Search

PurposeIn our experience treating locally advanced pancreatic cancer (PC) with magnetic resonance-guided radiation therapy (MRgRT), the true-fast imaging with steady-state free precession (TRUFI) sequences used to generate real-time 2D MRI (2D cine) impart differing intensities for relevant structures when compared to the pre-treatment high resolution 3D MRI (3D MRI). Since these variations can confound target tracking selection, we propose that an understanding of the differing contrast profiles could improve selection of tracking structures.Methods and MaterialsWe retrospectively reviewed both 2D cine and 3D MRI images for 20 patients with PC treated with MRgRT. At simulation, an appropriate tracking target was identified and contoured on a single 3mm sagittal slice of the 3D MRI. This sagittal slice was directly compared to the co-registered 7mm 2D cine to identify structures with notable discrepancies in signal intensity. The 3D MRI was then explored in additional planes to confirm structure identities. For quantitative verification of the clinically observed differences, the pixel intensity distributions of 2D cine and 3D MRI DICOM image datasets were statistically compared.ResultsIn all patients reviewed, arteries (aorta, celiac, SMA, HA) appeared mildly hyperintense on both scans. However, veins (PV, SMV) appeared hyperintense on 2D cine but isointense on 3D MRI. Biliary structures appeared mildly hyperintense on 2D cine but starkly hyperintense on 3D MRI. The pixel intensity distributions extracted from 2D cine and 3D MRI images were confirmed to differ significantly (two sample Kolmogorov-Smirnov test; test statistic =0.40; p ConclusionsThere are significant variations in image intensity between the immediate pre-treatment 2D cine when compared to the initial planning 3D MRI. Understanding variations of image intensity between the different MRI sequences used in MRgRT is valuable to radiation oncologists and may lead to improved target tracking and optimized treatment delivery.

A, Immunoblots of control RPE1 cells and cells depleted for Chk2 using Chk2 siRNA stained using anti-Chk2 antibody and anti-actin antibody as a loading control. B, Chromosome mis-segregation in control RPE1 cells and cells depleted for Chk2 using Chk2 siRNA in the presence or absence of Doxorubicin. Bars represent mean, n = 150 cells, 3 experiments, **, p

IR does not significantly perturb the spindle assembly checkpoint (SAC). A, Experimental schema of assessing the SAC after IR. Noc, Nocodazole. Bar graph depicting mitotic indices as a function of IR dose of Nocodazole-arrested cells 1 hour after irradiation; ns, p>0.2, χ2-test, n=187-523 cells. B, Experimental schema of assessing the SAC after Doxorubicin exposure. Noc, Nocodazole; Doxo, Doxorubicin. Graph depicting the number of mitotic cells after mitotic shakeoff in the absence of nocodazole (control), or in the presence of nocodazole only (Noc), or Nocodazole after a 1-hour exposure to Doxorubicin (Noc + Doxo).

IR does not significantly affect sister chromatid cohesion. A, Experimental schema of assessing sister chromatid cohesion after IR exposure. Noc, Nocodazole. Bar graphs show percentage of mitotic spreads containing chromosomes with intact sister-chromatid cohesion or uncohesed chromosomes as a function of IR dose. n>300 mitotic spreads, p>0.14, χ2-test for all cell lines B, Experimental schema of assessing sister chromatid cohesion after Doxorubicin exposure. Noc, Nocodazole; Doxo, Doxorubicin. Graphs depicting the percentage of mitotic spreads with intact sister chromatid cohesion over time. n>300 spreads, 3 experiments. C, Examples of mitotic spreads from control (left) and irradiated (middle) cells and spreads containing uncohesed chromosomes (right). Scale bar, 25-μm.

Control and irradiated (12 Gy) RPE1 cells stained for Aurora-B (A), p-Hec1 (C), p-Histone H3 (E), and p-Cenp-A (G) in green, and DNA (blue). Centromeres (in red) were stained using anti-centromere antibody (CREST). Insets in A show centromere and Aurora B staining at higher magnifications. Relative fluorescence intensity of p-Hec1 (B), p-Histone H3 (D), and p-Cenp-A (F) compared to centromere staining. Bars represent mean {plus minus} SD, n = 10 cells, >300 kinetochores.

Supplementary Figure Legends from DNA-Damage Response during Mitosis Induces Whole-Chromosome Missegregation

IR does not dramatically alter spindle geometry of irradiated mitotic cells. Examples of monopolar (A) and multipolar (B) Spindles of U251 cells stained for kinetochores (green), DNA (blue), and microtubules (red). Scale bar, 5-μm. Graphs represent the percentage of monopolar (A) and multipolar (B) spindles as a function of IR dose. Circles represent mean {plus minus} s.e.m, n = 150 cells, 3 experiments.

A, Example of an anaphase spindle with lagging chromosomes and the number of lagging chromosomes per anaphase spindle as a function of IR dose. B, Example of a multipolar anaphase spindle and the percentage of anaphase spindles with acentric chromatin as a function of IR dose. C, Example of an anaphase spindle with acentric chromatin fragments and the number of multipolar mitoses as a function of IR dose. Circles represent mean {plus minus} s.e.m, n = 150 cells, 3 experiments. Representative mitotic spindles are stained for Hec1 to denote kinetochores (green), DNA (blue), and microtubules (red). Scale bar 5-μm.

IMPORTANCE: Novel toxicity metrics that account for all AE grades and frequency of events within a grade may enhance toxicity reporting in clinical trials. OBJECTIVES: To evaluate the feasibility of using the Toxicity Index (TI) methodology in two prospective anal cancer trials, and to evaluate whether more conformal radiation (using IMRT) results in improved toxicity as measured by the TI. DESIGN: Ancillary analysis of two prospective trials SETTING: Data from 2 NRG multicenter trials PARTICIPANTS: Patients with stage II-III anal cancer treated with definitive 5-FU/MMC and concurrent IMRT as part of the NRG/RTOG 0529 trial (12/2006–3/2008) or nonconformal RT enrolled on NRG/RTOG 9811 (10/1998–6/2005). EXPOSURES: All patients received chemoradiation with 5-FU/Mitomycin using IMRT or nonconformal RT. MAIN OUTCOMES AND MEASURES: The TI for all adverse events and for combined Gastrointestinal (GI)/Genitourinary (GU)/Hematologic (Heme)/Dermatologic (Derm) events in patients treated with nonconformal RT on the 5-FU/MMC arm of NRG/RTOG 9811 were compared to patients treated with IMRT on NRG/RTOG 0529. Multi-variable probabilistic models controlling for demographic predictors of TI were evaluated. RESULTS: Fifty one patients were treated with IMRT on NRG/RTOG 0529 and 324 on the standard 5-FU/MMC arm of NRG/RTOG 9811. Patients treated on NRG/RTOG 0529 had lower median TI compared to patients treated with nonconformal RT on NRG/RTOG 9811 for combined GI/GU/Heme/Derm events [3.935 vs 3.996, P=0.014]. Median TI in patients requiring a treatment break was higher than those patients not requiring a break [4.00 vs 3.937, P

Purpose The value of Cherenkov imaging as an on-patient, real-time, treatment delivery verification system was examined in a 64-patient cohort during routine radiation treatments in a single-center study. Methods and Materials Cherenkov cameras were mounted in treatment rooms and used to image patients during their standard radiation therapy regimen for various sites, predominantly for whole breast and total skin electron therapy. For most patients, multiple fractions were imaged, with some involving bolus or scintillators on the skin. Measures of repeatability were calculated with a mean distance to conformity (MDC) for breast irradiation images. Results In breast treatments, Cherenkov images identified fractions when treatment delivery resulted in dose on the contralateral breast, the arm, or the chin and found nonideal bolus positioning. In sarcoma treatments, safe positioning of the contralateral leg was monitored. For all 199 imaged breast treatment fields, the interfraction MDC was within 7 mm compared with the first day of treatment (with only 7.5% of treatments exceeding 3 mm), and all but 1 fell within 7 mm relative to the treatment plan. The value of imaging dose through clear bolus or quantifying surface dose with scintillator dots was examined. Cherenkov imaging also was able to assess field match lines in cerebral-spinal and breast irradiation with nodes. Treatment imaging of other anatomic sites confirmed the value of surface dose imaging more broadly. Conclusions Daily radiation therapy can be imaged routinely via Cherenkov emissions. Both the real-time images and the posttreatment, cumulative images provide surrogate maps of surface dose delivery that can be used for incident discovery and/or continuous improvement in many delivery techniques. In this initial 64-patient cohort, we discovered 6 minor incidents using Cherenkov imaging; these otherwise would have gone undetected. In addition, imaging provides automated, quantitative metrics useful for determining the quality of radiation therapy delivery.

