Citations

Abstract Background: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of mature T-cell and natural-killer-cell aggressive non-Hodgkin lymphomas associated with poor prognosis with current therapies. Numerous studies have reported poor survival for PTCL patients with a median Overall Survival (OS) shorter than 2 years and 5-year survival rates of <30%. Traditionally, patients with PTCL have been treated with a cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-like first-line chemotherapeutic regimen. Unfortunately, the prognosis remains poor with most patients relapsing within 2 years. Thus, improved front line treatment strategies are needed. Pralatrexate (Folotyn) is a folate analogue metabolic inhibitor that was the first drug approved in the US for the treatment of patients with relapsed or refractory PTCL (R/R PTCL). Approval was based on results from the pivotal Phase 2 PROPEL study (O'Connor et al, JCO, 2011) of pralatrexate in R/R PTCL, in which pralatrexate monotherapy demonstrated a durable clinical benefit (objective response rate of 29%). Pralatrexate is administered intravenously (IV) at a dose of 30 mg/m2 weekly for 6 weeks of a 7-week treatment cycle. Since pralatrexate and each of the components of the CHOP regimen target different aspects of tumor cell growth and proliferation, there is a potential for synergistic anti-tumor effect, and limited additive toxicities. Objectives: The primary endpoint of the study is the determination of the MTD of pralatrexate in combination with CHOP (Fol-CHOP) in previously untreated PTCL patients. Secondary endpoints included safety, tolerability and ORR (complete response [CR] + partial response [PR]) and pharmacokinetics. Methods: In this study, patients with PTCL received CHOP in combination with pralatrexate, repeated every 3-weeks for up to 6 cycles. Part 1 of the study was to determine the Maximum Tolerated Dose (MTD) of the Fol-CHOP combination. Once the MTD was determined, an additional 10 patients were treated in the Expansion Phase (Part 2). The cohort schema followed a traditional "3+3" design. Pralatrexate was to be administered as 10, 15, 20, 25, or 30 mg/m2 IV push over 3 to 5 minutes on Days 1 and 8 of each cycle. The starting cohort was CHOP + 10 mg/m2 of pralatrexate. Patients received prophylaxis with acyclovir and sulfamethoxazole/trimethoprim during the study and primary prophylaxis with growth factor (filgrastim or pegfilgrastim) support. Dose-limiting toxicities (DLT) were considered during the 1st cycle and included: Severe infections, study treatment-related non-hematological toxicity Grade 3-4, platelet count < 25 X 109/L at any time or ANC < 0.5 X 109/L lasting more than 7 days despite G-CSF administration. Results: A total of 12 patients have been enrolled in Part 1 of the study at the time of abstract submission. Nine patients have completed Cycle 1 and no DLT was reported. Among these nine patients, three patients each were treated at CHOP + 10 mg/m2, 15 mg/m2 and 20 mg/m2 of pralatrexate. One patient (11%) treated with CHOP + 10 mg/m2 had one serious adverse event (SAE) of febrile neutropenia that was deemed unrelated to any study drug. Only four Grade 3 AEs (anemia, constipation, mucosal inflammation, and nausea) were reported, in one patient (11%). The enrollment into the study continues. Conclusions: These interim results demonstrate that the combination of pralatrexate with CHOP (Fol-CHOP) is well tolerated, with all components of CHOP as well as pralatrexate being given at close to or at standard doses. The rates of AEs are comparable to those typically reported with CHOP alone. The study is ongoing to confirm the MTD and to assess preliminary efficacy of the Fol-CHOP combination. Updated results will be presented at the meeting. Disclosures Oki: Novartis: Research Funding. Barta:Celgene, Merck, Seattle Genetics: Research Funding; Janssen: Honoraria, Speakers Bureau. Sharma:Spectrum Pharmaceuticals: Employment. Song:Spectrum Pharmaceuticals: Employment. Mourya:Spectrum Pharmaceuticals: Employment.

