Citations

Abstract Purpose: ZIP4 is overexpressed in human pancreatic cancer and promotes tumor growth. However, little is known about the role of ZIP4 in advanced stages of this dismal neoplasm. Our goal is to study the underlying mechanism and define a novel signaling pathway controlled by ZIP4-modulating pancreatic tumor metastasis. Experimental Design: The expression of ZIP4, ZO-1, claudin-1, and ZEB1 in human pancreatic cancer tissues, genetically engineered mouse model, xenograft tumor model, and pancreatic cancer cell lines were examined, and the correlations between ZIP4 and those markers were also analyzed. Functional analysis of ZO-1, claudin-1, and ZEB1 was investigated in pancreatic cancer cell lines and orthotopic xenografts. Results: Genetic inactivation of ZIP4 inhibited migration and invasion in pancreatic cancer and increased the expression of ZO-1 and claudin-1. Conversely, overexpression of ZIP4 promoted migration and invasion and increased the expression of ZEB1 and downregulation of the aforementioned epithelial genes. ZIP4 downregulation of ZO-1 and claudin-1 requires the transcriptional repressor ZEB1. Further analysis demonstrated that ZIP4-mediated repression of ZO-1 and claudin-1 leads to upregulation of their targets FAK and Paxillin. Silencing of ZIP4 caused reduced phosphorylation of FAK and Paxillin, which was rescued by simultaneous blocking of ZO-1 or claudin-1. Clinically, we demonstrated that ZIP4 positively correlates with the levels of ZEB1 and inversely associates with the expression of ZO-1 and claudin-1. Conclusions: These findings suggest a novel pathway activated by ZIP4-controlling pancreatic cancer invasiveness and metastasis, which could serve as a new therapeutic target for this devastating disease. Clin Cancer Res; 24(13); 3186–96. ©2018 AACR.

Background and purpose Vertebrobasilar dolichoectatic and fusiform aneurysms (VBDAs) are known to have a poor natural history, with high rates of growth, rupture, and stroke. The purpose of this study was to identify hemodynamic characteristics that differ between VBDAs associated with growth, rupture, and stroke. Materials and methods VBDAs with CT angiography or MR angiography followed longitudinally without treatment were studied. Unstable aneurysms were defined as those that grew or ruptured during follow-up. Aneurysms associated with stroke were defined as those associated with posterior circulation infarct at follow-up. Baseline data, including demographics, comorbidities, and aneurysm morphology and size were collected. Image based computational fluid dynamics models were created and run under pulsatile flow conditions. Relevant hemodynamic and geometric variables were calculated and compared between groups (stable vs unstable and no stroke vs stroke) using the Wilcoxon test. Results A total of 37 VBDAs were included (24 stable, 13 unstable; 30 no stroke, 7 stroke). Unstable aneurysms had lower shear rates (P=0.05), blood flow velocity (P=0.03), and lower vorticity (P=0.049) than stable aneurysms. In addition, unstable aneurysms had higher mean oscillatory shear indices (P=0.001). There were no differences in the hemodynamic characteristics of aneurysms in the stroke group compared with the non-stroke group. Conclusion This small study suggests there may be hemodynamic differences between unstable and stable VBDAs. Unstable VBDAs appear to be under lower flow conditions with lower velocity, vorticity, and shear rates, and have more oscillatory flow. There was no difference in the hemodynamic characteristics of aneurysms in the stroke and no stroke group.

BackgroundWith radiotherapy having entered the era of image guidance, or image‐guided radiation therapy (IGRT), imaging procedures are routinely performed for patient positioning and target localization. The imaging dose delivered may result in excessive dose to sensitive organs and potentially increase the chance of secondary cancers and, therefore, needs to be managed.AimsThis task group was charged with: a) providing an overview on imaging dose, including megavoltage electronic portal imaging (MV EPI), kilovoltage digital radiography (kV DR), Tomotherapy MV‐CT, megavoltage cone‐beam CT (MV‐CBCT) and kilovoltage cone‐beam CT (kV‐CBCT), and b) providing general guidelines for commissioning dose calculation methods and managing imaging dose to patients.Materials & MethodsWe briefly review the dose to radiotherapy (RT) patients resulting from different image guidance procedures and list typical organ doses resulting from MV and kV image acquisition procedures.ResultsWe provide recommendations for managing the imaging dose, including different methods for its calculation, and techniques for reducing it. The recommended threshold beyond which imaging dose should be considered in the treatment planning process is 5% of the therapeutic target dose.DiscussionAlthough the imaging dose resulting from current kV acquisition procedures is generally below this threshold, the ALARA principle should always be applied in practice. Medical physicists should make radiation oncologists aware of the imaging doses delivered to patients under their care.ConclusionBalancing ALARA with the requirement for effective target localization requires that imaging dose be managed based on the consideration of weighing risks and benefits to the patient.

