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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.

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

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.

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.

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.

Patients with colorectal cancer (CRC) report debilitating fatigue that is caused by both disease and chemotherapy. An inflammatory mechanism for fatigue and affective symptoms has been proposed in cancer patients. This prospective study investigated tryptophan and tyrosine metabolism and symptom severity in 33 CRC patients undergoing oxaliplatin-based chemotherapy. During the 12-week study, patients rated symptom severity weekly using the M.D. Anderson Symptom Inventory (MDASI). Serum samples were collected before and after 3 and 6 chemotherapy cycles. Fatigue was the most severe patient-reported symptom before and during chemotherapy. Non-parametric generalized regression models were used to assess correlations between symptom severity and markers of guanosine triphosphate cyclohydrolase 1 (GTP-CH1) and indoleamine-2,3-dioxygenase (IDO) activity. At week 12, the kynurenine/tryptophan ratio was significantly associated with fatigue and sadness (both p

Purpose: To explore advantages and uncertainties of IMPT for accelerated partial breast irradiation (APBI), and compare the dosimetry with passive scatteringprotons (PSPB) and clinic photon 3D radiotherapy (3DCRT). Method and Materials: Two theoretical proton IMPT plans, i.e. one with two tangential fields (OPPOSED_PAIR) and one with a tangential field and an en face field (ORTHOGONAL_PAIR), were created for 11 patients and compared with PSPB and 3DCRT. The impact of range and patient setup uncertainties and scanned spots mismatching between fields for IMPT plans was evaluated. Results: Compared with 3DCRT, IMPT plans with both beam configurations significantly reduced the dose to lungs, normal breast tissues,heart and breast skin and have significantly better dose coverage for target volume using ORTHOGONAL_PAIR and comparable coverage using OPPOSED_PAIR. Compare with PSPB, IMPT with both beam configurations was significantly better for V90 and V75 of breast skin, and V90 and V75 of ipsilateral normal breast, and comparable for V50 and V30 of breast skin, V100 of ipsilateral normal breast, V5Gy and mean dose of ipsilateral lung, maximum dose of heart and contralateral breast, and mean dose of contralateral lung. IMPT using ORTHOGONAL_PAIR was comparable for V10 of breast skin, V50 and V20 of ipsilateral normal breast, and V10Gy and V20Gy of ipsilateral lung, but significantly worse using OPPOSED_PAIR. For IMPT, CTV coverage of 95% prescription dose was over 90% considering range and patients setup uncertainties, but could drop to 80% with scanned spots mismatching between two beams in worst scenario. The en face beam has significantly more dose fluctuation in chestwall region than tangential beam. Conclusion: IMPT plans showed potential for normal tissuedose reduction and target coverage improvement compared with PSPB and 3DCRT. It is robust considering range and patient setup uncertainties, but vulnerable to the scanned spots mismatching among different beams.

9094 Background: Oxaliplatin-based chemotherapy (FOLFOX or FOLFIRI), a standard first-line chemotherapy for patients with colorectal cancer (CRC), is not only associated with dose-limiting toxicity...

e19627 Background: Patients with multiple myeloma (MM) undergoing induction therapy experience both disease- and therapy-related symptoms. This study selectively focused on the trajectory of pain, ...

5523 Background: Previously we reported that 1/3 of patients had moderate to severe (MS) levels of fatigue 2 months after completing radiation therapy (RT) or chemoradiation (CRT) for head and neck cancer (HNC) as measured by the M. D. Anderson Symptom Inventory – Head and Neck Module (MDASI-HN). However, the rate and severity of patient-reported fatigue beyond this and particularly in long term survivors has not been established. We collected long term patient-reported fatigue using the Brief Fatigue Inventory (BFI), a validated fatigue assessment tool. Methods: Patients treated with RT or CRT for HNC, with no evidence of disease at last follow up were eligible for this cross sectional study using the BFI. Patient, tumor and treatment characteristics were collected. Moderate to severe (MS) responses were defined as patient ratings of 5 or greater on a 0-10 scale. We report the prevalence and pattern of fatigue using descriptive statistics. Chi-square test was used to determine differences by treatment gr...

5539 Background: Long-term patient reported symptom burden data is lacking and required for the adequate support of OPCa survivors. The long-term impact of IMRT has not been evaluated. Methods: A cross sectional study of 122 OPCa patients in remission treated at a single institution since 2000 was performed using the M. D. Anderson Symptom Inventory-Head/Neck (MDASI-HN). The relationship between treatment group and symptom burden was evaluated using chi-square or Fisher exact tests. Results: 122 patients were included. 90% were men. Patients with T1-2 and T3-4 tumors, and N0-2a and N2b+ numbered 85 and 37, and 41 and 81 respectively. All had RT with 93 and 29 having IMRT and 3DRT respectively. For chemotherapy, 49 had none, 34 induction alone, 39 concurrent alone, and 10 both. The follow up exceeds 5 years for 75%, and the median is 5.8 years. The top 7 frequent symptoms with moderate to severe levels are listed for all patients, 3DRT and IMRT technique with the p-value for the difference between techniqu...

