Using Geriatric Assessment Strategies to Lead End-of-Life Care Discussions

Abstract

End-of-life discussions with geriatric oncology patients are a vital part of the comprehensive care of the senior adult patient. Developing a roadmap for these conversations can be challenging. Patients and caregivers may have expectations that are not concordant with what is reasonably achievable if the patient is frail. Measuring baseline cognition, nutritional status, and physical function and discussing goals of care are all essential pieces of information that can be obtained through a comprehensive geriatric assessment (CGA). Objective findings from the CGA can be crucial in developing end-of-life care plans that reflect both the patient's health status and personal values.

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Curcumin Reverses the Diazepam-Induced Cognitive Impairment by Modulation of Oxidative Stress and ERK 1/2/NF-κB Pathway in Brain

Oxidative stress and inflammation can be involved in cognitive dysfunction associated with neurodegenerative disorders. Diazepam (DZP) administration has been chosen to simulate the memory impairment. The aim of this study was to evaluate the effects of curcumin (CUR) on spatial cognition, ambulatory activity, and blood and brain oxidative stress levels. The ERK/NF-κB signaling pathway and the histopathological changes in the hippocampus and frontal lobe, in diazepam-treated rats, were also analyzed. The animals were divided into 4 groups: control, carboxymethylcellulose (CMC) + CUR, CMC + DZP, and CUR + CMC + DZP. CUR (150 mg/kg b.w.) was orally administered for 28 days. DZP (2 mg/kg b.w.) was intraperitoneally administered 20 minutes before the behavioral tests (open field test, Y-maze, and elevated plus maze). CUR improved the spontaneous alternation behavior, decreased the oxidative stress levels, both in the blood and in the hippocampus, and downregulated the extracellular signal-regulated kinase (ERK 1/2)/nuclear transcription factor- (NF-) κB/pNF-κB pathway in the hippocampus and the iNOS expression in the hippocampus and frontal lobe of the DZP-treated rats. Histopathologically, no microscopic changes were found. The immunohistochemical signal of iNOS decreased in the DZP and CUR-treated group. Thus, our findings suggest that curcumin administration may improve the cognitive performance and may also have an antioxidant effect.

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Optical clearing of small intestine for three-dimensional visualization of cellular proliferation within crypts

Abstract

New methods on optical clearing provide a valuable alternative to traditional physical section histology. Optical clearing allows investigation of relatively large tissue samples at histological resolution while maintaining the three-dimensional architecture of the intact system. There is significant potential for applying optical clearing to gastrointestinal tissues. In particular, intestinal crypts contain high concentrations of stem cells, making these structures especially important for research on cellular proliferation in the intestinal epithelium. The objective of our study is to demonstrate an optical clearing method that is easy to implement and is compatible with mitotic fluorescent labeling. The optical clearing method we present utilizes a Triton/DMSO delipidization step followed by refractive index matching, rendering the tissue nearly transparent. We use EdU click chemistry to fluorescently label mitotic cell nuclei. Our results demonstrate successful clearing of jejunal samples with readily visible EdU staining by means of confocal microscopy. Three-dimensional reconstruction of labeled samples reveals preservation of intestinal cytoarchitecture including muscular, submucosal, and mucosal layers. Additionally, the morphology of intestinal crypts and individual EdU-positive mitotic nuclei are visible in sharp detail within their intact three-dimensional organization. In summary, we present an optical clearing method that is easy to implement and has the potential to provide more accurate assessment of cellular proliferation within the gastrointestinal tract in both healthy and disease states.

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Differential gene regulation and tumor inhibitory activities of alpha-, delta- and gamma-tocopherols in estrogen-mediated mammary carcinogenesis

Despite experimental evidence elucidating the anti-tumor activities of tocopherols, clinical trials with α-tocopherol (α-T) have failed to demonstrate its beneficial effects in cancer prevention. This study compared the chemopreventive efficacy of individual tocopherols (α-, -, -T) and a -T rich tocopherol mixture (-TmT) in the August Copenhagen Irish (ACI) rat model of estrogen-mediated mammary cancer. Female ACI rats receiving 17β-estradiol (E2) implants were administered with 0.2% α-T, -T, -T or -TmT for 30 weeks. While α-T had no significant effects on mammary tumor growth in ACI rats, -T, -T and -TmT reduced mammary tumor volume by 51% (p < 0.05), 60% (p < 0.01) and 59% (p < 0.01), respectively. Immunohistochemical analysis revealed that -T, -T and -TmT reduced levels of the cell proliferation marker, PCNA, in the rat mammary tumors. To gain further insight into the biological functions of different forms of tocopherols, RNA-seq analysis of the tumors was performed. Treatment with -T induced robust gene expression changes in the mammary tumors of ACI rats. IPA analysis identified 'Cancer' as a top disease pathway and 'Tumor growth' and 'Metastasis' as the top signaling pathways modulated by -T. Although the results need further functional validation, this study presents an unbiased attempt to understand the differences between biological activities of individual forms of tocopherols at the whole transcriptome level. -T, -T and -TmT could be promising agents for the prevention of estrogen-mediated mammary carcinogenesis. -T suppressed growth of mammary tumors most effectively in ACI rats.

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In This Issue

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Issue Information

Cover of this issue. Radiation-resistant X60 cells contained increased amounts of mitochondria. See also Sato et al. (pages 2004-2010 of this issue).

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Influence of temperature on the tyre rolling resistance

Abstract

Temperature is a very important factor controlling rolling resistance of road vehicle tyres. There are at least three different temperatures that may be considered as important factors controlling thermal conditions of the rolling tyre. The most common measure of the thermal conditions during tyre rolling is ambient air temperature. The other two are: pavement temperature and "tyre" temperature. Tyre temperature is the most difficult to establish, as temperatures of different parts of rolling tyres differ considerably, thus there is a problem to obtain representative values. In the authors' opinion, air temperature is the most universal and reliable parameter to measure. The article presents results obtained in the Technical University of Gdańsk during laboratory and road measurements of different car tyres rolling on different pavements. The knowledge of rolling resistance characteristics is important for modelling car dynamics as well as fuel consumption. It is also necessary to establish proper test conditions in the future standardized on-road method of measuring rolling resistance. The results indicate that generally each tyre and pavement combination is influenced by the air temperature in a unique way, but at the same it is possible to propose some general influence factors that may be used to normalize measurements to the standard temperature of 25 °C.

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Dynamics characteristics analysis and control of FWID EV

Abstract

Compared with internal combustion engine (ICE) vehicles, four-wheel-independently-drive electric vehicles (FWID EV) have significant advantages, such as more controlled degree of freedom (DOF), higher energy efficiency and faster torque response of an electric motor. The influence of these advantages and other characteristics on vehicle dynamics control need to be evaluated in detail. This paper firstly analyzed the dynamics characteristics of FWID EV, including the feasible region of vehicle global force, the improvement of powertrain energy efficiency and the time-delays of electric motor torque in the direct yaw moment feedback control system. In this way, the influence of electric motor output power limit, road friction coefficient and the wheel torque response on the stability control, as well as the impact of motor idle loss on the torque distribution method were illustrated clearly. Then a vehicle dynamics control method based on the vehicle stability state was proposed. In normal driving condition, the powertrain energy efficiency can be improved by torque distribution between front and rear wheels. In extreme driving condition, the electric motors combined with the electro-hydraulic braking system were employed as actuators for direct yaw moment control. Simulation results show that dynamics control which take full advantages of the more controlled freedom and the motor torque response characteristics improve the vehicle stability better than the control based on the hydraulic braking system of conventional vehicle. Furthermore, some road tests in a real vehicle were conducted to evaluate the performance of proposed control method.

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Effect of operating parameters on diesel/propane dual fuel premixed compression ignition in a diesel engine

Abstract

In this research, the effects of three operating parameters (Diesel injection timing, propane ratio, and exhaust gas recirculation (EGR) rates) in a diesel-propane dual fuel combustion were investigated. The characteristics of dual-fuel combustion were analyzed by engine parameters, such as emission levels (Nitrogen oxides (NO_x) and particulate matter (PM)), gross indicated thermal efficiency (GIE) and gross IMEP Coefficient of Variance (CoV). Based on the results, improving operating strategies of the four main operating points were conducted for dual-fuel PCCI combustion with restrictions on the emissions and the maximum pressure rise rate. The NOx emission was restricted to below 0.21 g/kWh in terms of the indicated specific NO_x (ISNO_x), PM was restricted to under 0.2 FSN, and the maximum pressure rise rate (MPRR) was restricted to 10 bar/deg. Dual-fuel PCI combustion can be available with low NO_x, PM emission and the maximum pressure rise rate in relatively low load condition. However, exceeding of PM and MPRR regulation was occurred in high load condition, therefore, design of optimal piston shape for early diesel injection and modification of hardware optimizing for dual-fuel combustion should be taken into consideration.