We developed a deep learning (DL) model for fast deformable image registration using 2-dimensional sagittal cine magnetic resonance imaging (MRI) acquired during radiation therapy and evaluated its potential for real-time target tracking compared with conventional image registration methods.Our DL model uses a pair of cine MRI images as input and provides a motion vector field (MVF) as output. The MVF is then applied to align the input images. A retrospective study was conducted to train and evaluate our model using cine MRI data from patients undergoing treatment for abdominal and thoracic tumors. For each treatment fraction, MR-linear accelerator delivery log files, tracking videos, and cine image files were analyzed. Individual MRI frames were temporally sampled to construct a large set of image registration pairs used to evaluate multiple methods. The DL model was optimized using 5-fold cross validation, and model outputs (transformed images and MVFs) using test set images were saved for comparison with 3 conventional registration methods (affine, b-spline, and demons). Evaluation metrics were 3-fold: (1) registration error, (2) MVF stability (both spatial and temporal), and (3) average computation time.We analyzed21 hours of cine MRI (629,000 frames) acquired during 86 treatment fractions from 21 patients. In a test set of 10,320 image registration pairs, DL registration outperformed conventional methods in both registration error (affine, b-spline, demons, DL; root mean square error: 0.067, 0.040, 0.036, 0.032; paired t test demons vs DL: t[20] = 4.2, P.001) and computation time per frame (51, 1150, 4583, 8 ms). Among deformable methods, spatial stability of resulting MVFs was comparable; however, the DL model had significantly improved temporal consistency.DL-based image registration can leverage large-scale MR cine data sets to outperform conventional registration methods and is a promising solution for real-time deformable motion estimation in radiation therapy.

718 Background: Acute grade 3+ toxicity was rare in the multi-institutional phase 2 stereotactic MR-guided on-table adaptive radiation therapy (SMART) trial (NCT03621644) for locally advanced and borderline resectable pancreatic cancer (LAPC/BRPC). Surgery may be considered after ablative SMART although the feasibility and safety of this is not well understood. Postoperative outcomes of the subset of patients in the SMART trial are examined here. Methods: Trial eligibility included BRPC or LAPC without metastases after a minimum of 3 months of induction chemotherapy. All patients received SMART prescribed to 50 Gy in 5 fractions using an integrated 0.35T MR-radiation therapy device equipped with cutting edge soft tissue tracking, automatic beam gating, and on-table adaptive replanning. Surgery was permitted after SMART, often after multi-disciplinary review. Perioperative details and postoperative outcomes, including morbidity, mortality, and overall survival (OS), were analyzed. Results: 136 patients across 13 sites were enrolled between 2019-2022. 44 patients (32.4%) had surgery after SMART (33 BRPC, 11 LAPC). Surgical procedures included pancreaticoduodenectomy (81.8%), distal pancreatectomy with splenectomy (9.1%), total pancreatectomy (6.8%), and distal pancreatectomy with celiac axis resection (2.3%). 52.3% required vascular resection/reconstruction, a majority of which were venous resections (65.2%), with a smaller proportion needing both venous/arterial (21.7%), or arterial (13%). Surgery was performed after a mean 51.4 ± 52.8 days from SMART. Postoperative hospitalization was 10.5 ± 8.9 days. Nine patients (20.5%) had Clavien-Dindo complications of grade III or higher; 3 deaths resulted from post-pancreatectomy hemorrhage in patients who had portal vein resection. One-year OS in patients who had surgery versus no surgery after SMART was 66% vs. 43%, respectively. Conclusions: These are the first prospectively evaluated surgical outcomes after 5-fraction ablative SMART for BRPC/LAPC. The rate of surgery for BRPC compares favorably to radiated patients on the Alliance A021501 trial. Despite the use of ablative radiation dose and frequent need for vascular resection, the incidence of serious surgical complications was similar to what is reported after non-ablative radiation therapy. However, several deaths occurred after surgery and we therefore we urge caution when considering surgery after ablative radiation therapy. Further analysis of other variables such as the time between SMART and surgery, approaches to vascular resections, and discrete events such as delayed gastric emptying, operative duration, and post-operative pancreatic fistula are needed to better understand the surgical morbidity seen in these patients. Clinical trial information: NCT03621644 .

Pathologic complete response (pCR) to neoadjuvant chemoradiation for locally advanced esophageal adenocarcinoma (EAC) confers significantly improved survival. The ability to infer pCR may spare esophagectomy in some patients. Currently, there are no validated biomarkers of pCR. This study sought to evaluate whether a distinct signature of DNA copy number alterations (CNA) can be predictive of pCR in EAC. Pretreatment biopsies from 38 patients with locally advanced EAC (19 with pCR and 19 with pathologic partial/poor response) were assessed for CNA using OncoScan assay. A novel technique was employed where within every cytogenetic band, the quantity of bases gained by each sample was computed as the sum of gained genomic segment lengths weighted by the surplus copy number of each segment. A threefold cross-validation was used to assess association with pCR or pathologic partial/poor response. Forty patients with locally advanced EAC from The Cancer Genome Atlas (TCGA) constituted an independent validation cohort. Gains in the chromosomal loci 14q11 and 17p11 were preferentially associated with pCR. Average area under the receiver operating characteristic curve (AUC) for predicting pCR was 0.80 among the threefold cross-validation test sets. Using 0.3 megabases as the cutoff that optimizes trade-off between sensitivity (63%) and specificity (89%) in the discovery cohort, similar prediction performance for clinical and radiographic response was demonstrated in the validation cohort from TCGA (sensitivity 61%, specificity 82%). Copy number gains in the 14q11 and 17p11 loci may be useful for prediction of pCR, and, potentially, personalization of esophagectomy in EAC.

Purpose: Bendamustine and rituximab (BR) has been established as a superior frontline therapy over R-CHOP in the treatment of follicular lymphoma (FL). Yttrium-90 Ibritumomab tiuxetan (90YIT) is an effective consolidation strategy after chemotherapy induction. This prospective, single-arm, multicenter, phase II trial evaluated the response rate, progression-free survival (PFS), and tolerability of BR followed by consolidation with 90YIT in patients with untreated FL. Patients and Methods: The study included grade 1 to 3a FL patients aged ≥18 years, chemotherapy-naïve, and requiring treatment for stage II–IV disease. Study treatment included an initial rituximab treatment, followed by four cycles of BR. Patients were eligible for consolidation with 90YIT, 6 to 12 weeks after BR, if they obtained at least a partial response after induction had adequate count recovery and bone marrow infiltration < 25%. Results: Thirty-nine patients were treated. Eighty-two percent had an intermediate or high-risk Follicular Lymphoma International Prognostic Index score, and 6 of 39 (15%) were grade 3a. The response rate was 94.8%, and the complete response(CR)/CR unconfirmed (CRu) rate was 77% in the intention-to-treat analysis. The conversion rate from PR to CR/Cru after 90YIT was 81%. After median follow-up of 45 months, the PFS was 0.71 (95% confidence interval, 0.57–0.89). Conclusions: This report demonstrates that four cycles of BR followed by consolidation with 90YIT achieve high response rates that are durable. In addition, consolidation with 90YIT results in a high conversion rate of PR to CR/CRu. A short course of BR followed by 90YIT is a safe and effective regimen for frontline treatment of FL.