143 Background: Presurgical ADT does not improve long-term outcomes in patients (pts) with high-risk localized PCa. Since the VEGF and PDGF signaling pathways have been implicated in PCa progression, and ADT results in endothelial cell apoptosis in the prostate by a VEGF-mediated mechanism, we hypothesized that combined treatment with sunitinib malate (SU), an oral inhibitor of the tyrosine kinases of VEGFR and PDGFR, might improve the efficacy of ADT in this pt population. Methods: Pts with no radiological evidence of metastases and either PCa ≥ clinical (c)T3 disease or Gleason grade 8-10 or serum prostate-specific antigen (PSA) ≥ 20 ng/mL or cT2b-c and Gleason 7 and PSA ≥10 ng/mL (AJCC, 1992), received i.m. leuprolide and oral SU for three 30-day cycles followed by surgery. SU was administered continuously at 37.5 mg daily (25 mg daily in the initial 6 pts). The primary endpoint of this phase II trial was rate of pathologic complete response (pCR). Secondary endpoints included safety and time to progression (TTP). Unresectable pelvic nodal disease, confirmed post-operative PSA ≥ 0.2 ng/mL, or administration of post-operative radiation or ADT, defined treatment failure. Results: Forty-four pts completed accrual, with a median age of 58 years (range 47-72); 34 Caucasian, 5 African-American, 4 Hispanic, and 1 Indian. High-risk criteria included cT3 (24/44), Gleason 8-10 (30/44), PSA ≥ 20 ng/mL (16/44). Two men were ineligible/declined therapy and one postponed surgery. No grade 4 toxicities or related discontinuations were observed. Thirty-five pts completed 3 months on 37.5 mg daily SU plus ADT and surgery with no unexpected complications. Of these, 2 pts experienced a pCR. Twenty (57%) pts have failed treatment or died, with a median TTP 27 months (95% CI: 12 – not estimable). The median follow-up of the remaining event-free pts is 35 months (range 23-41). Conclusions: The 3-months preoperative combination of SU and ADT is safe and well tolerated in pts with high-risk primary PCa. We observed 2 complete remissions in 35 patients. Ongoing characterization of molecular changes in the epithelial and stromal compartments will help understand the mechanisms of SU activity in PCa. [Table: see text]

208 Background: The identification of PC patients at high risk for cachexia may allow for early intervention to prevent this outcome. Symptoms such as pain, nausea, and anorexia might predict weight loss. Likewise, inflammatory cytokines are also associated with cachexia. We evaluated the ability of each to predict weight loss in patients beginning treatment for PC. Methods: We evaluated 44 newly diagnosed advanced or metastatic PC patients for baseline symptomatology via the M. D. Anderson Symptom Inventory (MDASI). This survey assesses symptom severity, such as nausea, vomiting, fatigue, pain, diarrhea, and constipation, on a 1-10 scale. Baseline serum levels of IL-1a, IL-1b, IGF-1, CXCL-12, CXCL-16, CRP, IL-6, IL-8, VEGF, CEA, and CA 19-9 were assessed. Logistic regression analysis was performed to determine the odds ratio (OR) and confidence interval (CI) for the association of different parameters with 10% weight loss at 60 days from treatment initiation. Student t-test was used to compare the mean values across different strata. Results: A weight loss of >10% was observed in 15 patients (34%). Only the use of mild (but not strong) opioids was associated with weight loss; estimated OR = 6.2 (C.I. 1.2-31.9, p=.03). No association was observed for the MDASI parameters. Baseline levels of cytokines were available for 23 patients. We observed significant differences in the mean values of CXCL-16 (p=.05) and IL-6 (p=.045) in patients with weight loss as compared to those without weight loss. Moreover, serum level of erythropoietin may be negatively associated with weight loss (p=0.06). Conclusions: Alterations in serum cytokine levels may correlate more strongly with cachexia than clinical symptoms and underscore the importance of cytokine analysis in identifying PC patients at high risk for cachexia. [Table: see text]