Abstract MYCN is a major driver for the childhood cancer, neuroblastoma, however, there are no inhibitors of this target. Enhanced MYCN protein stability is a key component of MYCN oncogenesis and is maintained by multiple feedforward expression loops involving MYCN transactivation target genes. Here, we reveal the oncogenic role of a novel MYCN target and binding protein, proliferation-associated 2AG4 (PA2G4). Chromatin immunoprecipitation studies demonstrated that MYCN occupies the PA2G4 gene promoter, stimulating transcription. Direct binding of PA2G4 to MYCN protein blocked proteolysis of MYCN and enhanced colony formation in a MYCN-dependent manner. Using molecular modeling, surface plasmon resonance, and mutagenesis studies, we mapped the MYCN–PA2G4 interaction site to a 14 amino acid MYCN sequence and a surface crevice of PA2G4. Competitive chemical inhibition of the MYCN–PA2G4 protein–protein interface had potent inhibitory effects on neuroblastoma tumorigenesis in vivo. Treated tumors showed reduced levels of both MYCN and PA2G4. Our findings demonstrate a critical role for PA2G4 as a cofactor in MYCN-driven neuroblastoma and highlight competitive inhibition of the PA2G4-MYCN protein binding as a novel therapeutic strategy in the disease. Significance: Competitive chemical inhibition of the PA2G4–MYCN protein interface provides a basis for drug design of small molecules targeting MYC and MYCN-binding partners in malignancies driven by MYC family oncoproteins.

Abstract Assessment of x-ray angiography system performance is typically performed using stationary test objects with simple geometries such as a disk on a uniform background. However, these methods do not represent realistic imaging conditions in interventional cardiology as anatomy and devices are inherently non-stationary due to cardiac motion. In this work, a novel implementation of the channelized Hotelling observer (CHO) was used to assess the influence of motion blur on object detectability. A standard CHO model assumes imaging system stationarity whereby the detectability index of a test object is independent of location. However, real angiography systems are inherently non-stationary. While vendor correction gain factors and offset maps are used to compensate for visual non-uniformities, these corrections do not restore stationarity to the images. Methods to accommodate non-stationarity and allow assessment of the influence of motion blur on test object detectability will be presented. The effect of motion blur was quantified with the relative detectability index ( ), where the for an object when moving with constant linear velocity was compared to a low velocity ‘pseudo-stationary’ condition to account for system non-stationarity. The pseudo-stationary condition was used to isolate the influences of spatial non-stationarity and motion blur. Three different test object shapes (disks, spheres and capsules) with linear velocity in the range 0–30 cm · s −1 were tested. For 1 mm diameter objects and linear velocity 30 cm · s −1 , was degraded by 37%, 33% and 42% for the disk, sphere and capsule respectively, relative to the pseudo-stationary condition. Considering all test objects with diameter greater than 2 mm and linear velocity 30 cm · s −1 , was degraded by less than 10% due to motion. In summary, this work describes a new approach to assess performance of x-ray angiography systems using the CHO model and moving test objects.

Abstract The acquisition of resistance to EGFR tyrosine kinase inhibitors (TKIs) remains a critical problem in lung cancer clinic, but the underlying mechanisms have remained incompletely understood. Although the TKI-induced or -selected genetic changes are known to drive resistance, resistance also occurs in tumor cells without genetic changes through poorly-characterized processes. Here, we show that the extracellular matrix (ECM) from various components of the tumor microenvironment, including neighboring tumor cells and fibroblasts, may be the driver of resistance in the absence of genetic changes. Unlike genetic changes, which may evolve during relatively long time of chronic EGFR TKI treatment to drive resistance, briefly culturing on de-cellularized ECM, or co-culturing with the ECM donor cells, immediately confers resistance to tumor cells that are otherwise sensitive to EGFR TKIs. We show evidence that collagen in the ECM may be its primary constituent driving resistance, at least partly through the collagen receptor Integrin-β1. Intriguingly, such effect of ECM and collagen is dose-dependent and reversible, suggesting a potential clinic-relevant application for targeting this effect. Collectively, our results reveal that the stromal ECM acts as a microenvironmental cue promoting EGFR TKI resistance in lung cancer cells, and targeting collagen and Integrin-β1 may be useful for treating resistance, especially the resistance without clearly-defined genetic changes, for which effective therapeutics are lacking. Citation Format: Ting Zhang, Lixia Guo, Yuanyuan Wang, Tao Ren, Yanan Yang. Stromal extracellular matrix is a microenvironmental cue promoting resistance to EGFR tyrosine kinase inhibitors in lung cancer cells [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 122.