During a first-in-humans clinical trial investigating electron paramagnetic resonance tumor oximetry, a patient injected with the particulate oxygen sensor Printex ink was found to have unexpected fluorodeoxyglucose (FDG) uptake in a dermal nodule via positron emission tomography (PET). This nodule co-localized with the Printex ink injection; biopsy of the area, due to concern for malignancy, revealed findings consistent with ink and an associated inflammatory reaction. Investigations were subsequently performed to assess the impact of oxygen sensors on FDG-PET/CT imaging. A retrospective analysis of three clinical tumor oximetry trials involving two oxygen sensors (charcoal particulates and LiNc-BuO microcrystals) in 22 patients was performed to evaluate FDG imaging characteristics. The impact of clinically used oxygen sensors (carbon black, charcoal particulates, LiNc-BuO microcrystals) on FDG-PET/CT imaging after implantation in rat muscle (n = 12) was investigated. The retrospective review revealed no other patients with FDG avidity associated with particulate sensors. The preclinical investigation found no injected oxygen sensor whose mean standard uptake values differed significantly from sham injections. The risk of a false-positive FDG-PET/CT scan due to oxygen sensors appears low. However, in the right clinical context the potential exists that an associated inflammatory reaction may confound interpretation.

Purpose The American College of Radiology (ACR), American Brachytherapy Society (ABS), American College of Nuclear Medicine (ACNM), American Society for Radiation Oncology (ASTRO), Society of Interventional Radiology (SIR), and Society of Nuclear Medicine and Molecular Imaging (SNMMI) have jointly developed a practice parameter on selective internal radiation therapy (SIRT) or radioembolization for treatment of liver malignancies. Radioembolization is the embolization of the hepatic arterial supply of hepatic primary tumors or metastases with a microsphere yttrium-90 brachytherapy device. Materials and Methods The ACR -ABS -ACNM -ASTRO -SIR -SNMMI practice parameter for SIRT or radioembolization for treatment of liver malignancies was revised in accordance with the process described on the ACR website ( https://www.acr.org/ClinicalResources/Practice-Parameters-and-Technical-Standards ) by the Committee on Practice Parameters—Interventional and Cardiovascular Radiology of the ACR Commission on Interventional and Cardiovascular, Committee on Practice Parameters and Technical Standards—Nuclear Medicine and Molecular Imaging of the ACR Commission on Nuclear Medicine and Molecular Imaging and the Committee on Practice Parameters—Radiation Oncology of the ACR Commission on Radiation Oncology in collaboration with ABS, ACNM, ASTRO, SIR, and SNMMI. Results This practice parameter is developed to serve as a tool in the appropriate application of radioembolization in the care of patients with conditions where indicated. It addresses clinical implementation of radioembolization including personnel qualifications, quality assurance standards, indications, and suggested documentation. Conclusions This practice parameter is a tool to guide clinical use of radioembolization. It focuses on the best practices and principles to consider when using radioemboliozation effectively. The clinical benefit and medical necessity of the treatment should be tailored to each individual patient.

PURPOSETo provide expert guidance to clinicians and policymakers in resource-constrained settings on the management of patients with late-stage colorectal cancer.METHODSASCO convened a multidisciplinary, multinational Expert Panel that reviewed existing guidelines, conducted a modified ADAPTE process, and used a formal consensus process with additional experts for two rounds of formal ratings.RESULTSExisting sets of guidelines from four guideline developers were identified and reviewed; adapted recommendations from five guidelines form the evidence base and provided evidence to inform the formal consensus process, which resulted in agreement of ≥ 75% on all recommendations.RECOMMENDATIONSCommon elements of symptom management include addressing clinically acute situations. Diagnosis should involve the primary tumor and, in some cases, endoscopy, and staging should involve digital rectal exam and/or imaging, depending on resources available. Most patients receive treatment with chemotherapy, where chemotherapy is available. If, after a period of chemotherapy, patients become candidates for surgical resection with curative intent of both primary tumor and liver or lung metastatic lesions on the basis of evaluation in multidisciplinary tumor boards, the guidelines recommend patients undergo surgery in centers of expertise if possible. On-treatment surveillance includes a combination of taking medical history, performing physical examinations, blood work, and imaging; specifics, including frequency, depend on resource-based setting. Additional information is available at www.asco.org/resource-stratified-guidelines .

541 Background: MR-guided stereotactic body radiation therapy (MR-SBRT) is a novel method of treating mobile tumors with soft-tissue gating and on-table adaptive planning. In our experience using the ViewRay MRIdian system (VR) for treating locally advanced pancreatic cancer (PA) with MR-SBRT, the true-fast imaging with steady-state free precession (TRUFI) sequences on the VR impart differing intensities for relevant structures seen on the pre-treatment high resolution 3D MRI (3D MRI) versus the real-time 2D cine MRI (2D cine) used for target tracking. Since these variations can confound target tracking selection, we propose that an understanding of the differing contrast profiles could improve selection of tracking structures and optimize treatment delivery. Methods: We retrospectively reviewed both 3D MRI and 2D cine images for patients (pts) with PA (n =20) treated on the VR. At simulation, an appropriate tracking target was identified and contoured on a single 3mm sagittal slice of the 3D MRI. This sagittal slice was directly compared to the registered 7mm 2D cine to identify structures with notable discrepancies in signal intensity. The 3D MRI was then explored in additional planes to confirm structure identities. For quantitative verification of the clinically observed differences, the pixel intensity distributions of 3D MRI and 2D cine DICOM image datasets were statistically compared. Results: In all pts reviewed, arteries (aorta, celiac, SMA) appeared with similar contrast profiles on both images. However, veins (portal vein, SMV) appeared hypointense on 3D MRI but hyperintense on 2D cine. Biliary structures appeared hyperintense on 3D MRI but only mildly hyperintense on 2D cine. The pixel intensity distributions extracted from 3D MRI and 2D cine images were confirmed to differ significantly (two sample Kolmogorov-Smirnov test; test statistic =0.40; p < 0.001). Conclusions: There are significant variations in image intensity between the initial treatment planning 3D MRI and the immediate pre-treatment 2D cine obtained with the VR. Understanding these discrepancies can guide radiation oncologists in choosing optimal tracking targets. Future work will focus on identifying the particular causes and frequencies of target tracking failures and exploring alternative tracking algorithms using artificial intelligence which could ultimately allow for VMAT on the ViewRay system.

Purpose/Objective(s) Magnetic resonance imaging-guided radiation therapy (MRgRT) utilization is rapidly expanding worldwide, driven by advanced capabilities including continuous intrafraction visualization, automatic triggered beam delivery, and on-table adaptive replanning. Our objective was to describe patterns of 0.35T-MRgRT utilization in the United States (US) among early adopters of this novel technology. Materials/Methods Anonymized administrative data from all US 0.35T-MRgRT treatment systems were extracted for patients completing treatment from 2014-2020. Detailed treatment information was available for all 0.35T-MR Linac system and some cobalt system patients. Most cobalt patients were included in total only. Results 17 systems at 16 centers treated 5,733 patients, delivering 40,171 fractions (fractions unavailable for 1,225 cobalt patients), of which 6,244 (15.5%) were adapted. Thirteen centers (81.3%) had treated for > = 1 year, of which 9 treated > 100 patients/year and 6 treated > 150 patients/year. Ultra-hypofractionation (1-5 fractions) was delivered for 72.9% of all patients. The proportion of fractions adapted in patients receiving ultra-hypofractionation was 28.6%, with an average of 3.2 adapted fractions per course. The most commonly treated tumor types were pancreas (20.7%), liver (16.5%), prostate (12.5%), breast (11.5%), and lung (9.4%), respectively, with significantly increased number of fractions delivered from 2018-2020 compared to 2014-2017 for each (pancreas: 5,161 vs. 1,155; liver: 3,597 vs. 921; prostate: 5,795 vs. 1,398; breast: 2,221 vs. 1,876; lung: 2,589 vs. 660). The compound annual growth rate (CAGR) in the number of patients was 59.5%, growing from 111 in 2014 to 1,830 in 2020. Ultra-hypofractionation increased from 31.8% of all treated MR-Linac patients in 2014 to 87.0% in 2020 (n = 1,576/1,811). The proportion of adapted fractions in all patients and ultra-hypofractionation patients increased from 0% in the first two years to 24.3% (n = 3,071/12,639) and 33.8% (n = 2,677/7,911) respectively, by the end of 2020. No patient had adaptive treatment in 2014 although adaptive replanning steadily increased over time. For example, in 2020 vs. 2018 the proportion of adaptive fractions was highest for pancreas (60.6% vs. 50.8%), liver (17.8% vs. 9.9%), and lung (17.8% vs. 1.8%) cancers. Conclusion This is the first comprehensive study reporting patterns of utilization among early adopters of a 0.35T-MRgRT system in the US. Intrafraction MR guidance, advanced motion management, and increasing adoption of adaptive RT has accelerated a transition to ultra-hypofractionation regimens. MRgRT has been predominantly used to treat abdominal and pelvic tumors, and increasingly with adaptive replanning, which is a radical departure from legacy radiotherapy practices.