551 Background: Neuropathy attributed to oxaliplatin-based chemotherapy is a dose limiting factor in the administration of chemotherapy. With premising clinical outomes, bevacizumab (BV) has been added with colorectal cancer (CRC) patients in first line and second- line therapy. Although toxicity been well documented, there is no evidence of the impact of adding BV to oxaliplatin-based chemotherapy on patient's neuropathy development during therapy. Methods: The study enrolled 66 colorectal cancer patients naïve to oxaliplatin or to any microtubule stabilizing agents scheduled for oxaliplatin-based chemotherapy, 29 (44%) of whom also received BV. From first therapy cycle start date, patients rated symptoms weekly during chemotherapy via the M. D. Anderson Symptom Inventory (MDASI), and continued symptom assessment every two weeks for up to 48 weeks. Longitudinal symptom responses were analyzed by mixed-effect modeling which controlled for age, sex, staging, prior diabetes, and total cycles of chemotherapy received. All cases completed at least 2 cycles chemotherapy. Results: A third of the sample was female; 24% were older than 65 years; 59% with stage IV disease. The five most severe symptoms were numbness, fatigue, sleep disturbance, drowsiness, and distress on MDASI symptom items. The severity of patient-reported numbness/tingling, rated on MDASI, increased overtime in following 48 weeks after started therapy (p < 0.0001). Oxaliplatin-based therapy plus BV, compared to no BV in the regimen, resulted a significant lower severity on numbness/tingling during the study period (estimate = -1.1325, p = 0.0005). Older patients reported more numbness/tingling. In contrast, pain severity remained low during the initial cycles of therapy, but significantly increased over time during therapy. Therapy with or without BV did not produce differences in pain development. Conclusions: This prospective study suggests that adding BV to standard oxaliplitin-based therapy for CRC was associated with significantly reduced numbness/tingling development. This observation needs to be confirmed in larger studies. The mechanism(s) by which neuropathy could be attenuated by BV are unknown. No significant financial relationships to disclose.

Purpose: The adaptive radiotherapy involves replanning process based on daily computed tomography(CT), which is impractical with the manual recontouring and trial‐and‐error replanning process. An automated adaptive planning(AAP) method, i.e. automated contouring and automated plan optimization without any manual intervention, was proposed and validated for IMRT and SmartArc planning to account for inter‐fractional changes in prostate cancer.Method and Materials: 9 CT datasets (simulation CT and 8 daily CTs) of a prostate cancer patient with large daily anatomical changes were selected. In the AAP method, contours on each daily CT were automatically generated by mapping the contours from simulation CT using Demons Image Registration. An in‐house developed automated planning method was used to generate the initial, the replanned IMRT and SmartArc plans. The final treatment plan evaluation was based on physician‐drawn contours on simulation CT and each daily CT. The cumulative dose‐volume‐histograms(DVHs) of the target and the normal tissues were acquired by averaging the DVHs based on the physician‐drawn contours of each daily CT and compared to those of the initial plans recalculated just by shifting the isocenter. Results: After adaption using AAP, the percentage volume covered by prescription dose for prostate and SV reached 98.8% and 96.7% for IMRT, and 97.2% and 95.5% for SmartArc, which was an absolute increase of respectively 10.8% and 15.3% for IMRT, and 5.4% and 10.9% for SmartArc plan compared to shifting‐iso method. The V70 and mean dose for rectum were 10.7% and 40.5Gy for IMRT, and 10.3% and 33.3Gy for SmartArc, an absolute reduction of 10.3% and 8.5Gy for IMRT, and 10.8% and 6.8Gy for SmartArc, compared to shifting‐iso method. Conclusion: The AAP method, which is fully automated, is practically effective for on‐line compensation of the target dose deficit and critical organ overdose caused by inter‐fractional anatomical change for prostate cancer.

3585 Background: Paresthetic neurotoxicity attributed to oxaliplatin-based chemotherapy is a treatment limiting factor in the administration of chemotherapy. The term neuropathy is often associated with pain, but many distressing components of neuropathy may emerge at different timing of therapy, and measurable by patient reported outcomes. Longitudinal studies could establish the development pattern of neuropathy-related symptoms during chemotherapy trajectories. Methods: Patients undergoing oxaliplatin-based chemotherapy (FOLFOX) for colorectal cancer (n = 59) rated symptoms weekly during chemotherapy via the M. D. Anderson Symptom Inventory (MDASI). Symptom responses were analyzed by mixed-effect modeling controlled for age, sex, diabetics, and cancer staging. Results: A third of the sample was female; 17% were older than 65 years. Controlling for covariance, the severity of patient-reported numbness/tingling increased steadily each week in following 12 weeks after started therapy (p < 0.001). The numb...

9003 Background: Patients undergoing chemotherapy for late-stage non-small cell lung cancer (NSCLC) have multiplesymptoms related to disease and therapy. We determined factors associated longitudin...