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Development of a self-driving car that can handle the adverse weather

Abstract

Lane and road recognition are essential for self-driving where GPS solution is inaccurate due to the signal block or multipath in an urban environment. Vision based lane or road recognition algorithms have been studied extensively, but they are not robust to changes in weather or illumination due to the characteristic of the sensor. Lidar is a sensor for measuring distance, but it also contains intensity information. The road mark on the road is made to look good with headlight at night by using a special paint with good reflection on the light. With this feature, road marking can be detected with lidar even in the case of changes in illumination due to the rain or shadow. In this paper, we propose equipping autonomous cars with sensor fusion algorithms intended to operate in a different weather conditions. The proposed algorithm was applied to the self-driving car EureCar (KAIST) in order to test its feasibility for real-time use.

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Schlieren, Shadowgraph, Mie-scattering visualization of diesel and gasoline sprays in high pressure/high temperature chamber under GDCI engine low load condition

Abstract

Three visualization methods, Schlieren, Shadowgraph, and Mie-scattering, were applied to compare diesel and gasoline spray structures in a constant volume chamber. Fuels were injected into a high pressure/high temperature chamber under the same in-cylinder pressure and temperature conditions of low load in a GDCI (gasoline direct injection compression ignition) engine. Two injection pressures (40 MPa and 80 MPa), two ambient pressures (4.2 MPa and 1.7 MPa), and two ambient temperatures (908 K and 677 K) were use. The images from the different methods were overlapped to show liquid and vapor phases more clearly. Vapor developments of the two fuels were similar; however, different liquid developments were seen. At the same injection pressure and ambient temperature, gasoline liquid propagated more quickly and disappeared more rapidly than diesel liquid phase. At the low ambient temperature and pressure condition, gasoline and diesel sprays with higher injection pressures showed longer liquid lengths due to higher spray momentum. At the higher ambient temperature condition, the gasoline liquid length was shorter for the higher injection pressure. Higher volatility of gasoline is the main reason for this shorter liquid length under higher injection pressure and higher ambient temperature conditions. For a design of GDCI engine, it is necessary to understand the higher volatility of gasoline.

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Similarity of the measured NIC of a BioRID II dummy in car-to-car rear end impact and sled experiments

Abstract

The Japan New Car Assessment Program (J-NCAP) evaluates the performance of cars in terms of protection against whiplash injuries in rear-end collisions. In the test protocol, a simplified triangular acceleration is applied to the sled. This study clarifies whether biofidelic rear-impact dummy II (BioRID II) measurements obtained for simplified triangular acceleration reflect car-to-car rear-end impacts in real-world accidents in Japan. We conducted a car-to-car rear-end impact experiment and a simplified-triangular-acceleration sled test. Our results indicate that the time series of dummy responses were approximately consistent in the two test conditions. The neck injury criterion (NIC) and maximum acceleration of the head and T1 measured using the BioRID II dummy were similar in the car-to-car and sled experiments. This revealed that the J-NCAP test protocol using simplified triangular acceleration reflects the car-to-car rear-end impact experiment using Japanese cars, in terms of the NIC and maximum acceleration of the head and T1.

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Flame propagation model for a rotary Atkinson cycle SI engine

Abstract

The rotary Atkinson cycle engine includes two modes of combustion: combustion initiation and propagation in ignition chamber and then flame jet entrainment and propagation in expansion chamber. The turbulent flame propagation model is a predictive model for SI engines which could be developed for this type of combustion for the rotary Atkinson engine similar to the congenital engine with pre-chamber; in split combustion chamber SI engines, small amount of fuel is burned in pre-chamber while the fuel burned in ignition chamber of rotary Atkinson cycle is considerable. In this study a mathematical modeling of spherical flame propagation inside ignition chamber and new combined conical flame and spherical flame propagation model of a new two-stroke Atkinson cycle SI engine will be presented. The mathematical modeling is carried out using two-zone combustion analysis and the model also is validated against experimental tests and compared with previous study using non-predictive Weibe function model.

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Allocation control algorithms design and comparison based on distributed drive electric vehicles

Abstract

For a distributed drive electric vehicle (DDEV) which is equipped with redundant actuators, allocation control is a key technique. Three different allocation control algorithms are designated with fixed efficiency matrix, dynamic efficiency matrix, and direct yaw moment distribution, respectively. All these algorithms are applied in a vehicle stability control system with hierarchical control structure and evaluated from three aspects, namely, control precision, real-time characteristics, and control energy. Comparison results demonstrate that the algorithm with dynamic efficiency matrix has the best comprehensive performance, which is also validated in field tests based on a DDEV equipped with four motors.

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Influence of the geometric parameters of the vehicle frontal profile on the pedestrian’s head accelerations in case of accidents

Abstract

The goal of this paper is to determine how the geometry of the vehicle's frontal profile is influencing the pedestrian's head accelerations (linear and angular) in car-to-pedestrian accidents. In order to achieve this goal, a virtual multibody dummy of the pedestrian was developed and multiple simulations of accidents were performed using vehicles with different frontal profile geometry, from different classes. The type of accidents considered is characteristic for urban areas and occur at relatively low speed (around 30 km/h) when an adult pedestrian is struck from the rear and the head acceleration variation are the measurement of the accident severity. In the accident simulation 3D meshes were applied on the geometry of the vehicles, in order to define the contact surface with the virtual dummy, similar with real vehicles. The validation of the virtual pedestrian dummy was made by performing two crash-tests with a real dummy, using the same conditions as in the simulations. The measured accelerations in the tests were the linear and angular accelerations of the head during the impact, and these were compared with the ones from the simulations. After validating the virtual model of the car-to-pedestrian accident, we were able to perform multiple simulations with different vehicle shapes. These simulations are revealing how the geometric parameters of the vehicle's frontal profile are influencing the head acceleration. This paper highlights the main geometric parameters of the frontal profile design that influence the head injury severity and the way that the vehicles can be improved by modifying these parameters. The paper presents an approach to determine the "friendliness" of the vehicle's frontal profile in the car-to-pedestrian collision.

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Osteocalcin and serum insulin-like growth factor-1 as biochemical skeletal maturity indicators

With change in concepts of growth determination methods, there is a surge in the measurement of biomarkers for appraisal of growth status. Osteocalcin is a bone-specific protein and was observed to parallel th...

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Studies on acute and chronic toxicity of cadmium to freshwater snail Lymnaea acuminata (Lamarck) with special reference to behavioral and hematological changes

Abstract

Molluscs have long been regarded as promising bioindicator and biomonitoring subjects for heavy metals as molluscs are highly tolerant to heavy metals and exhibit high accumulation in their body. In spite of several previous studies about the impact of cadmium on molluscs, little information exists in literatures concerning the toxic effects of cadmium on Lymnaea acuminata, especially pertaining to behavioral and hematological changes as these are considered effective bioindicators and biomonitoring variables for detecting heavy metals in polluted water bodies. In the present study, the median lethal concentrations of cadmium chloride to snail, Lymnaea acuminata, were estimated to be 9.66, 7.69, 6.26, and 5.54 mg/L at 24, 48, 72, and 96 h, respectively. For behavioral studies, variable test concentrations of cadmium from 0.00 to 10 mg/L were used. The clumping tendency, crawling activity, and touch reflex in the exposed snails were gradually decreased with higher concentrations at 72 and 96 h. For measuring the hemocyte numbers in the circulating hemolymph of snail during chronic cadmium exposure, two sublethal doses of cadmium (10 and 20% 96-h LC₅₀—0.55 and 1.11 mg/L, respectively) were used. A significant variation (p < 0.05) from the control at all exposure times (7, 14, 21, and 28 days) was recorded at 1.11 mg/L concentration. The total count of circulating hemocytes was significantly reduced (p < 0.05) compared to the controls at both concentrations of cadmium exposure at all time periods except 14 and 21 days exposure at 0.55 mg/L where values were non-significantly increased. In comparison between two sublethal doses, blood cells were significantly (p < 0.05) lowered at 1.11 mg/L cadmium treatment. Considering the behavioral and hematological data, it seems possible to forecast the physiological state of snails in cadmium-contaminated water bodies and these findings can be used in determining the safe disposal level of cadmium in aquatic ecosystem.