PurposeWhile scatter from the patient is assumed to be the primary source of occupational radiation dose associated with fluoroscopically guided interventional procedures, the potential contribution of scatter from the x‐ray collimator assembly is unknown. The purpose of this work was to survey clinical x‐ray angiography systems to assess the potential contribution of collimator assembly scatter on occupational radiation dose.MethodsExperimental methods were designed to measure the relative contributions of scatter originating from within the collimator assembly of the x‐ray tube to total scatter, which included scatter from a patient‐simulating phantom. Measurements were acquired as a function of lateral distance from the x‐ray beam center using a posterior anterior (PA) projection and at a fixed location for variable right anterior oblique to left anterior oblique projections in the range −90º to 90º. For one system, the collimator assembly was partially disassembled to assess the scatter contribution of individual components. For two systems, 0.5 mm Pb was added to the inner surface of the collimator assembly cover and tested for efficacy to block collimator assembly scatter.ResultsConsidering all x‐ray systems and only the PA projection, collimator assembly scatter contributed 20–50% to total scatter. For x‐ray projection angles of −90º to 90º, the relative contribution of collimator assembly to total scatter was dependent on projection angle and ranged from 5% to 56%. X‐ray systems with kerma‐area product meters demonstrated higher collimator assembly scatter than those without. Considering all projection angles, the addition of 0.5 mm Pb to the inside of the collimator assembly cover reduced collimator assembly scatter from 28% to 16% of total scatter for both systems.ConclusionFindings from this work suggest that contemporary radiation safety practices and guidelines should be revised to account for scatter originating from the collimator assembly of angiographic x‐ray tubes.

PurposePhoton‐counting‐detector‐computed tomography (PCD‐CT) allows separation of multiple, simultaneously imaged contrast agents, such as iodine (I), gadolinium (Gd), and bismuth (Bi). However, PCDs suffer from several technical limitations such as charge sharing, K‐edge escape, and pulse pile‐up, which compromise spectral separation of multi‐energy data and degrade multi‐contrast imaging performance. The purpose of this work was to determine the performance of a dual‐source (DS) PCD‐CT relative to a single‐source (SS) PCD‐CT for the separation of simultaneously imaged I, Gd, and Bi contrast agents.MethodsPhantom experiments were performed using a research whole‐body PCD‐CT and head/abdomen‐sized phantoms containing vials of different I, Gd, Bi concentrations. To emulate a DS‐PCD‐CT, the phantoms were scanned twice on the SS‐PCD‐CT using different tube potentials for each scan. A tube potential of 80 kV (energy thresholds = 25/50 keV) was used for low‐energy tube, while the high‐energy tube used Sn140 kV (Sn indicates tin filter) and thresholds of 25/90 keV. The same phantoms were scanned also on the SS‐PCD‐CT using the chess acquisition mode. In chess mode, the 4 × 4 subpixels within a macro detector pixel are split into two sets based on a chess‐board pattern. With each subpixel set having two energy thresholds, chess mode allows four energy‐bin data sets, which permits simultaneous multi‐contrast imaging. Because of this design, only 50% area of each detector pixel is configured to receive photons of a pre‐defined threshold, leading to 50% dose utilization efficiency. To compensate for this dose inefficiency, the radiation dose for this scan was doubled compared to DS‐PCD‐CT. A 140 kV tube potential and thresholds = 25/50/75/90 keV were used. These settings were determined based on the K‐edges of Gd, and Bi, and were found to yield good differentiation of I/Gd/Bi based on phantom experiments and other literature. The energy‐bin images obtained from each scan (scan pair) were used to generate I‐, Gd‐, Bi‐specific image via material decomposition. Root‐mean‐square‐error (RMSE) between the known and measured concentrations was calculated for each scenario. A 20‐cm water cylinder phantom was scanned on both systems, which was used for evaluating the magnitude of noise, and noise power spectra (NPS) of I/Gd/Bi‐specific images.ResultsPhantom results showed that DS‐PCD‐CT reduced noise in material‐specific images for both head and body phantoms compared to SS‐PCD‐CT. The noise level of SS‐PCD was reduced from 2.55 to 0.90 mg/mL (I), 1.97 to 0.78 mg/mL (Gd), and 0.85 to 0.74 mg/mL (Bi) using DS‐PCD. NPS analysis showed that the noise texture of images acquired on both systems is similar. For the body phantom, the RMSE for SS‐PCD‐CT was reduced relative to DS‐PCD‐CT from 10.52 to 2.76 mg/mL (I), 7.90 to 2.01 mg/mL (Gd), and 1.91 to 1.16 mg/mL (Bi). A similar trend was observed for the head phantom: RMSE reduced from 2.59 (SS‐PCD) to 0.72 (DS‐PCD) mg/mL (I), 2.02 to 0.58 mg/mL (Gd), and 0.85 to 0.57 mg/mL (Bi).ConclusionWe demonstrate the feasibility of performing simultaneous imaging of I, Gd, and Bi materials on DS‐PCD‐CT. Under the condition without cross scattering, DS‐PCD reduced the RMSE for quantification of material concentration in relative to a SS‐PCD‐CT system using chess mode.