5600 Background: Previous studies have shown that patient-reported outcomes with QOL instruments are predictive of survival. We investigate the relationship between HNC patient-reported symptoms and survival in addition to clinician ratings of ECOG performance status (PS). Methods: 129 patients with HNC participated in the study. Patients completed the M. D. Anderson Symptom Inventory - Head and Neck module (MDASI-HN) prior to radiotherapy or chemoradiotherapy. Cluster analysis was used to identify those who were symptomatic due to their disease prior to treatment. Cox regression was used to examine differences in survival between symptom burden groups with PS as covariate. Logistic regression was used to determine the relationship of overall survival status with symptom burden and performance status. Results: 46% (60/129) of HNC patients were identified to have symptoms prior to therapy. The top symptoms at presentation were fatigue, emotional distress, pain, disturbed sleep, drowsiness and sadness. Unde...

5573 Background: Radiation therapy (RT) for HNC causes significant toxicity. Most patients do not return for medical follow up for about 6 weeks after completing RT. There is no symptom data reported about this interval, and most patients do not receive ongoing symptom assessment or intervention. We performed a longitudinal study including this interval using the M.D. Anderson Symptom Inventory - Head and Neck module (MDASI-HN). Methods: 161 HNC patients participated. Patients completed the MDASI-HN using paper and pencil before RT/chemo-RT and weekly during the 6-7 weeks of treatment, and for another 8 weeks using an interactive voice response (IVR) system. We report the prevalence of symptom burden over time using descriptive statistics. Results: Fewer than 10% HNC patients had moderate or severe (M/S) symptoms before treatment. Symptom burden peaks for most patients by the end of treatment, but some patients reach their M/S symptom peak after treatment. For the selected potentially serious symptoms for...

Purpose: 4D CT is increasingly used to define the ITV, the envelope of the CTV as it moves during breathing, and PTV (ITV + set up margin). IMRT plans are designed to provide uniform dose to the PTV. We propose a planning method to design true 4D IMRT plans in which the PTVs of the individual phases of the 4D CT as well as the conventional PTV may receive non‐uniform doses, but the cumulative doses to the PTVs of individual phases, computed using deformable image registration (DIR), are uniform. Methods: The non‐uniform dose prescription for conventional PTV was obtained by solving linear equations by requiring motion‐convolved 4D dose to be uniform to the PTV for the end exhale phase (PTV50%) and by constraining maximum inhomogeneity to be 30%. A plug‐in code to Pinnacle was developed to perform the IMRT optimization based on this non‐uniform PTV dose prescription. The 4D dose was obtained by summing the mapped doses from individual phases of the 4D CT using DIR. This 4D dose distribution was compared with that of the ITV method. The robustness of 4D plans over the course of radiotherapy was evaluated by computing the sum of the 4D dose distributions for each weekly CT mapped to the planning 4D CT using DIR. Results: The 4D dose distribution provided additional lung sparing by 5% for V5, V10, V20 and V30 compared to the use of the ITV method. The dose volume histograms of PTV50%, CTV, lung, spinal cord, and heart for the cumulative dose over the course of IMRT were similar to those for 4D dose at the time of original planning. Conclusion: The proposed 4D planning method may increase lung sparing compared to the ITV method used commonly in the clinics and is robust against inter fractional set‐up and anatomy changes.

Purpose: The purpose of this study was to evaluate the potential of our recently developed automated planning method for automated on‐line re‐planning to account for inter‐fractional changes encountered in prostate IMRT.Method and Materials: Three prostate cancer patients treated in our institution were randomly selected for this study. For each patient, an initial plan was generated on the planning CT using automated optimization algorithm (AOA) without trial and error. Three on‐line image guided strategies were evaluated: 1) the original plan applied to the repeated CT scan using the prostate‐center‐of‐mass alignment; 2) re‐optimized plan using the same objectives as those in the original plan; and 3) automated re‐optimized plan by AOA. Results: On average for 3 plans on 8 repeat CTs, V40, V60, and V70 for the rectum, V60 and V70 for the bladder of strategy 3 were reduced by at least 30.03%, 18.32%, and 12.12%, 6.98% and 5.43%, respectively, compared to those of strategies 1 and 2 for patient 1, by 22.23%, 14.89%, and 10.08%, 5.15% and 3.89%, respectively, for patient 2, and by 14.81%, 9.21%, and 6.90%, 4.56% and 3.77%, respectively, for patient 3. Strategy 3 also reduced the doses to the normal tissues (body excluding rectum, bladder and PTV) than strategy 1 and 2. CTV coverage for patient 2 in strategy 1 was compromised, but adequate for all other strategies for all three patients. Conclusion: Fully automated, without trial and error IMRT re‐planning is an effective approach for on‐line compensation of the target dose deficit and critical organ overdose caused by inter‐fractional anatomical change for CT‐guided adaptive IMRT for prostate cancer.