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Fractions and transformation of organic phosphorus in sediments from a eutrophic lake in China

Abstract

Several organic phosphorus compounds (Po) in sediment from a representative eutrophic lake were surveyed using a sequential fractionation procedure, which included microbial biomass phosphorus (Biomass-P), fulvic acid phosphorus (FA-P), humic acid phosphorus (HU-P), and residual phosphorus (Res-P). In addition, several organic compounds including orthophosphate monoesters, orthophosphate diesters, and pyrophosphate were simultaneously measured using ³¹P nuclear magnetic resonance (³¹P NMR). Results showed that Po contributed over 50% of total phosphorus (TP), and the average concentration of Po species generally decreased from Res-P > FA-P > HU-P > Biomass-P. Additionally, the relative proportions of phosphorus compounds in the sediment followed the decreasing order of orthophosphate monoesters > orthophosphate diesters > pyrophosphate. In general, Po was the dominant phosphorus species. Residual P was not a single species but comprised of a group of species, and tended to be stable. Although orthophosphate monoesters had the highest concentrations and ratios in Po, orthophosphate diesters displayed a more distinct remineralization trend. Principal component analysis (PCA) coupled with correlation analysis suggested that a greater amount of orthophosphate diesters resided in Res-P, than HU-P or FA-P.

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Organic ligand induced release of vanadium from the dissolution of stone coal oxide ore

Abstract

The effects of low-molecular-weight dissolved organic matters (LMWDOMs) on the release of vanadium (V) under environmental conditions are part of a broader study on the environmental geochemistry behavior of V. Eight typical naturally occurring LMWDOMs with carboxyl, hydroxyl, and amidogen groups were chosen: citric acid, oxalic acid, EDTA, salicylic acid, catechol, glycine, cysteine, and glucose. The results showed that the release of V was largely promoted by LMWDOMs with carboxyl functional groups under acidic conditions and with catechol under basic conditions. In the presence of citric acid, oxalic acid, or EDTA at pH 4.0, the initial release rates of V were approximately 25–39 times greater than the rates in the control experiments; the steady release rates were 164, 95, and 49 times than the rates in the control experiments, respectively. For catechol, the release rate at pH 8.0 was approximately 20 times the rate at pH 4.0. Amino acids and alcohols had a minimal effect on the release of V. Ligand-promoted release rates of V were found primarily due to the faster detachment of surface complexes, the protonated sites from the mineral surface and the reduction of dissolved V (V) in the presence of citric acid, oxalic acid, EDTA, and catechol. This study helps understand the pollution risk of V in some mine areas and the fate of V in the environment.

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Liquid biopsies may help predict response to immune checkpoint inhibitors

According to research published in Clinical Cancer Research, a journal of the American Association for Cancer Research. The number of alterations detected in the DNA collected from blood samples (liquid biopsies) of cancer patients treated with immune...

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By decoding how HPV causes cancer, researchers find a new potential treatment strategy

A study that teases apart the biological mechanisms by which human papillomaviruses (HPV) cause cancer has found what researchers at Georgetown University Medical Center say is a new strategy that might provide targeted treatment for these cancers. HPV...

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How to write a Critically Appraised Topic: evidence to underpin routine clinical practice

Summary

Critically appraised topics (CATs) are essential tools for busy clinicians who wish to ensure that their daily clinical practice is underpinned by evidence-based medicine. CATs are short summaries of the most up-to-date, high-quality available evidence that is found using thorough structured methods. They can be used to answer specific, patient-orientated questions that arise recurrently in real-life practice. This article provides readers with a detailed guide to performing their own CATs. It is split into four main sections reflecting the four main steps involved in performing a CAT: formulation of a focused question, a search for the most relevant and highest-quality evidence, critical appraisal of the evidence and application of the results back to the patient scenario. As well as helping to improve patient care on an individual basis by answering specific clinical questions that arise, CATs can help spread and share knowledge with colleagues on an international level through publication in the evidence-based dermatology section of the British Journal of Dermatology.

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Bevacizumab Induces Acute Hypoxia and Cancer Progression in Patients with Refractory Breast Cancer: Multimodal Functional Imaging and Multiplex Cytokine Analysis

Purpose: Bevacizumab, an antibody against endothelial growth factor, is a key but controversial drug in the treatment of metastatic breast cancer. We, therefore, aimed to determine the intrinsic resistance to bevacizumab at the physiologic and molecular levels in advanced breast cancer using PET, dynamic contrast-enhanced MRI, diffuse optical spectroscopic imaging (DOSI), and multiplex cytokine assays.

Experimental Design: In total, 28 patients diagnosed with advanced stage III/IV breast cancer receiving single-agent bevacizumab for 1 week followed by paclitaxel combined with bevacizumab underwent ¹⁸F-fluorodeoxyglucose (FDG)-PET, ¹⁸F-fluoromisonidazole (FMISO)-PET, and MRI at both baseline and two courses after treatment initiation. Hemodynamic measurement using DOSI and blood sample collection were performed at baseline and multiple times during the first week after the initiation of single-agent bevacizumab. We distinguished nonresponders from responders by serial FDG-PET based on their glycolytic changes to chemotherapy.

Results: Nonresponders showed significantly higher hypoxic activity on FMISO-PET and less tumor shrinkage than responders. Hemodynamic parameters showed higher tumor blood volume and a remarkable decrease in the tissue oxygen level in nonresponders compared with responders after the infusion of single-agent bevacizumab. Multiplex cytokine assays revealed increased plasma levels of both proangiogenic and hypoxia-related inflammatory cytokines in nonresponders and decreased levels in responders.

Conclusions: Nonresponders exhibited a higher degree of angiogenesis with more severe hypoxia than responders during bevacizumab treatment. These findings demonstrated that the addition of bevacizumab to paclitaxel treatment under hypoxic conditions could be ineffective and may result in acute hypoxia and increased cytokine secretion associated with cancer progression. Clin Cancer Res; 23(19); 5769–78. ©2017 AACR.

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Hypermutated Circulating Tumor DNA: Correlation with Response to Checkpoint Inhibitor-Based Immunotherapy

Purpose: Tumor mutational burden detected by tissue next-generation sequencing (NGS) correlates with checkpoint inhibitor response. However, tissue biopsy may be costly and invasive. We sought to investigate the association between hypermutated blood-derived circulating tumor DNA (ctDNA) and checkpoint inhibitor response.

Experimental Design: We assessed 69 patients with diverse malignancies who received checkpoint inhibitor–based immunotherapy and blood-derived ctDNA NGS testing (54–70 genes). Rates of stable disease (SD) ≥6 months, partial and complete response (PR, CR), progression-free survival (PFS), and overall survival (OS) were assessed based on total and VUS alterations.

Results: Statistically significant improvement in PFS was associated with high versus low alteration number in variants of unknown significance (VUS, >3 alterations versus VUS ≤3 alterations), SD ≥6 months/PR/CR 45% versus 15%, respectively; P = 0.014. Similar results were seen with high versus low total alteration number (characterized plus VUS, ≥6 vs. <6). Statistically significant OS improvement was also associated with high VUS alteration status. Two-month landmark analysis showed that responders versus nonresponders with VUS >3 had a median PFS of 23 versus 2.3 months (P = 0.0004).

Conclusions: Given the association of alteration number on liquid biopsy and checkpoint inhibitor–based immunotherapy outcomes, further investigation of hypermutated ctDNA as a predictive biomarker is warranted. Clin Cancer Res; 23(19); 5729–36. ©2017 AACR.

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FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma

On December 18, 2015, the FDA granted regular approval to pembrolizumab (KEYTRUDA; Merck Sharp & Dohme Corp.) for treatment of patients with unresectable or metastatic melanoma based on results of two randomized, open-label, active-controlled clinical trials. In trial PN006, 834 patients with ipilimumab-naïve metastatic melanoma were randomized (1:1:1) to pembrolizumab 10 mg/kg i.v. every 2 or 3 weeks until disease progression or ipilimumab 3 mg/kg every 3 weeks for up to four doses. In trial PN002, 540 patients with ipilimumab-refractory metastatic melanoma were randomized (1:1:1) to pembrolizumab 2 or 10 mg/kg i.v. every 3 weeks or to investigator's choice of chemotherapy. In trial PN006, patients randomized to pembrolizumab demonstrated a statistically significant improvement in overall survival compared with ipilimumab [every-2-week arm: hazard ratio (HR) = 0.63; 95% confidence interval (CI), 0.47–0.83; P < 0.001; every-3-week arm: HR = 0.69; 95% CI, 0.52–0.90; P = 0.004]. In both trials, patients receiving pembrolizumab demonstrated statistically significant improvements in progression-free survival. The most common (≥2%) immune-mediated adverse reactions in a pooled safety analysis were hypothyroidism, pneumonitis, and hyperthyroidism. Key considerations for approval were determination of pembrolizumab dose and interpretation of tumor response–based endpoints using RECIST or immune-related RECIST. Clin Cancer Res; 23(19); 5661–5. ©2017 AACR.