The optimal type of stent for the palliation of malignant biliary obstruction in patients with pancreatic adenocarcinoma undergoing neoadjuvant chemoradiotherapy with curative intent is unknown. We performed a prospective trial comparing 3 types of biliary stents-fully covered self-expandable metal (fcSEMS), uncovered self-expandable metal (uSEMS), and plastic-to determine which best optimized cost-effectiveness and important clinical outcomes.In this prospective randomized trial, consecutive patients with malignant biliary obstruction from newly diagnosed pancreatic adenocarcinoma who were to start neoadjuvant chemoradiotherapy were randomized to receive fcSEMSs, uSEMSs, or plastic stents during the index ERCP. The primary outcomes were time to stent occlusion, attempted surgical resection, or death after the initiation of neoadjuvant therapy, and the secondary outcomes were total patient costs associated with the stent, including the index ERCP cost, downstream hospitalization cost due to stent occlusion, and the cost associated with procedural adverse event.Fifty-four patients were randomized and reached the primary end point: 16 in the fcSEMS group, 17 in the uSEMS group, and 21 in the plastic stent group. No baseline demographic or tumor characteristic differences were noted among the groups. The fcSEMSs had a longer time to stent occlusion compared with uSEMSs and plastic stents (220 vs 74 and 76 days, P .01), although the groups had equivalent rates of stent occlusion, attempted surgical resection, and death. Although SEMS placement cost more during the index ERCP (uSEMS = $24,874 and fcSEMS = $22,729 vs plastic = $18,701; P .01), they resulted in higher procedural AE costs per patient (uSEMS = $5522 and fcSEMS = $12,701 vs plastic = $0; P .01). Conversely, plastic stents resulted in an $11,458 hospitalization cost per patient due to stent occlusion compared with $2301 for uSEMSs and $0 for fcSEMSs (P .01).In a prospective trial comparing fcSEMSs, uSEMSs, and plastic stents for malignant biliary obstruction in patients undergoing neoadjuvant therapy with curative intent for pancreatic adenocarcinoma, no stent type was superior in optimizing cost-effectiveness, although fcSEMSs resulted in fewer days of neoadjuvant treatment delay and a longer time to stent occlusion. (Clincial trial registration number: NCT01038713.).

This practice parameter is intended to guide appropriately trained and licensed physicians performing therapy with unsealed radiopharmaceutical sources. Such therapy requires close cooperation and communication between the physicians who are responsible for the clinical management of the patient and those who administer radiopharmaceutical therapy and manage the attendant side effects. Adherence to this practice parameter should help to maximize the efficacious use of these procedures, maintain safe conditions, and ensure compliance with applicable regulations. The goal of therapy with unsealed radiopharmaceutical sources is to provide either cure or effective palliation of disease while minimizing untoward side effects and complications.

Many cancers display both structural (s-CIN) and numerical (w-CIN) chromosomal instabilities. Defective chromosome segregation during mitosis has been shown to cause DNA damage that induces structural rearrangements of chromosomes (s-CIN). In contrast, whether DNA damage can disrupt mitotic processes to generate whole chromosomal instability (w-CIN) is unknown. Here, we show that activation of the DNA-damage response (DDR) during mitosis selectively stabilizes kinetochore–microtubule (k-MT) attachments to chromosomes through Aurora-A and PLK1 kinases, thereby increasing the frequency of lagging chromosomes during anaphase. Inhibition of DDR proteins, ATM or CHK2, abolishes the effect of DNA damage on k-MTs and chromosome segregation, whereas activation of the DDR in the absence of DNA damage is sufficient to induce chromosome segregation errors. Finally, inhibiting the DDR during mitosis in cancer cells with persistent DNA damage suppresses inherent chromosome segregation defects. Thus, the DDR during mitosis inappropriately stabilizes k-MTs, creating a link between s-CIN and w-CIN. Significance: The genome-protective role of the DDR depends on its ability to delay cell division until damaged DNA can be fully repaired. Here, we show that when DNA damage is induced during mitosis, the DDR unexpectedly induces errors in the segregation of entire chromosomes, thus linking structural and numerical chromosomal instabilities. Cancer Discov; 4(11); 1281–9. ©2014 AACR. See related commentary by Jelluma and Kops, p. 1256 This article is highlighted in the In This Issue feature, p. 1243

BACKGROUND: Persistent chromosome segregation errors represent a conspicuous feature of human neoplasms. It is widely accepted that this chromosomal instability is associated with poor prognosis; however, its effect on therapeutic response is a matter of conjecture. METHODS: Here, the role of chromosome segregation errors in the response of patients with rectal adenocarcinoma to chemoradiation therapy (CRT) was examined. Pretreatment samples from 62 patients were surveyed for evidence of chromosome mis-segregation and mis-segregation frequency was correlated to the pathological response to CRT as determined by the tumor regression grade after surgical resection of irradiated tumors. RESULTS: Surprisingly, it was found that errors in chromosome segregation predicted enhanced pathological response of rectal adenocarcinoma to CRT (odds ratio, 3.9; P 5.02). Furthermore, tumor response inversely correlated with the frequency of cells that exhibited segregation errors during anaphase (correlation coefficient, 0.94; P

Electron paramagnetic resonance (EPR) spectroscopy has been well established as a viable technique for measurement of free radicals and oxygen in biological systems, from in vitro cellular systems to in vivo small animal models of disease. However, the use of EPR in human subjects in the clinical setting, although attractive for a variety of important applications such as oxygen measurement, is challenged with several factors including the need for instrumentation customized for human subjects, probe, and regulatory constraints. This article describes the rationale and development of the first clinical EPR systems for two important clinical applications, namely, measurement of tissue oxygen (oximetry) and radiation dose (dosimetry) in humans. The clinical spectrometers operate at 1.2 GHz frequency and use surface-loop resonators capable of providing topical measurements up to 1 cm depth in tissues. Tissue pO2 measurements can be carried out noninvasively and repeatedly after placement of an oxygen-sensitive paramagnetic material (currently India ink) at the site of interest. Our EPR dosimetry system is capable of measuring radiation-induced free radicals in the tooth of irradiated human subjects to determine the exposure dose. These developments offer potential opportunities for clinical dosimetry and oximetry, which include guiding therapy for individual patients with tumors or vascular disease by monitoring of tissue oxygenation. Further work is in progress to translate this unique technology to routine clinical practice.

