the median time to local failure was 3.0 months (range, 2.7-16.7 months). Patterns of failure indicated that the majority (11/13, 85%) had a component of epidural disease progression, and 46% (6/13) had a component of paraspinal tumor progression. No radiation-induced VCF or myelopathy were observed. Conclusions: Salvage SBRT is feasible and preliminary data support efficacy for SBRT failures. The most common treatment regimen was 30 Gy in 4 fractions. No serious adverse events were observed but long-term follow-up is required before definitive conclusions can be drawn. Author Disclosure: I. Thibault: None. M. Campbell: None. C. Tseng: None. A. Al-Omair: None. F. Lochray: None. D. Letourneau: None. E. Yu: None. Y.K. Lee: None. M.G. Fehlings: None. A. Sahgal: None.

Purpose: IMPT plan design is highly dependent on planner’s experiences. VMAT plan design is relatively mature and can even be automated. The quality of IMPT plan designed by in-experienced planner could be inferior to that of VMAT plan designed by experienced planner or automatic planning software. Here we introduce a method for designing IMPT plan based on VMAT plan to ensure the IMPT plan be superior to IMRT/VMAT plan for majority clinical scenario. Methods: To design a new IMPT plan, a VMAT plan is first generated either by experienced planner or by in-house developed automatic planning system. An in-house developed tool is used to generate the dose volume constrains for the IMPT plan as plan template to Eclipse TPS. The beam angles for IMPT plan are selected based on the preferred angles in the VMAT plan. IMPT plan is designed by importing the plan objectives generated from VMAT plan. Majority thoracic IMPT plans are designed using this plan approach in our center. In this work, a thoracic IMPT plan under RTOG 1308 protocol is selected to demonstrate the effectiveness and efficiency of this approach. The dosimetric indices of IMPT are compared with VMAT plan. Results: The PTV D95, lung V20, MLD, mean heart dose, esophagus D1, cord D1 are 70Gy, 31%, 17.8Gy, 25.5Gy, 73Gy, 45Gy for IMPT plan and 65.3Gy, 34%, 21.6Gy, 35Gy, 74Gy, 48Gy for VMAT plan. For majority cases, the high dose region of the normal tissue which is in proximity of PTV is comparable between IMPT and VMAT plan. The low dose region of the IMPT plan is significantly better than VMAT plan. Conclusion: Using the knowledge gained in VMAT plan design can help efficiently and effectively design high quality IMPT plan. The quality of IMPT plan can be controlled to ensure the superiority of IMPT plan compared to VMAT/IMRT plan.

Purpose: To assess the feasibility of treating lung SBRT patients with the ipsilateral arm adducted beside the body instead of elevated above the head. Methods: Patients receiving lung SBRT at our institution are typically treated with both arms raised above their head. However, several patients had difficulty maintaining their arms in an elevated position. In this study, lung SBRT patients who underwent PET-CT imaging with an adducted ipsilateral arm were selected to investigate the dosimetric effects of this treatment setup. PET-CT datasets were fused with treatment planning CT images to simulate the adducted arm position. One VMAT treatment plan was created per patient using the Pinnacle treatment planning system. Plans were optimized to achieve minimal dose to the ipsilateral arm while keeping the target coverage and critical structure doses within clinical limits. The target dose coverage, conformity index (CI) for the target, and DVHs of critical structures for the adducted arm plan were calculated. These parameters were compared with the clinical plan and reported along with the mean and maximum doses of the ipsilateral arm. Results: The target coverage, CI and DVHs for the adducted arm plans of two patients (one with peripheral lesion and one with central lesion) were comparable with the clinical plans. Dose constraints for the chest wall limited further reduction of ipsilateral arm doses for the peripheral lesion plan. The mean ipsilateral arm doses for the central and peripheral lesions were 0.33 Gy and 2.4 Gy, respectively. The maximum ipsilateral arm doses for the central and peripheral lesions were 1.0 Gy and 6.2 Gy, respectively. Conclusion: The results suggested patients with central lung SBRT tumors were more suitable for treatment with the adducted arm position. More patients with various lung tumor locations will be studied to find optimal tumor locations for treatment with this arm position.

Two factors, is classification and its immunogenetics, may have contributed to an incomplete understanding of the pathogenic mechanism in the disease group commonly termed 'cicatricial pemphigoid'. We have previously demonstrated that pure ocular cicatricial pemphigoid (OCP) is a unique clinical and immunopathological entity. In an effort to better define the immunogenetic characteristics for patients with pure OCP, we performed HLA typing for the class II MHC gene HLA-DQB1*0301 allele, by amplifying genomic DNA extracted from patients with polymerase chain reaction, followed by hybridization with a sequence-specific oligonucleotide probe on dot-blotted and Southern-blotted amplified DNA samples. Ninety percent (9/10) of patients with pure OCP had the DQB1*0301 allele, in contrast to 52% (17/33) of normal individuals who had the DQB1*0301 allele. The high frequency of the HLA-DQB1*0301 allele in patients with pure OCP may point to a distinct immunogenetic pattern and possibly a distinct pathomechanism for the disease.

Purpose: We report a hybrid scattering and scanning beam delivery approach, termed as (HimpsPT), which demonstrated that majority IMPT delivery can be potentially replaced with hybrid IMPT and PSPT delivery with similar or better plan quality. Methods: Three representative clinical cases, including head and neck (HN), skull base chordoma (CNS) and lung cancer, treated in MDACC Proton Therapy Center with IMPT were retrospectively redesigned using HimpsPT. The PSPT plans are designed with the same prescriptions as those of IMPT plans. The whole treatment can be delivered by either alternating or sequential PSPT and IMPT delivery. The dosimetric data and dose distributions of HimpsPT plans are compared with those of IMPT plans. We also performed a worst-case robust analysis for all plans. Results: The target coverages for all cases are comparable. For the HN case, the mean dose of esophagus larynx, left parotid and right submandibular, oral cavity V20, the max dose of cord is 18.0, 36.1, 23.6, 47.2, 0.1, 31.7 Gy in HimpsPT plan, and 25.5, 33.8, 24.9, 49.1, 0.2, 33.8 Gy in IMPT plan. For the lung case, the lung V5, V20, V30, mean lung dose, heart V40, esophagus V70, cord maximum dose are 50.5%, 37.0%, 31.7%, 21.3 Gy, 7.2%, 4.9%, 35.5 Gy in HimpsPT plan, and 55.4%, 36.7%, 30.1%, 21.3 Gy, 7.7%, 8.4%, 36.8Gy in IMPT plans. For the CNS case, brainstem maximum dose is 50.5 Gy in HimpsPT plan and 55.4 Gy in IMPT plan due to sharp penumbra offered by the aperture of the PSPT plan in HimpsPT technique. Conclusion: For majority disease sites, the dosimetric advantage of IMPT technique can be achieved by the hybrid PSPT and IMPT technique, which enables the centers equipped with both scattering and scanning beam facilities to treat more patients which can be benefited by the scanning beam.