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Therapy of Small Cell Lung Cancer (SCLC) with a Topoisomerase-I-inhibiting Antibody-Drug Conjugate (ADC) Targeting Trop-2, Sacituzumab Govitecan

Purpose: We evaluated a Trop-2–targeting antibody conjugated with SN-38 in metastatic small cell lung cancer (mSCLC) patients.

Experimental Design: Sacituzumab govitecan was studied in patients with pretreated (median, 2; range, 1–7) mSCLC who received either 8 or 10 mg/kg i.v. on days 1 and 8 of 21-day cycles. The primary endpoints were safety and objective response rate (ORR); duration of response, progression-free survival (PFS), and overall survival (OS) were secondary endpoints.

Results: Sixty percent of patients showed tumor shrinkage from baseline CTs. On an intention-to-treat basis (N = 50), the ORR was 14% (17% for the 10-mg/kg group); the median response duration, 5.7 months; the clinical benefit rate (CBR ≥4 months), 34%; median PFS, 3.7 months; and median OS, 7.5 months. There was a suggested improvement in PR, CBR, and PFS with sacituzumab govitecan in second-line patients who were sensitive to first-line therapy, but no difference between first-line chemosensitive versus chemoresistant patients in the overall population. There was a statistically significant higher OS in those patients who received prior topotecan versus no topotecan therapy in a small subgroup. Grade ≥3 adverse events included neutropenia (34%), fatigue (13%), diarrhea (9%), and anemia (6%). Trop-2 tumor staining was not required for patient selection. No antibodies to the drug conjugate or its components were detected on serial blood collections.

Conclusions: Sacituzumab govitecan appears to have a safe and effective therapeutic profile in heavily pretreated mSCLC patients, including those who are chemosensitive or chemoresistant to first-line chemotherapy. Additional studies as a monotherapy or combination therapy are warranted. Clin Cancer Res; 23(19); 5711–9. ©2017 AACR.

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FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma

On September 4, 2014, the FDA approved pembrolizumab (KEYTRUDA; Merck Sharp & Dohme Corp.) with a recommended dose of 2 mg/kg every 3 weeks by intravenous infusion for the treatment of patients with unresectable or metastatic melanoma who have progressed following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on demonstration of objective tumor responses with prolonged response durations in 89 patients enrolled in a randomized, multicenter, open-label, dose-finding, and activity-estimating phase 1 trial. The overall response rate (ORR) by blinded independent central review per RECIST v1.1 was 24% (95% confidence interval, 15–34); with 6 months of follow-up, 86% of responses were ongoing. The most common (≥20%) adverse reactions were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. Immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, hypophysitis, and thyroid disorders. The benefits of the observed ORR with prolonged duration of responses outweighed the risks of immune-mediated adverse reactions in this life-threatening disease and represented an improvement over available therapy. Important regulatory issues in this application were role of durability of response in the evaluation of ORR for accelerated approval, reliance on data from a first-in-human trial, and strategies for dose selection. Clin Cancer Res; 23(19); 5666–70. ©2017 AACR.

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Diffusion MRI Phenotypes Predict Overall Survival Benefit from Anti-VEGF Monotherapy in Recurrent Glioblastoma: Converging Evidence from Phase II Trials

Purpose: Anti-VEGF therapies remain controversial in the treatment of recurrent glioblastoma (GBM). In the current study, we demonstrate that recurrent GBM patients with a specific diffusion MR imaging signature have an overall survival (OS) advantage when treated with cediranib, bevacizumab, cabozantinib, or aflibercept monotherapy at first or second recurrence. These findings were validated using a separate trial comparing bevacizumab with lomustine.

Experimental Design: Patients with recurrent GBM and diffusion MRI from the monotherapy arms of 5 separate phase II clinical trials were included: (i) cediranib (NCT00035656); (ii) bevacizumab (BRAIN Trial, AVF3708g; NCT00345163); (iii) cabozantinib (XL184-201; NCT00704288); (iv) aflibercept (VEGF Trap; NCT00369590); and (v) bevacizumab or lomustine (BELOB; NTR1929). Apparent diffusion coefficient (ADC) histogram analysis was performed prior to therapy to estimate "ADC_L," the mean of the lower ADC distribution. Pretreatment ADC_L, enhancing volume, and clinical variables were tested as independent prognostic factors for OS.

Results: The coefficient of variance (COV) in double baseline ADC_L measurements was 2.5% and did not significantly differ (P = 0.4537). An ADC_L threshold of 1.24 μm²/ms produced the largest OS differences between patients (HR ~ 0.5), and patients with an ADC_L > 1.24 μm²/ms had close to double the OS in all anti-VEGF therapeutic scenarios tested. Training and validation data confirmed that baseline ADC_L was an independent predictive biomarker for OS in anti-VEGF therapies, but not in lomustine, after accounting for age and baseline enhancing tumor volume.

Conclusions: Pretreatment diffusion MRI is a predictive imaging biomarker for OS in patients with recurrent GBM treated with anti-VEGF monotherapy at first or second relapse. Clin Cancer Res; 23(19); 5745–56. ©2017 AACR.

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Efficacy of Sequential Ipilimumab Monotherapy versus Best Supportive Care for Unresectable Locally Advanced/Metastatic Gastric or Gastroesophageal Junction Cancer

Purpose: Ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte–associated protein-4 interactions, enhances T-cell activation and promotes tumor immunity. This phase II study evaluated the safety and efficacy of ipilimumab monotherapy versus best supportive care (BSC) among patients with advanced/metastatic gastric or gastroesophageal junction cancer who achieved at least stable disease with first-line chemotherapy.

Experimental Design: Eligible patients were randomized to ipilimumab 10 mg/kg every 3 weeks for four doses, then 10 mg/kg every 12 weeks for up to 3 years, or BSC, which could include continuation of fluoropyrimidine until progression or toxicity. The primary endpoint was immune-related progression-free survival (irPFS); secondary endpoints included PFS by modified World Health Organization criteria and overall survival (OS).

Results: Of 143 patients screened, 57 were randomized to each arm. irPFS with ipilimumab versus BSC was not improved [2.92 months, 95% confidence interval (CI), 1.61–5.16 vs. 4.90 months, 95% CI, 3.45–6.54, HR = 1.44; 80% CI, 1.09–1.91; P = 0.097], resulting in study cessation. At study closeout, which occurred 8 months after the interim analysis, the median OS durations were 12.7 months (95% CI, 10.5–18.9) and 12.1 months (95% CI, 9.3–not estimable), respectively. Grade 3/4 treatment-related adverse events occurred in 23% of ipilimumab-treated patients, in whom diarrhea (9%) and fatigue (5%) were most frequent, and in 9% of active BSC-treated patients.

Conclusions: Although ipilimumab at 10 mg/kg was manageable, it did not improve irPFS versus BSC. However, comparable median OS of approximately 1 year and a favorable safety profile support the investigation of ipilimumab in combination with other therapies for advanced gastric cancer. Clin Cancer Res; 23(19); 5671–8. ©2017 AACR.

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Co-administration of RANKL and CTLA4 Antibodies Enhances Lymphocyte-Mediated Antitumor Immunity in Mice

Purpose: Novel partners for established immune checkpoint inhibitors in the treatment of cancer are needed to address the problems of primary and acquired resistance. The efficacy of combination RANKL and CTLA4 blockade in antitumor immunity has been suggested by recent case reports in melanoma. Here, we provide a rationale for this combination in mouse models of cancer.

Experimental Design: The efficacy and mechanism of a combination of RANKL and CTLA4 blockade was examined by tumor-infiltrating lymphocyte analysis, tumor growth, and metastasis using a variety of neutralizing antibodies and gene-targeted mice.

Results: RANKL blockade improved the efficacy of anti-CTLA4 mAbs against solid tumors and experimental metastases, with regulatory T-cell (Treg)–depleting anti-CTLA4 mAbs of the mouse IgG2a isotype showing greatest combinatorial activity. The optimal combination depended on the presence of activating Fc receptors and lymphocytes (NK cells for metastatic disease and predominantly CD8⁺ T cells for subcutaneous tumor control), whereas anti-RANKL alone did not require FcR. The significantly higher T-cell infiltration into solid tumors post anti-RANKL and anti-CTLA4 was accompanied by increased T-cell effector function (cytokine polyfunctionality), and anti-RANKL activity occurred independently of Treg depletion. The majority of RANKL expression in tumors was on T cells whereas RANK-expressing cells were mostly tumor-associated macrophages (TAM), with some expression also observed on dendritic cells (DC) and myeloid-derived suppressor cells (MDSC).