Background: Standard of care for locally advanced (stage II-III) esophageal adenocarcinoma is neoadjuvant chemoradiation followed by esophagectomy. Pathologic complete response (pCR) to neoadjuvant therapy occurs in 25-30% of patients. Three-year overall and progression-free survival of patients with pCR are nearly double those of incomplete responders (86% and 80% versus 48% and 39%, respectively). Therefore accurate prediction of pCR prior to esophagectomy can potentially spare patients the intraoperative risks and postoperative changes in quality of life associated with surgery. However, no well-established biomarkers of pCR currently exist. Methods: Paired pre-treatment biopsies and post-chemoradiation resections from patients with stage II-III esophageal adenocarcinoma between 2003 and 2017 were retrieved at a single institution. pCR was defined as absence of cancer cells in the treated specimen, while pathologic poor response (pPR) was defined as greater than 10% of tumor cells remaining in the specimen. In total, 27 pCR and 25 pPR resections were identified along with 20 and 12 of their corresponding DNA samples from pre-treatment biopsies that passed quality control on the OncoScan platform to call copy number alteration events. Within every cytogenetic band in the human genome, the quantity of bases gained by each sample was computed as the sum of gained genomic segment lengths weighted by the surplus copy number of each segment. These cytogenetic band gains were compared between pCR and pPR samples. An independent validation dataset of 47 patients with stage II-III esophageal adenocarcinoma was obtained from The Cancer Genome Atlas (TCGA). Results: In 3-fold cross-validation, genomic gains in chromosome 14q11 and chromosome 19p13 displayed the most significant difference between pCR and pPR samples in all 3 training sets. Across the test sets, average AUC for correctly predicting pCR/pPR status was 0.829. Selecting 1.1 megabases as the cutoff that optimizes tradeoff between sensitivity and specificity in the discovery dataset also stratified survival in TCGA. Among TCGA patients, those possessing genomic gains in chr14q11 and chr19p13 that exceed 1.1 megabases had superior 5-year overall survival (44% versus 0%, HR = 0.324, P = 0.0249) with median survival of 46 months versus 20 months. Conclusion: Genomic gains in 14q11 and 19p13 may be a valuable biomarker for inference of pCR/pPR among patients with esophageal adenocarcinoma. To our knowledge, it is the first such biomarker with demonstrated utility in an independent set of patients. Further prospective validation is warranted. Citation Format: David C. Qian, Joel A. Lefferts, Bassem I. Zaki, Pavlo Mishyn, Elizabeth B. Brickley, Yue Xue, Mikhail Lisovsky. Prediction of pathologic complete response to neoadjuvant therapy for esophageal adenocarcinoma using copy number alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1657.

With possibilities for radiation terrorism and intensified concerns about nuclear accidents since the recent Fukushima Daiichi event, the potential exposure of large numbers of individuals to radiation that could lead to acute clinical effects has become a major concern. For the medical community to cope with such an event and avoid overwhelming the medical care system, it is essential to identify not only individuals who have received clinically significant exposures and need medical intervention but also those who do not need treatment. The ability of electron paramagnetic resonance to measure radiation-induced paramagnetic species, which persist in certain tissues (e.g., teeth, fingernails, toenails, bone, and hair), has led to this technique becoming a prominent method for screening significantly exposed individuals. Although the technical requirements needed to develop this method for effective application in a radiation event are daunting, remarkable progress has been made. In collaboration with General Electric and through funding committed by the Biomedical Advanced Research and Development Authority, electron paramagnetic resonance tooth dosimetry of the upper incisors is being developed to become a Food and Drug Administration-approved and manufacturable device designed to carry out triage for a threshold dose of 2 Gy. Significant progress has also been made in the development of electron paramagnetic resonance nail dosimetry based on measurements of nails in situ under point-of-care conditions, and in the near future this may become a second field-ready technique. Based on recent progress in measurements of nail clippings, it is anticipated that this technique may be implementable at remotely located laboratories to provide additional information when the measurements of dose on-site need to be supplemented. The authors conclude that electron paramagnetic resonance dosimetry is likely to be a useful part of triage for a large-scale radiation incident.

Neoadjuvant therapy for pancreatic adenocarcinoma requires referral to multiple specialists before initiating therapy. We evaluated the effect of establishing a multidisciplinary clinic (MDC) for patients with newly diagnosed pancreatic adenocarcinoma on treatment access and time to therapy.Patients with newly diagnosed pancreatic adenocarcinoma diagnosed and treated at our center were included. Two patient groups were defined: preclinic represented those patients diagnosed before 2008 and MDC represented those patients diagnosed since 2009 who were treated in the newly created MDC and were initially candidates for neoadjuvant therapy. The primary outcomes were days from diagnosis to first treatment (initiation of chemotherapy or external beam radiation), days to completion of all required consultations, and number of visits needed before initiation of therapy.Ninety-seven patients were diagnosed and treated at our medical center from 2003 to 2008; 22 were treated in 2009 after the implementation of the MDC. Compared with the preclinic group, patients treated in the MDC had shorter times from biopsy to treatment (7.7 days v 29.5 days, P.001), shorter time to completion of all required pretreatment consultations (7.1 days v 13.9 days, P.001), and fewer visits to complete all consultations (1.1 v 4.3, P.001). Thirty-three percent of patients seen in the MDC enrolled onto clinical research trials.In patients with pancreatic adenocarcinoma undergoing neoadjuvant therapy, the establishment of a multidisciplinary pancreas tumor clinic led to improved patient access to consultations and shorter time to initial treatment.

Intraoperative radiation therapy (RT) may improve outcomes after pancreaticoduodenectomy for periampullary cancer; however, there is a 20% risk of late portomesenteric venous obstruction. This retrospective study evaluated the percutaneous treatment of portomesenteric venous obstruction that occurred a mean of 10 months after pancreaticoduodenectomy and intraoperative RT. Five patients with medically refractory ascites and portomesenteric obstruction on computed tomographic angiography had successful recanalization with elimination of the pressure gradient and no procedural complications. One patient showed no improvement clinically. Recurrent ascites after stent occlusion was successfully treated in two patients. Percutaneous transhepatic recanalization appears to be a safe and effective therapy in this population.

Background It is unknown whether neoadjuvant chemoradiotherapy, compared with adjuvant chemoradiotherapy, decreases the rate of local recurrence after resection of pancreatic adenocarcinoma. Study Design This is a retrospective case review of 102 patients with pancreatic adenocarcinoma who underwent pancreatic resection between 1993 and 2005. Results Of 102 patients with pancreatic adenocarcinoma who underwent surgical resection, 19 (19%) had no additional treatment, 41 (40%) underwent adjuvant chemoradiotherapy, and 42 (41%) were treated preoperatively with neoadjuvant chemoradiotherapy. Patients selected to receive neoadjuvant therapy were more likely to have locally advanced tumors. Based on initial CT scan, the percentage of patients with unresectable or borderline resectable tumors in the neoadjuvant group was 67%, compared with 22% in the adjuvant group. Nevertheless, patients receiving neoadjuvant chemoradiotherapy were less likely to have a local recurrence develop than patients receiving adjuvant chemoradiotherapy (5% versus 34%, p=0.02). For those patients with tumors determined to be resectable on initial CT scan, local recurrences were observed in 31% (10 of 32) of patients in the adjuvant therapy group, compared with only 7% (1 of 14) of the neoadjuvant group. Intraoperative radiation therapy, administered to 51% of patients, was not associated with a lower rate of local recurrence. Conclusions Neoadjuvant chemoradiotherapy is associated with improved local tumor control in patients undergoing resection for pancreatic carcinoma.

Objectives Pancreatic cancer-associated diabetes mellitus (PaCDM) occurs in approximately 50% of patients. In patients with new-onset PaCDM undergoing neoadjuvant chemoradiation therapy before surgical resection, we hypothesized that pancreatic tumor destruction would lead to improvement in fasting glucose levels. Methods A retrospective chart review was performed on patients with newly diagnosed pancreatic adenocarcinoma without a history of DM treated with neoadjuvant therapy at our center. All patients underwent combined modality neoadjuvant chemoradiation therapy, followed by surgical excision of the primary tumor. Results Sixty-nine patients (31 with PaCDM) met inclusion criteria for the study; 18 had Evans grade II tumor kill response, 10 had grade III response, and 3 had grade IV response. In patients with grade IV response, the odds ratio (OR) for achieving a normal preoperative glucose was 5.0 (95% confidence interval [CI], 0.4–63.2), compared with grade III (OR, 0.5; 95% CI, 0.1–3.0) and grade II (OR, 1.1; 95% CI, 0.2–5.2). When adjusted for percent kilogram weight loss and tumor size in a multivariable regression model, the grade IV response became significant to an OR of 6.5 (95% CI, 1.2–77.3). Conclusions In patients with new-onset PaCDM undergoing neoadjuvant chemoradiation therapy, fasting glucose response may mirror the extent of tumor destruction.