Abstract Background: Patients with previously untreated mTNBC typically receive cytotoxic chemotherapy as first-line therapy for metastatic disease. However, efficacy and safety are suboptimal. KEYNOTE-086 (NCT02447003) is a multicohort, single-arm, phase 2 study of pembrolizumab monotherapy for mTNBC. In cohort B, we assessed the safety and antitumor activity of pembrolizumab as first-line therapy for patients with PD-L1-positive mTNBC. Methods: Key eligibility criteria for cohort B were age ≥18 y, centrally confirmed TNBC, no prior systemic anticancer therapy for metastatic disease, ECOG performance status 0-1, measurable disease per RECIST v1.1 by central review, no radiographic evidence of brain metastases, and a tumor PD-L1 combined positive score (CPS) ≥1. Pembrolizumab 200 mg was given once every 3 wk for 24 mo or until disease progression, intolerable toxicity, or investigator or patient decision. Tumor imaging was performed every 9 wk for 12 mo and every 12 wk thereafter. Clinically stable patients with radiologic progression could remain on pembrolizumab until progression was confirmed on subsequent assessment. Primary end point was safety. Secondary end points included ORR, duration of response, and PFS (all RECIST v1.1 by central review) and OS. Results: Of the 206 patients with tumors evaluable for PD-L1 expression, 128 (62%) had PD-L1 CPS ≥1. Of these, 84 met all eligibility criteria and enrolled. All patients were women, median age was 52.5 y, 29 (35%) had ECOG PS 1, 40 (48%) had elevated LDH, 55 (65%) had visceral ± nonvisceral metastases, and 73 (87%) received prior (neo)adjuvant therapy. All patients received ≥1 pembrolizumab dose, and after median follow-up of 10.6 mo, 18 (21%) remained on pembrolizumab. Treatment-related AEs occurred in 53 (63%) patients and were of grade 3-4 severity in 7 (8%); no patients died or discontinued pembrolizumab because of treatment-related AEs. The most common treatment-related AEs were fatigue (26%), nausea (13%), and diarrhea (12%). No grade 3-4 treatment-related AE occurred in >1 patient. The most common immune-mediated AE was hypothyroidism (10%). Three patients had complete response and 16 had partial response for an ORR of 23% (95% CI 15-33). Of the 11 patients with a best response of stable disease, 1 had stable disease for ≥24 wk, leading to a disease control rate of 24% (95% CI 16-34). 12 of 19 (63%) responses were ongoing at data cutoff, and median duration of response was 8.4 mo (range 2.1+ to 13.9+). Median PFS was 2.1 mo (95% CI 2.0-2.2), with an estimated 6-mo PFS rate of 26%. Median OS was 16.1 mo (95% CI 11.3-NR), with an estimated 6-mo OS rate of 83%. Conclusions: Pembrolizumab monotherapy continues to demonstrate a favorable safety profile and robust, durable antitumor activity in patients with PD-L1-positive, previously untreated mTNBC. Citation Format: Adams S, Loi S, Toppmeyer DL, Cescon DW, De Laurentiis M, Nanda R, Winer EP, Mukai H, Tamura K, Armstrong AC, Liu MC, Iwata H, Ryvo L, Wimberger P, Rugo HS, Tan A, D'Aquanno C, Ding Y, Karantza V, Schmid P. KEYNOTE-086 cohort B: Pembrolizumab monotherapy for PD-L1–positive, previously untreated, metastatic triple-negative breast cancer (mTNBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD6-10.