Conclusions: These results provide a rationale for the further investigation of RANKL–RANK interactions in tumor immunity and a basis for development of translational markers of interest in human clinical trials. Clin Cancer Res; 23(19); 5789–801. ©2017 AACR.

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Local Adjuvant Treatment with Low-Dose CpG-B Offers Durable Protection against Disease Recurrence in Clinical Stage I-II Melanoma: Data from Two Randomized Phase II Trials

Purpose: Although risk of recurrence after surgical removal of clinical stage I–II melanoma is considerable, there is no adjuvant therapy with proven efficacy. Here, we provide clinical evidence that a local conditioning regimen, aimed at immunologic arming of the tumor-draining lymph nodes, may provide durable protection against disease recurrence (median follow-up, 88.8 months).

Experimental Design: In two randomized phase II trials, patients, diagnosed with stage I–II melanoma after excision of the primary tumor, received local injections at the primary tumor excision site within 7 days preceding re-excision and sentinel lymph node (SLN) biopsy of either a saline placebo (n = 22) or low-dose CpG type B (CpG-B) with (n = 9) or without (n = 21) low-dose GM-CSF.

Results: CpG-B treatment was shown to be safe, to boost locoregional and systemic immunity, to be associated with lower rates of tumor-involved SLN (10% vs. 36% in controls, P = 0.04), and, at a median follow-up of 88.8 months, to profoundly improve recurrence-free survival (P = 0.008), even for patients with histologically confirmed (i.e., pathologic) stage I–II disease (P = 0.02).

Conclusions: Potentially offering durable protection, local low-dose CpG-B administration in early-stage melanoma provides an adjuvant treatment option for a large group of patients currently going untreated despite being at considerable risk for disease recurrence. Once validated in a larger randomized phase III trial, this nontoxic immunopotentiating regimen may prove clinically transformative. Clin Cancer Res; 23(19); 5679–86. ©2017 AACR.

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Sorafenib in Patients with Hepatocellular Carcinoma--Results of the Observational INSIGHT Study

Purpose: Sorafenib is the only currently approved systemic therapy for advanced hepatocellular carcinoma (HCC). We aimed to evaluate the safety and efficacy of sorafenib therapy in patients with HCC under real-life conditions regarding patient, tumor characteristics, and any adverse events at study entry and at follow-up visits every 2 to 4 months.

Experimental Design: The current INSIGHT study is a noninterventional, prospective, multicenter, observational study performed in 124 sites across Austria and Germany between 2008 and 2014.

Results: Median overall survival and time to progression (RECIST) were found to be dependent on baseline Barcelona Clinic Liver Cancer (BCLC) tumor stage (A: 29.2, B: 19.6, C: 13.6, D: 3.1 and A: 6.0, B: 5.5, C: 3.9, and D: 1.7 months, respectively), Child–Pugh liver function (A: 17.6, B: 8.1, C: 5.6 and A: 5.3, B: 3.3, C: 2.5 months, respectively), and performance status of the patient; however, age did not affect prognosis. Sorafenib-related adverse events at any grade occurred in 64.9% of patients, with diarrhea (35.4%), hand–foot–skin reaction (16.6%), nausea (10.3%), and fatigue (11.2%) occurring most frequently.

Conclusions: Sorafenib treatment was shown to be effective in a real-life setting, in agreement with previously reported clinical trial data. The therapy was found to have an acceptable safety profile, with predominantly mild to moderate side effects. Clin Cancer Res; 23(19); 5720–8. ©2017 AACR.

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Neratinib Efficacy and Circulating Tumor DNA Detection of HER2 Mutations in HER2 Nonamplified Metastatic Breast Cancer

Purpose: Based on promising preclinical data, we conducted a single-arm phase II trial to assess the clinical benefit rate (CBR) of neratinib, defined as complete/partial response (CR/PR) or stable disease (SD) ≥24 weeks, in HER2^mut nonamplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2^mut detection.

Experimental Design: Tumor tissue positive for HER2^mut was required for eligibility. Neratinib was administered 240 mg daily with prophylactic loperamide. ctDNA sequencing was performed retrospectively for 54 patients (14 positive and 40 negative for tumor HER2^mut).

Results: Nine of 381 tumors (2.4%) sequenced centrally harbored HER2^mut (lobular 7.8% vs. ductal 1.6%; P = 0.026). Thirteen additional HER2^mut cases were identified locally. Twenty-one of these 22 HER2^mut cases were estrogen receptor positive. Sixteen patients [median age 58 (31–74) years and three (2–10) prior metastatic regimens] received neratinib. The CBR was 31% [90% confidence interval (CI), 13%–55%], including one CR, one PR, and three SD ≥24 weeks. Median PFS was 16 (90% CI, 8–31) weeks. Diarrhea (grade 2, 44%; grade 3, 25%) was the most common adverse event. Baseline ctDNA sequencing identified the same HER2^mut in 11 of 14 tumor-positive cases (sensitivity, 79%; 90% CI, 53%–94%) and correctly assigned 32 of 32 informative negative cases (specificity, 100%; 90% CI, 91%–100%). In addition, ctDNA HER2^mut variant allele frequency decreased in nine of 11 paired samples at week 4, followed by an increase upon progression.

Conclusions: Neratinib is active in HER2^mut, nonamplified MBC. ctDNA sequencing offers a noninvasive strategy to identify patients with HER2^mut cancers for clinical trial participation. Clin Cancer Res; 23(19); 5687–95. ©2017 AACR.

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Tumor Response Dynamics of Advanced Non-small Cell Lung Cancer Patients Treated with PD-1 Inhibitors: Imaging Markers for Treatment Outcome

Purpose: We evaluated tumor burden dynamics in patients with advanced non–small cell lung cancer (NSCLC) treated with commercial PD-1 inhibitors to identify imaging markers associated with improved overall survival (OS).

Experimental Design: The study included 160 patients with advanced NSCLC treated with commercial nivolumab or pembrolizumab monotherapy as a part of clinical care. Tumor burden dynamics were studied for the association with OS.

Results: Tumor burden change at best overall response (BOR) ranged from –100% to +278% (median, +3.5%). Response rate (RR) was 18% (29/160). Current and former smokers had a higher RR than never smokers (P = 0.04). Durable disease control for at least 6 months was noted in 26 patients (16%), which included 10 patients with stable disease as BOR. Using a landmark analysis, patients with <20% tumor burden increase from baseline within 8 weeks of therapy had longer OS than patients with ≥20% increase (median OS, 12.4 vs. 4.6 months, P < 0.001). Patients with <20% tumor burden increase throughout therapy had significantly reduced hazards of death (HR, 0.24; Cox P < 0.0001) after adjusting for smoking (HR, 0.86; P = 0.61) and baseline tumor burden (HR, 1.55; P = 0.062), even though some patients met criteria for RECIST progression while on therapy. One patient (0.6%) had atypical response pattern consistent with pseudoprogression.

Conclusions: Objective response or durable disease control was noted in 24% of patients with advanced NSCLC treated with commercial PD-1 inhibitors. A tumor burden increase of <20% from baseline during therapy was associated with longer OS, proposing a practical marker of treatment benefit. Pseudoprogression is rare in NSCLCs treated with PD-1 inhibitors. Clin Cancer Res; 23(19); 5737–44. ©2017 AACR.

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Phase I Trial of Intravenous Oncolytic Vaccinia Virus (GL-ONC1) with Cisplatin and Radiotherapy in Patients with Locoregionally Advanced Head and Neck Carcinoma

Purpose: Preclinical models have shown that the effectiveness of GL-ONC1, a modified oncolytic vaccinia virus, is enhanced by radiation and chemotherapy. The purpose of this study was to determine the safety of GL-ONC1 when delivered intravenously with chemoradiotherapy to patients with primary, nonmetastatic head and neck cancer.

Experimental Design: Patients with locoregionally advanced unresected, nonmetastatic carcinoma of the head/neck, excluding stage III–IVA p16-positive oropharyngeal cancers, were treated with escalating doses and cycles of intravenous GL-ONC1, along with radiotherapy and chemotherapy. The primary aims were to define the MTD and dose-limiting toxicities, and to recommend a dose for phase II trials.

Results: Between May 2012 and December 2014, 19 patients were enrolled. The most frequent adverse reactions included grade 1–2 rigors, fever, fatigue, and rash. Grade 3 adverse reactions included hypotension, mucositis, nausea, and vomiting. In 2 patients, the rash was confirmed as viral in origin by fluorescence imaging and viral plaque assay. In 4 patients, viral presence in tumor was confirmed on midtreatment biopsy by quantitative PCR. In 1 patient, live virus was confirmed in a tongue tumor 7 days after receiving the first dose of virus. The MTD was not reached. With median follow-up of 30 months, 1-year (2-year) progression-free survival and overall survival were 74.4% (64.1%) and 84.6% (69.2%), respectively.