BackgroundDistortion‐free, high‐resolution diffusion imaging using DIADEM (Distortion‐free Imaging: A Double Encoding Method), proposed recently, has great potential for clinical applications. However, it can suffer from prolonged scan times and its reliability for quantitative diffusion imaging has not been evaluated.PurposeTo investigate the clinical feasibility of DIADEM‐based high‐resolution diffusion imaging on a novel compact 3T (C3T) by evaluating the reliability of quantitative diffusion measurements and utilizing both the high‐performance gradients (80 mT/m, 700 T/m/s) and the sequence optimization with the navigator acquisition window reduction and simultaneous multislice (multiband) imaging.Study TypeProspective feasibility study.Phantom/SubjectsDiffusion quality control phantom scans to evaluate the reliability of quantitative diffusion measurements; 36 normal control scans for B0‐field mapping; six healthy and two patient subject scans with a brain tumor for comparisons of diffusion and anatomical imaging.Field Strength/Sequence3T; the standard single‐shot echo‐planar‐imaging (EPI), multishot DIADEM diffusion, and anatomical (2D‐FSE [fast‐spin‐echo], 2D‐FLAIR [fluid‐attenuated‐inversion‐recovery], and 3D‐MPRAGE [magnetization prepared rapid acquisition gradient echo]) imaging.AssessmentThe scan time reduction, the reliability of quantitative diffusion measurements, and the clinical efficacy for high‐resolution diffusion imaging in healthy control and brain tumor volunteers.Statistical TestBland–Altman analysis.ResultsThe scan time for high in‐plane (0.86 mm2) resolution, distortion‐free, and whole brain diffusion imaging were reduced from 10 to 5 minutes with the sequence optimizations. All of the mean apparent diffusion coefficient (ADC) values in phantom were within the 95% confidence interval in the Bland–Altman plot. The proposed acquisition with a total off‐resonance coverage of 597.2 Hz wider than the expected bandwidth of 500 Hz in human brain could yield a distortion‐free image without foldover artifacts. Compared with EPI, therefore, this approach allowed direct image matching with the anatomical images and enabled improved delineation of the tumor boundaries.Data ConclusionThe proposed high‐resolution diffusion imaging approach is clinically feasible on C3T due to a combination of hardware and sequence improvements.Level of Evidence3Technical EfficacyStage 1 J. Magn. Reson. Imaging 2020;51:296–310.

Background and objectives To evaluate the growth pattern of kidney cyst number and cyst volume in association with kidney size, demographics, and genotypes in autosomal dominant polycystic kidney disease. Design, setting, participants, & measurements Kidney cyst number and cyst volume were measured from serial magnetic resonance images, giving a maximum follow-up of 14.23 years, from 241 patients with autosomal dominant polycystic kidney disease (15–46 years old at baseline). The growth pattern was analyzed, in association with sex, age, height-adjusted total kidney volume, and genotype, using linear mixed models of repeated measurements and tests of interactions with age (as a time-dependent covariate) to assess rates of change over time. Models were also fit using Irazabal class. Genotypic groups were characterized as either ( 1 ) PKD1 truncating, PKD1 nontruncating, and PKD2 plus patients with no mutation detected; or ( 2 ) in combination with PKD1 mutation strength groups. Results Imaging and genetic data were collected (at least one visit) for 236 participants. The mean height-adjusted total cyst number increased exponentially over time from a baseline value of 762 to 1715 at the last clinic visit, while the mean height-adjusted total cyst volume increased exponentially from 305 to 770 ml. Height-adjusted total kidney volume, height-adjusted total cyst number, and height-adjusted total cyst volume were all highly correlated over time. Female participants and participants with larger height-adjusted total kidney volume at baseline showed smaller rates of change in the log of height-adjusted total cyst number and cyst volume. PKD1 was associated with significant increases in both cyst number and volume at a given age, but genotype did not significantly affect the rate of growth. Conclusions Both height-adjusted total cyst number and height-adjusted total cyst volume increased exponentially and more than doubled over 14.23 years of follow-up. Compared with PKD2 plus no mutation detected, PKD1 was associated with a greater cyst number and volume at a given age, but no significant difference in the rate of growth.