PurposeThe aim of this work was to develop an efficient daily quality assurance (QA) program with strict tolerance levels for pencil beam scanning (PBS) proton radiotherapy featuring simultaneous dosimetric testing on a single, nonuniform field.MethodsA nonuniform field measuring beam output, proton range, and spot position was designed for delivery onto a Sun Nuclear Daily‐QA 3 device. A custom acrylic block permitted simultaneous measurement of low‐ and high‐energy proton ranges in addition to beam output. Sensitivities to output, range, and spot position were evaluated to quantitate the device's response. Reproducibility tests were used to identify and control sources of measurement error as well as to assess the QA procedure's robustness. This procedure was implemented in each of our four treatment rooms independently; 4–6 months of daily QA measurements were collected.ResultsThe 1% output, 0.5 mm range, and 1.5 mm spot position tolerances derived from preliminary tests were tighter overall than tolerances found in the literature and equivalent to the limits used for proton system commissioning. The simplicity and automation of the procedure reduced the time required for daily QA to 10 min per treatment room, and competition for beam between multiple treatment rooms was minimized.ConclusionsAn efficient daily PBS QA procedure can be performed using a single, nonuniform field on a nondedicated QA device. A thorough quantitation of the device's response and careful control of measurement uncertainties allowed daily tolerances to match commissioning standards.

Background Intracranial aneurysms represent a significant health concern and are poorly understood despite decades of research. Our study focused on understanding temporal patterns of endothelial cell distribution in different spatial locations within the aneurysm early after creation in a rabbit model. Methods Elastase induced saccular aneurysms were created in rabbits and harvested on day 1 (n=3) and after 2 (n=5), 4 (n=4), 8 (n=5), and 12 (n=6) weeks. Sham operated controls (n=3) were harvested on the same day. Aneurysm and control tissue samples were subjected to en face whole mount CD31 staining for endothelial cells. Semiquantitative scoring was performed on the basis of endothelial coverage of the vessel wall (proximal, middle, and distal portions of the aneurysm dome). Mixed effects models were used to assess the effect of time and aneurysm section on endothelial coverage. Results Aneurysmal segments were near completely de-endothelialized at 4 and 8 weeks but had re-endothelialized by 12 weeks. Compared with controls, aneurysms at all time points showed decreased endothelialization, but the difference was only significant compared with the 4 and 8 week groups. Both time (P=0.03) and aneurysm section (P=0.07) were significantly associated with the degree of endothelialization. Proximal locations showed increased endothelialization compared with distal locations (P=0.03). Conclusion In experimental aneurysms of rabbits, endothelial cells regress during the first month after creation, followed by ascending re-endothelialization that stays incomplete. These findings suggest that re-population of endothelial cells comes from resident cells in the adjacent parent artery and that deranged hemodynamics may affect full reconstitution of endothelial cells long term.

Differences in the molecular structure or organ distribution of receptors can limit the usefulness of a given species for drug studies. In this work, we have studied cholecystokinin (CCK) receptors in cynomolgus monkey, an animal model useful for preclinical testing. The type A CCK receptor cDNA was cloned and predicted to encode a 428 amino acid peptide that was 98% identical to the human receptor. Only 2 of the 10 residues that were distinct from the human receptor were not present in other cloned CCK receptor species. A Chinese hamster ovary cell line that stably expressed this receptor was developed. The cynomolgus receptor expressed in this environment was functionally indistinguishable from the human receptor, binding CCK with high affinity [inhibition constant ( KI) = 1.8 ± 0.5 nM] and exhibiting a potent intracellular calcium signaling response to this hormone (EC50= 6.6 ± 2.1 pM). Like the human type A CCK receptor, this receptor was expressed prominently in monkey gallbladder and stomach and was expressed in low levels in brain and pancreas. The type B CCK receptor cDNA was cloned from stomach and brain (450 residue receptor that is 96% identical to the human receptor), where it was highly expressed yet was undetectable in gallbladder or pancreas. This work confirms the relevance of the cynomolgus species for preclinical testing of drugs acting on the type A CCK receptor.