BACKGROUND Some epithelial neoplasms of the appendix, including low-grade appendiceal mucinous neoplasm and adenocarcinoma, can result in pseudomyxoma peritonei (PMP). Little is known about the mutational spectra of these tumor types and whether mutations may be of clinical significance with respect to therapeutic selection. In this study, we identified somatic mutations using the Ion Torrent AmpliSeq Cancer Hotspot Panel v2. METHODS Specimens consisted of 3 nonneoplastic retention cysts/mucocele, 15 low-grade mucinous neoplasms (LAMNs), 8 low-grade/well-differentiated mucinous adenocarcinomas with pseudomyxoma peritonei, and 12 adenocarcinomas with/without goblet cell/signet ring cell features. Barcoded libraries were prepared from up to 10 ng of extracted DNA and multiplexed on single 318 chips for sequencing. Data analysis was performed using Golden Helix SVS. Variants that remained after the analysis pipeline were individually interrogated using the Integrative Genomics Viewer. RESULTS A single Janus kinase 3 (JAK3) mutation was detected in the mucocele group. Eight mutations were identified in the V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and GNAS complex locus (GNAS) genes among LAMN samples. Additional gene mutations were identified in the AKT1 (v-akt murine thymoma viral oncogene homolog 1), APC (adenomatous polyposis coli), JAK3, MET (met proto-oncogene), phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA), RB1 (retinoblastoma 1), STK11 (serine/threonine kinase 11), and tumor protein p53 (TP53) genes. Among the PMPs, 6 mutations were detected in the KRAS gene and also in the GNAS, TP53, and RB1 genes. Appendiceal cancers showed mutations in the APC, ATM (ataxia telangiectasia mutated), KRAS, IDH1 [isocitrate dehydrogenase 1 (NADP+)], NRAS [neuroblastoma RAS viral (v-ras) oncogene homolog], PIK3CA, SMAD4 (SMAD family member 4), and TP53 genes. CONCLUSIONS Our results suggest molecular heterogeneity among epithelial tumors of the appendix. Next generation sequencing efforts have identified mutational spectra in several subtypes of these tumors that may suggest a phenotypic heterogeneity showing mutations that are relevant for targeted therapies.

Background: Y90-Ibritumomab tiuxetan (90YIT) is approved for use for follicular lymphoma (FL) patients who have achieved a complete or partial response to frontline chemotherapy; however, its use after bendamustine and rituximab (BR) has not been reported. BR has proven to be a superior frontline therapy over R-CHOP in the treatment of FL and is a widely used initial treatment strategy. This analysis focuses on the long-term outcomes and safety of untreated follicular lymphoma patients treated with a short induction course of BR for 4 cycles followed by consolidation with 90YIT. Methods: Patients greater than 18 years with chemotherapy-naïve FL (grade 1-2 and 3a) requiring treatment were eligible. All patients had Stage II-IV disease and had adequate hematologic, liver, and renal function. Treatment consisted of an initial dose of rituximab 375 mg/m2. One week later, bendamustine 90 mg/m2 was administered on days 1 and 2, and rituximab 375 mg/m2 was given on day 1. BR was given for 4 cycles every 28 days. Patients were restaged 4-6 weeks after the last dose of BR. Patients were eligible for consolidation with 90YIT if they obtained at least a partial response after induction, had a platelet count greater than 100,000/mm3, a granulocyte count greater than 1,500/mm3, and bone marrow infiltration less than 25%. 90YIT was given 6-12 weeks after completion of the last cycle of BR. The primary endpoint is complete and unconfirmed complete response (CR/CRu) rate after sequential therapy with BR followed by 90YIT. Secondary endpoints are overall response rate after 4 cycles of BR, conversion rate from partial response (PR) after BR to CR/CRu after 90YIT, progression-free survival, and safety. The 1999 NHL Working Group Criteria was used to assess response. Results: From October 2010 to May 2014, forty-four patients were enrolled in this study (NCT01234766). 39 patients initiated treatment, and 5 were screen failures. Median age was 57 years [range 31-75]. The study enrolled FLIPI low (18%), intermediate (44%), and high (38%) risk patients; 33 of 39 (85%) were Grade 1-2 and 6 (15%) were Grade 3a. Twenty-two of 39 patients achieved CR/CRu (56%) and 16 of 39 patients had a PR (41%) for an overall response rate (ORR) of 97%. One patient had stable disease (SD). Four patients were not randomized to receive 90YIT: one in CR and one in PR were unable to receive 90YIT due to thrombocytopenia, one only achieved SD after BR, and one declined treatment. Thirty of 35 evaluable patients were in CR/CRu (86%), 4 remained in PR (11%) after 90YIT and one progressed during 90YIT, for an ORR of 97%. The number of patients in PR after BR who reached CR/CRu immediately after 90YIT were 10 of 16 (63%). Three (19%) additional patients converted to CR/CRu during follow-up, the latest occurring 16 months after 90YIT. After a median follow up of 30 months, 25 patients (71%) remain in CR/CRu, 10 patients (29%) have progressed/relapsed with a 24-month PFS of 80% (95% CI 63-90) [Figure]. The median PFS was not reached. Grade 3-4 hematologic toxicities during the 90YIT period included: neutropenia (34%), leukopenia (37%), thrombocytopenia (40%), lymphopenia (15%), and anemia (6%). There were no incidences of febrile neutropenia. One patient developed JC Virus/Progressive Multifocal Leukoencephalopathy, 13 months after receiving the last dose of rituximab and 90YIT on study. One patient developed chronic myeloid leukemia 11 months after, one patient developed acute myeloid leukemia 15 months after, and one patient developed uterine cancer 52 months after all study treatment. One patient died to progression of the lymphoma, 35 months after treatment. There have been no reported cases of myelodysplasia. Conclusions: In this 2.5 year report of patients that received BR followed by 90YIT, the CR/CRu rate of patients completing all study therapy is 71% and the 24-month PFS is 80%. There is a high rate of conversion in partial responders to CR/CRu (81%), some occurring more than one year after treatment with 90YIT. The durable PFS is comparable to what is reported in the FIT trial (Morschhauser et al. JCO 2013) and the phase II Spanish intergroup study (Canales et al. ASH 2013). BR followed by 90YIT is a well-tolerated regimen for follicular lymphoma with high response rates that is a safe and highly effective as first-line therapy. Long-term safety reflects the natural history of patients with indolent lymphomas. Figure Figure. Disclosures Lansigan: Pharmacyclics: Consultancy; Teva: Research Funding; Celgene: Consultancy; Spectrum: Consultancy, Research Funding.

Persistent chromosome segregation errors represent a conspicuous feature of human neoplasms. It is widely accepted that this chromosomal instability is associated with poor prognosis; however, its effect on therapeutic response is a matter of conjecture.Here, the role of chromosome segregation errors in the response of patients with rectal adenocarcinoma to chemoradiation therapy (CRT) was examined. Pretreatment samples from 62 patients were surveyed for evidence of chromosome mis-segregation and mis-segregation frequency was correlated to the pathological response to CRT as determined by the tumor regression grade after surgical resection of irradiated tumors.Surprisingly, it was found that errors in chromosome segregation predicted enhanced pathological response of rectal adenocarcinoma to CRT (odds ratio, 3.9; P = .02). Furthermore, tumor response inversely correlated with the frequency of cells that exhibited segregation errors during anaphase (correlation coefficient, 0.94; P.05). Strikingly, elevated chromosome mis-segregation combined with decreased levels of the DNA damage repair protein Mre11 portended a markedly enhanced response (odds ratio, 54.0; P = .008).The results of the current study demonstrate that chromosomal instability is a favorable predictor of response to CRT in patients with locally invasive rectal adenocarcinoma. Therefore, the authors propose that downstream structural damage to chromosomes resulting from segregation errors potentiates the effect of DNA-damaging therapies and synergizes with deficiencies in the DNA repair machinery. This work identifies a novel mechanistic marker that foretells treatment response to CRT and suggests that concomitant targeting of whole-chromosome segregation and DNA repair may constitute an effective therapeutic strategy.