Conclusions: Delivery of GL-ONC1 is safe and feasible in patients with locoregionally advanced head/neck cancer undergoing standard chemoradiotherapy. A phase II study is warranted to further investigate this novel treatment strategy. Clin Cancer Res; 23(19); 5696–702. ©2017 AACR.

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Clinical and Genome-Wide Analysis of Cisplatin-Induced Peripheral Neuropathy in Survivors of Adult-Onset Cancer

Purpose: Our purpose was to characterize the clinical influences, genetic risk factors, and gene mechanisms contributing to persistent cisplatin-induced peripheral neuropathy (CisIPN) in testicular cancer survivors (TCSs).

Experimental Design: TCS given cisplatin-based therapy completed the validated EORTC QLQ-CIPN20 questionnaire. An ordinal CisIPN phenotype was derived, and associations with age, smoking, excess drinking, hypertension, body mass index, diabetes, hypercholesterolemia, cumulative cisplatin dose, and self-reported health were examined for 680 TCS. Genotyping was performed on the Illumina HumanOmniExpressExome chip. Following quality control and imputation, 5.1 million SNPs in 680 genetically European TCS formed the input set. GWAS and PrediXcan were used to identify genetic variation and genetically determined gene expression traits, respectively, contributing to CisIPN. We evaluated two independent datasets for replication: Vanderbilt's electronic health database (BioVU) and the CALGB 90401 trial.

Results: Eight sensory items formed a subscale with good internal consistency (Cronbach α = 0.88). Variables significantly associated with CisIPN included age at diagnosis (OR per year, 1.06; P = 2 x 10^–9), smoking (OR, 1.54; P = 0.004), excess drinking (OR, 1.83; P = 0.007), and hypertension (OR, 1.61; P = 0.03). CisIPN was correlated with lower self-reported health (OR, 0.56; P = 2.6 x 10^–9) and weight gain adjusted for years since treatment (OR per kg/m², 1.05; P = 0.004). PrediXcan identified lower expressions of MIDN and RPRD1B, and higher THEM5 expression as associated with CisIPN (P value for each < 5 x 10^–6) with replication of RPRD1B meeting significance criteria (Fisher combined P = 0.0089).

Conclusions: CisIPN is associated with age, modifiable risk factors, and genetically determined expression level of RPRD1B. Further study of implicated genes could elucidate the pathophysiologic underpinnings of CisIPN. Clin Cancer Res; 23(19); 5757–68. ©2017 AACR.

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First-in-Human Study of AMG 820, a Monoclonal Anti-Colony-Stimulating Factor 1 Receptor Antibody, in Patients with Advanced Solid Tumors

Purpose: Binding of colony-stimulating factor 1 (CSF1) ligand to the CSF1 receptor (CSF1R) regulates survival of tumor-associated macrophages, which generally promote an immunosuppressive tumor microenvironment. AMG 820 is an investigational, fully human CSF1R antibody that inhibits binding of the ligands CSF1 and IL34 and subsequent ligand-mediated receptor activation. This first-in-human phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of AMG 820.

Experimental Design: Adult patients with relapsed or refractory advanced solid tumors received intravenous AMG 820 0.5 mg/kg once weekly or 1.5 to 20 mg/kg every 2 weeks until disease progression, adverse event (AE), or consent withdrawal.

Results: Twenty-five patients received ≥1 dose of AMG 820. AMG 820 was tolerated up to 20 mg/kg; the MTD was not reached. One dose-limiting toxicity was observed (20 mg/kg; nonreversible grade 3 deafness). Most patients (76%) had treatment-related AEs; the most common were periorbital edema (44%), increased aspartate aminotransferase (AST; 28%), fatigue (24%), nausea (16%), increased blood alkaline phosphatase (12%), and blurred vision (12%). No patients had serious or fatal treatment-related AEs; 28% had grade ≥3 treatment-related AEs. Grade 3 AST elevations resolved when treatment was withheld. AMG 820 showed linear pharmacokinetics, with minimal accumulation (<2-fold) after repeated dosing. Pharmacodynamic increases in serum CSF1 concentrations and reduced numbers of skin macrophages were observed. Best response was stable disease in 8 patients (32%).

Conclusions: AMG 820 was tolerated with manageable toxicities up to 20 mg/kg every 2 weeks. Pharmacodynamic response was demonstrated, and limited antitumor activity was observed. Clin Cancer Res; 23(19); 5703–10. ©2017 AACR.

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PD-1+ Polyfunctional T Cells Dominate the Periphery after Tumor-Infiltrating Lymphocyte Therapy for Cancer

Purpose: Infusion of highly heterogeneous populations of autologous tumor-infiltrating lymphocytes (TIL) can result in tumor regression of exceptional duration. Initial tumor regression has been associated with persistence of tumor-specific TILs 1 month after infusion, but mechanisms leading to long-lived memory responses are currently unknown. Here, we studied the dynamics of bulk tumor-reactive CD8⁺ T-cell populations in patients with metastatic melanoma following treatment with TILs.

Experimental Design: We analyzed the function and phenotype of tumor-reactive CD8⁺ T cells contained in serial blood samples of 16 patients treated with TILs.

Results: Polyfunctional tumor-reactive CD8⁺ T cells accumulated over time in the peripheral lymphocyte pool. Combinatorial analysis of multiple surface markers (CD57, CD27, CD45RO, PD-1, and LAG-3) showed a unique differentiation pattern of polyfunctional tumor-reactive CD8⁺ T cells, with highly specific PD-1 upregulation early after infusion. The differentiation and functional status appeared largely stable for up to 1 year after infusion. Despite some degree of clonal diversification occurring in vivo within the bulk tumor-reactive CD8⁺ T cells, further analyses showed that CD8⁺ T cells specific for defined tumor antigens had similar differentiation status.

Conclusions: We demonstrated that tumor-reactive CD8⁺ T-cell subsets that persist after TIL therapy are mostly polyfunctional, display a stable partially differentiated phenotype, and express high levels of PD-1. These partially differentiated PD-1⁺ polyfunctional TILs have a high capacity for persistence and may be susceptible to PD-L1/PD-L2–mediated inhibition. Clin Cancer Res; 23(19); 5779–88. ©2017 AACR.

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Inhibition of CDK4/6 by Palbociclib Significantly Extends Survival in Medulloblastoma Patient-Derived Xenograft Mouse Models

Purpose: Bioinformatics analysis followed by in vivo studies in patient-derived xenograft (PDX) models were used to identify and validate CDK 4/6 inhibition as an effective therapeutic strategy for medulloblastoma, particularly group 3 MYC-amplified tumors that have the worst clinical prognosis.

Experimental Design: A protein interaction network derived from a Sleeping Beauty mutagenesis model of medulloblastoma was used to identify potential novel therapeutic targets. The top hit from this analysis was validated in vivo using PDX models of medulloblastoma implanted subcutaneously in the flank and orthotopically in the cerebellum of mice.

Results: Informatics analysis identified the CDK4/6/CYCLIN D/RB pathway as a novel "druggable" pathway for multiple subgroups of medulloblastoma. Palbociclib, a highly specific inhibitor of CDK4/6, was found to inhibit RB phosphorylation and cause G₁ arrest in PDX models of medulloblastoma. The drug caused rapid regression of Sonic hedgehog (SHH) and MYC-amplified group 3 medulloblastoma subcutaneous tumors and provided a highly significant survival advantage to mice bearing MYC-amplified intracranial tumors.

Conclusions: Inhibition of CDK4/6 is potentially a highly effective strategy for the treatment of SHH and MYC-amplified group 3 medulloblastoma. Clin Cancer Res; 23(19); 5802–13. ©2017 AACR.

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Explaining the Obesity Paradox--Response

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A Prospective Study of Chronic Inflammation in Benign Prostate Tissue and Risk of Prostate Cancer: Linked PCPT and SELECT Cohorts

Background: We leveraged two trials to test the hypothesis of an inflammation–prostate cancer link prospectively in men without indication for biopsy.

Methods: Prostate Cancer Prevention Trial (PCPT) participants who had an end-of-study biopsy performed per protocol that was negative for cancer and who subsequently enrolled in the Selenium and Vitamin E Cancer Prevention Trial (SELECT) were eligible. We selected all 100 cases and sampled 200 frequency-matched controls and used PCPT end-of-study biopsies as "baseline." Five men with PSA > 4 ng/mL at end-of-study biopsy were excluded. Tissue was located for 92 cases and 193 controls. We visually assessed inflammation in benign tissue. We estimated ORs and 95% confidence intervals (CI) using logistic regression adjusting for age and race.

Results: Mean time between biopsy and diagnosis was 5.9 years. In men previously in the PCPT placebo arm, 78.1% of cases (N = 41) and 68.2% of controls (N = 85) had at least one baseline biopsy core (~5 evaluated per man) with inflammation. The odds of prostate cancer (N = 41 cases) appeared to increase with increasing mean percentage of tissue area with inflammation, a trend that was statistically significant for Gleason sum <4+3 disease (N = 31 cases; vs. 0%, >0–<1.8% OR = 1.70, 1.8–<5.0% OR = 2.39, ≥5% OR = 3.31, P_trend = 0.047). In men previously in the finasteride arm, prevalence of inflammation did not differ between cases (76.5%; N = 51) and controls (75.0%; N = 108).

Conclusions: Benign tissue inflammation was positively associated with prostate cancer.

Impact: This first prospective study of men without biopsy indication supports the hypothesis that inflammation influences prostate cancer development. Cancer Epidemiol Biomarkers Prev; 26(10); 1549–57. ©2017 AACR.

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Associations of Coffee Drinking and Cancer Mortality in the Cancer Prevention Study-II

Background: Associations of coffee consumption with cancer mortality are inconsistent for many types of cancer, and confounding by smoking is an important concern.

Methods: Cox proportional hazards regression was used to estimate multivariable-adjusted HRs for coffee consumption associated with death from all cancers combined and from specific cancer types among 922,896 Cancer Prevention Study-II participants ages 28–94 years who completed a four-page questionnaire and were cancer free at baseline in 1982.

Results: During follow-up through 2012, there were 118,738 cancer-related deaths. There was a nonlinear association between coffee consumption and all-cancer death among current smokers and former smokers and no association among never smokers. Among nonsmokers, a 2 cup/day increase in coffee consumption was inversely associated with death from colorectal [HR = 0.97; 95% confidence interval (CI) 0.95–0.99], liver [HR = 0.92; 95% CI, 0.88–0.96], and female breast (HR = 0.97; 95% CI, 0.94–0.99) cancers, and positively associated with esophageal cancer–related death (HR = 1.07; 95% CI, 1.02–1.12). For head and neck cancer, a nonlinear inverse association was observed starting at 2–3 cups per day (HR = 0.72; 95% CI, 0.55–0.95), with similar associations observed at higher levels of consumption.

Conclusions: These findings are consistent with many other studies that suggest coffee drinking is associated with a lower risk of colorectal, liver, female breast, and head and neck cancer. The association of coffee consumption with higher risk of esophageal cancer among nonsmokers in our study should be confirmed.

Impact: These results underscore the importance of assessing associations between coffee consumption and cancer mortality by smoking status. Cancer Epidemiol Biomarkers Prev; 26(10); 1477–86. ©2017 AACR.

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Novel Gene and Network Associations Found for Acute Lymphoblastic Leukemia Using Case-Control and Family-Based Studies in Multiethnic Populations

Background: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, suggesting that germline variants influence ALL risk. Although multiple genome-wide association (GWA) studies have identified variants predisposing children to ALL, it remains unclear whether genetic heterogeneity affects ALL susceptibility and how interactions within and among genes containing ALL-associated variants influence ALL risk.

Methods: Here, we jointly analyzed two published datasets of case–control GWA summary statistics along with germline data from ALL case–parent trios. We used the gene-level association method PEGASUS to identify genes with multiple variants associated with ALL. We then used PEGASUS gene scores as input to the network analysis algorithm HotNet2 to characterize the genomic architecture of ALL.

Results: Using PEGASUS, we confirmed associations previously observed at genes such as ARID5B, IKZF1, CDKN2A/2B, and PIP4K2A, and we identified novel candidate gene associations. Using HotNet2, we uncovered significant gene subnetworks that may underlie inherited ALL risk: a subnetwork involved in B-cell differentiation containing the ALL-associated gene CEBPE, and a subnetwork of homeobox genes, including MEIS1.

Conclusions: Gene and network analysis uncovered loci associated with ALL that are missed by GWA studies, such as MEIS1. Furthermore, ALL-associated loci do not appear to interact directly with each other to influence ALL risk, and instead appear to influence leukemogenesis through multiple, complex pathways.

Impact: We present a new pipeline for post hoc analysis of association studies that yields new insight into the etiology of ALL and can be applied in future studies to shed light on the genomic underpinnings of cancer. Cancer Epidemiol Biomarkers Prev; 26(10); 1531–9. ©2017 AACR.

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The Association of Mammographic Density and Molecular Breast Cancer Subtype

Background: Mammographic density (MD) is associated with increased breast cancer risk, yet limited data exist on an association between MD and breast cancer molecular subtypes.

Methods: Women ages 18 years and older with breast cancer and available mammograms between 2003 and 2012 were enrolled in a larger study on MD. MD was classified by the Breast Imaging Reporting and Data System (BI-RADS) classification and by volumetric breast percent density (Volpara Solutions). Subtype was assigned by hormone receptor status, tumor grade, and mitotic score (MS). Subtypes included: Luminal-A (ER/PR⁺ and grade = 1; ER/PR⁺ and grade = 2 and MS = 1; ER⁺/PR^– and grade = 1; n = 233); Luminal-B (ER⁺ and grade = 3 or MS = 3; ER⁺/PR^– and grade = 2; ER/PR⁺ and grade = 2 and MS = 2; n = 79); Her-2-neu⁺ (H2P; n = 59); triple-negative (ER/PR^–, Her-2^–; n = 86). Precancer factors including age, race, body mass index (kg/m²), family history of breast cancer, and history of lobular carcinoma in situ were analyzed.

Results: A total of 604 patients had invasive cancer; 457 had sufficient information for analysis. Women with H2P tumors were younger (P = 0.011) and had the highest volumetric percent density (P = 0.002) among subgroups. Multinomial logistic regression (LA = reference) demonstrated that although quantitative MD does not significantly differentiate between all subtypes (P = 0.123), the association between MD and H2P tumors is significant (OR = 1.06; confidence interval, 1.01–1.12). This association was not seen using BI-RADS classification in bivariable analysis but was statistically significant (P = 0.047) when controlling for other precancer factors.

Conclusions: Increased MD is more strongly associated with H2P tumors when compared with LA.

Impact: Delineating risk factors specific to breast cancer subtype may promote development of individualized risk prediction models and screening strategies. Cancer Epidemiol Biomarkers Prev; 26(10); 1487–92. ©2017 AACR.

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The Prevalence of Cancer-Associated Autoantibodies in Patients with Gastric Cancer and Progressive Grades of Premalignant Lesions

Background: Serum autoantibodies against tumor-associated antigens (TAAs) are detectable in early-stage gastric cancer patients; however, the time point during cancerogenesis when they appear in circulation is still obscure.

Methods: In this study, we developed a recombinant antigen microarray and analyzed the prevalence of autoantibodies against 102 TAAs in 829 gastric cancer patients and 929 healthy controls from Caucasian and Asian populations, as well as 100 patients with chronic atrophic gastritis and 775 individuals staged according to different grades of intestinal metaplasia.

Results: Six antigens, including CTAG1B/CTAG2, DDX53, IGF2BP2, TP53, and MAGEA3, were predominantly reacting with sera from gastric cancer patients when compared with healthy controls, and the seroreactivity was associated with intestinal-type gastric cancer, but not with patients' Helicobacter pylori status, grade, age, gender, or stage of gastric cancer. We detected gastric cancer–associated seroreactivity in 13% of patients with advanced/severe intestinal metaplasia, which was increased in comparison with mild/moderate intestinal metaplasia (5.3%) and was comparable with that seen in early-stage gastric cancer patients (12%). Moreover, by testing serum samples taken 1 to 9 years before the clinical diagnosis of 18 incident gastric cancer cases, we detected autoantibody responses against several TAAs—SOX2, MYC, BIRC5, IGF2BP1, and MUC1.

Conclusions: Our results suggest that humoral immune response against TAAs is generated already during premalignant stages.

Impact: Based on the obtained results, cancer-associated autoantibodies might make a valuable contribution to the stratification of high-risk patients with premalignant lesions in the stomach through enhancing the positive predictive power of existing risk models. Cancer Epidemiol Biomarkers Prev; 26(10); 1564–74. ©2017 AACR.

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Cervical Cancer Screening among Women from Muslim-Majority Countries in Ontario, Canada

Background: Immigrant women are less likely to be screened for cervical cancer in Ontario. Religion may play a role for some women. In this population-based retrospective cohort study, we used country of birth as a proxy for religious affiliation and examined screening uptake among foreign-born women from Muslim-majority versus other countries, stratified by region of origin.