e14514 Background: This dose escalation study was performed to determine the recommended phase II dose of capecitabine to be delivered concurrently with thoracic radiation therapy and weekly docetaxel in patients with locally advanced esophageal carcinoma. Methods: Patients with operable stage II or III esophageal carcinoma were staged by endoscopic ultrasonography and CT. Two cycles of docetaxel (80 mg/m2) and carboplatin (target AUC of 6) were delivered over 6 weeks, followed by concurrent weekly docetaxel (15 mg/m2), thoracic radiotherapy (50.4 Gy in 28 fractions), and increasing doses of capecitabine (500-3500 mg) given prior to each fraction of radiotherapy. After re-staging, responding patients continued to esophagectomy. Results: Forty-four patients were enrolled and 40 were evaluable for the dose-ranging component of chemoradiotherapy. The median age was 63 (range 47-87), 32 patients (80%) were male, and 36 (90%) had adenocarcinoma while 4 (10%) had squamous cell carcinoma. EUS stages at enrollment were T3N1 (29), T3N0 (4), T2N1 (6), and T4N0 (1). The maximum tolerated dose of capecitabine was 3500 mg. Common non-hematologic grade 3 or 4 toxicities were dysphagia (n=6, 15%) and nausea/vomiting (n=3, 8%). Common grade 3 or 4 hematologic toxicities were ANC and WBC abnormalities (n=10, 25% and n=9, 23% respectively). Overall, 58% of patients had no stage 3 or 4 toxicity. Thirty-six patients had surgery; 83% had R0 (curative) resection and 14% had complete pathological response (pCR). With a median follow-up time of 18.9 months, the median overall survival was 23.5 months, with 34% and 27% alive at three and five years, respectively. The three- and five-year relapse-free survival was 37%. In patients who had pCR or microscopically residual disease, 5-year survival was 74% (n=8). Conclusions: The recommended phase II dose of capecitabine is 3500 mg when given concurrently with 50.4 Gy in 28 fractions of thoracic radiotherapy with weekly docetaxel. This trimodality therapy for locally advanced esophageal carcinoma was well-tolerated and remarkably active. This regimen holds promise for treatment of esophageal carcinoma and warrants further investigation.

Background Neoadjuvant therapy has been investigated for localized and locally advanced pancreatic ductal adenocarcinoma (PDAC) but no standard of care exists. Combination cetuximab/gemcitabine/radiotherapy demonstrates encouraging preclinical activity in PDAC. We investigated cetuximab with twice-weekly gemcitabine and intensity-modulated radiotherapy (IMRT) as neoadjuvant therapy in patients with localized or locally advanced PDAC. Experimental design Treatment consisted of cetuximab load at 400 mg/m2 followed by cetuximab 250 mg/m2 weekly and gemcitabine 50 mg/m2 twice-weekly given concurrently with IMRT to 54 Gy. Following therapy, patients were considered for resection. Results Thirty-seven patients were enrolled with 33 assessable for response. Ten patients (30%) manifested partial response and 20 (61%) manifested stable disease by RECIST. Twenty-five patients (76%) underwent resection, including 18/23 previously borderline and 3/6 previously unresectable tumors. Twenty-three (92%) of these had negative surgical margins. Pathology revealed that 24% of resected tumors had grade III/IV tumor kill, including two pathological complete responses (8%). Median survival was 24.3 months in resected patients. Outcome did not vary by epidermal growth factor receptor status. Conclusions Neoadjuvant therapy with cetuximab/gemcitabine/IMRT is tolerable and active in PDAC. Margin-negative resection rates are high and some locally advanced tumors can be downstaged to allow for complete resection with encouraging survival. Pathological complete responses can occur. This combination warrants further investigation.

The ability to estimate individual exposures to radiation following a large attack or incident has been identified as a necessity for rational and effective emergency medical response. In vivo electron paramagnetic resonance (EPR) spectroscopy of tooth enamel has been developed to meet this need.A novel transportable EPR spectrometer, developed to facilitate tooth dosimetry in an emergency response setting, was used to measure upper incisors in a model system, in unirradiated subjects, and in patients who had received total body doses of 2 Gy.A linear dose response was observed in the model system. A statistically significant increase in the intensity of the radiation-induced EPR signal was observed in irradiated versus unirradiated subjects, with an estimated standard error of dose prediction of 0.9 ± 0.3 Gy.These results demonstrate the current ability of in vivo EPR tooth dosimetry to distinguish between subjects who have not been irradiated and those who have received exposures that place them at risk for acute radiation syndrome. Procedural and technical developments to further increase the precision of dose estimation and ensure reliable operation in the emergency setting are underway. With these developments EPR tooth dosimetry is likely to be a valuable resource for triage following potential radiation exposure of a large population.

Electron paramagnetic resonance (EPR) oximetry can be used to provide direct absolute measurements of pO(2) in living tissue using India ink as an O(2) reporter. In vivo measurements are made using low frequency (1.2 GHz) EPR spectroscopy and surface loop resonators, which enable measurements to be made at superficial sites through a non-invasive (after placing the ink in the tissues) and repeatable measurement procedure. Ongoing EPR oximetry studies in human subjects include measurement of subcutaneous pO(2) in the feet of healthy volunteers to develop procedures that could be used in the treatment of peripheral vascular disease and oximetry in tumors during courses of radiation and chemotherapy, to follow pO(2) so oxygen-dependent therapies can be optimized. In each case, we aim to provide quantitative measurements of tissue pO(2) which will aid physicians in the characterization of disease status and the effects of therapeutic measures, so that treatments can be applied with optimal effectiveness by taking into account the oxygen-dependent aspects of the therapy. The overall goal is to enhance clinical outcomes. Oximetry measurements of subcutaneous tissue on dorsal and plantar foot surfaces have been made in 9 volunteers, with measurements ongoing for each and the longest set of measurements carried out successfully over the last 5 years. Tumor oximetry measurements have been performed in tumor tissues of 10 patients during courses of radiation and chemotherapy. Tumor types include melanoma, basal cell, soft tissue sarcoma, and lymphoma, and measurement sites have ranged from the feet to the scalp. These studies demonstrate the feasibility of EPR oximetry in a clinical setting and the potential for more widespread use in the treatment of these and other oxygen-dependent diseases.

Background: Brain metastases from colorectal cancer (CRC) are uncommon. There has been relatively little published on the host and tumor factors that might lead to this clinical scenario. We reviewed all cases of brain metastases from CRC at Dartmouth-Hitchcock Medical Center over a more than 20-year period to establish incidence and to identify patient and cancer characteristics which were associated with their development. Patients and Methods: We present a retrospective review of 39 confirmed cases of brain metastases from CRC diagnosed between 1984 and 2006. Immunohistochemical staining for CXCR4 was performed on all available brain metastasis biopsy specimens. Results: The incidence of brain metastases from CRC was 2.3%. Left-sided primary colon tumors predominated. The majority of patients had pulmonary metastases at the time brain metastases were identified, and those with preexisting pulmonary metastases had progression of that disease. All patients were symptomatic from brain metastases, and the cerebellum was the most common area of brain involvement. Immunohistochemical analysis confirmed strong expression of CXCR4 in all brain metastases sampled. Conclusion: The incidence of brain metastases from CRC is low. Primary tumor in the left colon, long-standing pulmonary metastases, especially those with recent progression, and CXCR4 expression by tumor cells are all associated with increased risk of brain metastases. Increased survival among patients with metastatic CRC will likely result in an increased incidence of brain metastases. Further characterization of the role of tumor and host factors might yield better insight into the development, and potentially the prevention, of this devastating situation.

Background: Y90 Ibritumumab tiuxetan (90YIT) is approved for use for follicular lymphoma (FL) patients (pts) who have achieved a complete or partial response to frontline chemotherapy; however, its use after bendamustine and rituximab (BR) has never been studied. BR has proven to be a superior frontline therapy over R-CHOP in the treatment of FL and is a widely used initial treatment strategy. In this prospective, single-arm, open-label, multicenter phase II trial, we assessed the response rate and safety of a short induction course of BR for 4 cycles followed by consolidation with 90YIT for chemotherapy-naïve pts with FL. Methods: Consenting pts greater than 18 years with chemotherapy naïve FL (grade 1-2 and 3a) requiring treatment were eligible for this study. All pts had Stage II-IV disease and had adequate hematologic, liver, and renal function. Treatment consisted of an initial dose of rituximab 375mg/m2. One week later, bendamustine 90mg/m2 was administered on days 1 and 2, and rituximab 375mg/m2 was given on day 1. BR was given for 4 cycles every 28 days. Pts were restaged 4-6 weeks after the last dose of BR. Pts were considered eligible for consolidation with 90YIT if they obtained at least a partial response after induction, had a platelet count greater than 100,000/mm3, a granulocyte count greater than 1,500/mm3, and bone marrow infiltration less than 25%. 90YIT was give 6-12 weeks after completion of the last cycle of BR. The primary endpoint of this study is complete and unconfirmed complete response (CR/CRu) rate after sequential therapy with BR followed by 90YIT. Secondary endpoints are overall response rate after 4 cycles of BR, conversion rate from partial response (PR) after BR to CR/CRu after 90YIT, progression-free survival, and safety. The 1999 NHL Working Group Criteria was used to assess response. Results: Forty-two pts were enrolled in this study: 38 pts initiated study treatment, and 4 were screen failures. Median age was 58 years [range 31-74]. The study enrolled FLIPI low (18%), intermediate (47%), high (34%) risk pts; 32 of 38 (84%) were Grade 1-2 and 6 (16%) were Grade 3a. Response rates after 4 cycles of BR: Thirty-eight pts have completed 4 cycles of BR and 38 are evaluable for response. Twenty-two of 38 evaluable pts achieved a CR/CRu (58%) and 15 of 38 pts had a PR (39%) for an overall response rate (ORR) of 97%. One pt had stable disease (SD). Response rates after BR followed by 90YIT: Thirty of 38 BR-treated pts have received 90YIT and are evaluable for the primary endpoint of CR/CRu. Of the 38 BR treated pts, two in CR were unable to receive 90YIT due low platelets, one was not eligible to receive 90YIT due to achievement of SD only, one declined treatment, and four are not yet evaluable for response. Twenty-five of 30 evaluable pts are in CR/CRu (83%), 4 remain in PR (13%) after 90YIT and one progressed during 90YIT, for an ORR of 96%. Of the 14 pts who had a PR after BR, 7 (50%) converted to a CR/CRu immediately after 90YIT, with three (21%) additional conversions to CR/CRu in follow-up, the latest occurring 16 months after 90YIT. Grade 3-4 hematologic toxicities during BR included: lymphopenia (36%), neutropenia (8%), thrombocytopenia (3%), leukopenia (3%). Non-hematologic toxicities included grade 2 phlebitis (14%) and grade 3 hyperglycemia (8%), hyponatremia (3%), diarrhea (3%), infusion-related reaction (3%), headache (3%), rectal hemorrhage (3%). Grade 3-4 hematologic toxicities after 90YIT included: neutropenia (33%), leukopenia (36%), thrombocytopenia (36%), lymphopenia (14%), anemia (3%). Non-hematologic toxicities included skin infection (3%). Median neutrophil recovery was 8 weeks [range 8 to 12] and median platelet recovery was 9 weeks [range 5 to 36] after Y90IT. There have been no incidences of neutropenic fever. One pt developed chronic myelogenous leukemia, occurring 11 months after treatment with BR followed by Y90-IT. There have been no cases of myelodysplasia or acute myelogenous leukemia. Conclusions: In this nearly final analysis, the CR/CRu rate of pts completing all study therapy (BR followed by 90YIT) is 83%, the ORR is 96%, and the conversion rate from PR to CR/CRu is 71%. We conclude that sequential treatment with BR followed by Y90IT is highly effective and safe, and should be considered as a frontline treatment option for FL. Disclosures Lansigan: Teva Pharmaceuticals: Research Funding; Spectrum Pharmaceuticals: Research Funding.

Pancreatic cancer remains highly lethal. Previous attempts with neoadjuvant therapy in this disease have been inconclusive, but a potential for benefit exists. We conducted a phase II trial of dose-intense docetaxel and gemcitabine followed by twice-weekly gemcitabine and external beam radiotherapy in patients with pancreatic adenocarcinoma.Patients with stage I to III disease were eligible. Docetaxel 65 mg/m(2) intravenously over 1 hour and gemcitabine 4000 mg/m(2) given intravenously over 30 minutes were given on days 1, 15, and 29. On day 43, radiotherapy was begun at 50.4 Gy with gemcitabine 50 mg/m(2) intravenously over 30 minutes twice weekly for 12 doses. After treatment, patients were considered for resection.Twenty-four assessable patients were recruited onto the trial. All but one patient completed a full 12 weeks of therapy. Grade 3 and 4 hematological and nonhematological toxicities were common but manageable, and neutropenic fever did not occur. No patient had local tumor progression. Twelve patients (50%) responded by Response Evaluation Criteria in Solid Tumors Group (RECIST) criteria, including one radiographic complete response. Seventeen patients underwent resection after therapy. Margin-negative resections were performed in 13 patients, including 9 patients whose disease was borderline or unresectable before treatment. A treatment effect was seen in all resection specimens. There have been no local recurrences of tumor, and several patients remain alive without evidence of disease.Docetaxel/gemcitabine followed by gemcitabine/radiotherapy is active in the treatment of pancreatic adenocarcinoma, with manageable toxicity. Tumor downstaging occurs in some patients to allow complete resection. Further investigation of this regimen is warranted.

Purpose/Objective(s): Tumor Treating Fields (TTFields), currently used as an antimitotic modality, induce forces on polar macromolecules resulting in impaired mitotic spindle function. TTFields are expected to affect negatively charged, small DNA fragments produced by ionizing radiation (IR). Such an effect can result in impaired ligation of DNA strand breaks causing IR sensitization and decreased tumor survival. The objective of the present work is to test TTFields effect on DNA Damage Repair. Materials/Methods: A model describing the effects of TTFields on small DNA fragments was constructed and evaluated by measuring DNA migration in gel electrophoresis during TTFields application. Experimentally, TTFields effects on DNA strand breaks repair alone and in combination with IR were studied in glioma and non-small cell lung cancer (NSCLC) cells using the comet assay, g-H2AX foci formation, and RAD51 foci formation and resolution. Cell survival was measured by MTT and cell count as well as clonogenic survival. Results: Within the framework of the theoretical model, DNA fragments of about 400 bp oscillate over a distance of one base-pair at TTFields frequency of 100 kHz, while larger fragments are not affected. Support for the model was provided by the analysis of fragment mobility in gel electrophoresis. The comet assay demonstrated that TTFields reduce repair of IR-induced DNA damage in glioma cells. Treatment with a combination of IR and TTFields resulted in increased number of g-H2AX and RAD51 foci compared with either treatment alone. Importantly, in both glioma and NSCLC cells combination of IR and TTFields reduced cell viability and clonogenic survival. Conclusions: We show that TTFields influence DNA-break repair capacity of tumor cells likely by influencing DNA fragment positioning and DNA strand break ligation thus sensitizing tumor cells to IR. Author Disclosure: K. Zielinska-Chomej: None. M. Giladi: A. Employee; Novocure. A. Tichon: A. Employee; Novocure. J. Tu: None. R. Schneiderman: A. Employee; Novocure. K. Viktorsson: None. E. Kirson: A. Employee; Novocure. Y. Palti: K. Advisory Board; Novocure. M. Stock; Novocure. R. Lewensohn: None.

e15189 Background: The role of neoadjuvant therapy in pancreatic ductal adenocarcinoma (PDAC) remains unclear, but has demonstrated benefit in many studies. CA 19-9 is a commonly used tumor marker ...

e15262 Background: Patients receiving gemcitabine-based neoadjuvant chemoradiotherapy for non-metastatic pancreatic cancer often have difficulty tolerating full treatment courses. Providers are thu...