Methods: We linked provincial databases and identified all women eligible for cervical cancer screening between April 1, 2012, and March 31, 2015. Women were classified into regions based on country of birth. Countries were classified as Muslim-majority or not.

Results: Being born in a Muslim-majority country was significantly associated with lower likelihood of being up-to-date on Pap testing, after adjustment for region of origin, neighborhood income, and primary care–related factors [adjusted relative risk (ARR), 0.93; 95% (confidence interval) CI, 0.92–0.93]. Sub-Saharan African women from Muslim-majority countries had the highest prevalence of being overdue (59.6%), and the lowest ARR for screening when compared with women from non–Muslim-majority Sub-Saharan African countries (ARR, 0.77; 95% CI, 0.76–0.79). ARRs were lowest for women with no primary care versus those in a capitation-based model (ARR, 0.28; 95% CI, 0.27–0.29 overall).

Conclusions: We have shown that being born in a Muslim-majority country is associated with a decreased likelihood of being up-to-date on cervical screening in Ontario and that access to primary care has a sizeable impact on screening uptake.

Impact: Screening efforts need to take into account the background characteristics of population subgroups and to focus on increasing primary care access for all. Cancer Epidemiol Biomarkers Prev; 26(10); 1493–9. ©2017 AACR.

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Highlights of This Issue

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The Cost-Effectiveness of Visual Triage of Human Papillomavirus-Positive Women in Three Low- and Middle-Income Countries

Background: World Health Organization guidelines support human papillomavirus (HPV) testing alone (followed by treatment with cryotherapy) or in conjunction with visual inspection with acetic acid (VIA) triage testing. Our objective was to determine the cost-effectiveness of VIA triage for HPV-positive women in low-resource settings.

Methods: We calibrated mathematical simulation models of HPV infection and cervical cancer to epidemiologic data from India, Nicaragua, and Uganda. Using cost and test performance data from the START-UP demonstration projects, we assumed screening took place either once or three times in a lifetime between ages 30 and 40 years. Strategies included (i) HPV alone, followed by cryotherapy for all eligible HPV-positive women; and (ii) HPV testing with VIA triage for HPV-positive women, followed by cryotherapy for eligible women who were also VIA-positive (HPV-VIA). Model outcomes included lifetime risk of cervical cancer and incremental cost-effectiveness ratios (ICERs; international dollars/year of life saved).

Results: In all three countries, HPV alone was more effective than HPV-VIA. In Nicaragua and Uganda, HPV alone was also less costly than HPV-VIA; ICERs associated with screening three times in a lifetime (HPV alone) were below per capita GDP. In India, both HPV alone and HPV-VIA had ICERs below per capita GDP.

Conclusions: VIA triage of HPV-positive women is not likely to be cost-effective in settings with high cervical cancer burden. HPV alone followed by treatment may achieve greater health benefits and value for public health dollars.

Impact: This study provides early evidence on the cost-effectiveness of HPV testing followed by VIA triage versus an HPV screen-and-treat strategy. Cancer Epidemiol Biomarkers Prev; 26(10); 1500–10. ©2017 AACR.

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Impact of Sixteen Established Pancreatic Cancer Susceptibility Loci in American Jews

Background: The higher risk of pancreatic cancer in Ashkenazi Jews compared with non-Jews is only partially explained by the increased frequency of BRCA1 and BRCA2 mutations in Ashkenazi Jews.

Methods: We evaluated the impact of 16 established pancreatic cancer susceptibility loci in a case–control sample of American Jews, largely Ashkenazi, including 406 full-Jewish pancreatic cancer patients and 2,332 full-Jewish controls, genotyped as part of the Pancreatic Cancer Cohort and Case–Control Consortium I/II (PanScan I/II), Pancreatic Cancer Case-Control Consortium (PanC4), and Resource for Genetic Epidemiology Research on Adult Health and Aging (GERA) datasets. We compared risk in full-Jewish subjects with risk in part-Jewish; non-Jewish Southern European; and in the combined non-Jewish Eastern, Northern, Southern, and Western European (non-Jewish white European) subjects from the same datasets. Jewish ancestries were genetically identified using seeded Fast principal component analysis. Data were analyzed by unconditional logistic regression, and adjusted for age, sex, and principal components.

Results: One SNP on chromosome 13q22.1 (rs9543325; OR, 1.36; 95% confidence interval, 1.16–1.58; P = 10^–4.1) was significant in full-Jews. Individual ORs and minor allele frequencies were similar between Jewish and non-Jewish white European subjects. The average ORs across the 16 pancreatic cancer susceptibility loci for full-Jewish, full- plus part-Jewish, non-Jewish Southern European, and non-Jewish white European subjects were 1.25, 1.30, 1.31, and 1.26, respectively.

Conclusions: The 16 pancreatic cancer susceptibility loci similarly impact Jewish and non-Jewish white European subjects, both individually and as summary odds.

Impact: These 16 pancreatic cancer susceptibility loci likely do not explain the higher risk seen in Ashkenazi Jews. Cancer Epidemiol Biomarkers Prev; 26(10); 1540–8. ©2017 AACR.

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Recent Trends in Ovarian Cancer Incidence and Relative Survival in the United States by Race/Ethnicity and Histologic Subtypes

Background: Incidence and survival rates of nonserous epithelial ovarian cancer in racial/ethnic minorities remain relatively unknown in the United States. We examined the trends in incidence and survival rates for epithelial ovarian cancer by histologic subtypes and race/ethnicity.

Methods: Ovarian cancer incidence and mortality data from 2000 to 2013 were obtained from the Surveillance, Epidemiology, and End Results database. Age-adjusted incidence rate, incidence rate ratio, and annual percentage changes (APC) were calculated by histology and race/ethnicity subgroups and stratified by age at diagnosis. Five-year relative survival rates were calculated by stage and race/ethnicity.

Results: A small but significant decrease in incidence rates was seen in non-Hispanic white (NHW), non-Hispanic black (NHB), and Hispanic women (APC –1.58, –0.84, and –1.31, respectively), while incidence rates remained relatively stable in Asian women (APC –0.37). With exception of significant increase in the incidence rate of clear cell carcinoma among Asian woman (APC 1.85), an overall trend toward decreasing incidence rates was seen across histologic subtypes and age-strata, although not all results were statistically significant. Compared with NHW women, NHB women experienced poorer 5-year survival at every stage across histologic subtypes, while Hispanic and Asian women had equivalent or better survival.

Conclusions: Over the last decade, incidence rates of epithelial ovarian cancer in the United States have decreased or remained stable across race/ethnic and histologic subgroups, except for clear cell carcinoma. Survival remains poorest among NHB women.

Impact: Comparative histologic subtype distribution and incidence trends do not explain the ovarian cancer survival disparity disproportionately affecting NHB women. Cancer Epidemiol Biomarkers Prev; 26(10); 1511–8. ©2017 AACR.

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Mediating Effect of Postsurgical Chemotherapy on Presence of Dementia and Survival among Patients 65 and Older with Stage III Colon Cancer

Introduction: Both colon cancer and dementia are prevalent among the elderly and have a high risk of cooccurrence. Previous studies found that patients with dementia were treated less aggressively. In this study, we hypothesized that presence of preexisting dementia was associated with worse survival for stage III colon cancer patients, and that postoperative chemotherapy was on the causal pathway.

Methods: We defined preexisting dementia in Surveillance Epidemiology and End Results Medicare data through either a formal diagnosis or a prescription for dementia drugs or both before the diagnosis of cancer. We applied multivariable Cox regression to estimate the effect of preexisting dementia on survival, adjusting for demographic factors, tumor characteristics, and receipt of chemotherapy. We assessed mediating effects in the context of the counterfactual framework using the accelerated failure time model.

Results: There were 4,573 patients diagnosed with stage III colon cancer between 2007 and 2009 identified. A preexisting diagnosis of dementia significantly increased the risk of death by 45% (HR = 1.45, 95% CI: 1.29–1.63). Patients with either a formal diagnosis of dementia or a related prescription had significantly lower cause-specific survival than their cognitively healthy counterparts. Receipt of chemotherapy was a significant mediator on the causal pathway. The effect of presence of dementia was mediated by receipt of chemotherapy by 13% for preexisting dementia.

Conclusions: Preexisting dementia is significantly associated with worse survival for stage III colon cancer patients, and its deleterious effect is partially explained by decreased likelihood of postoperative chemotherapy receipt.

Impact: This is the first study that provides estimate of the mediating effect of diminished chemotherapy in patients with stage III colon cancer and dementia, simultaneously demonstrating the cancer-specific survival benefit of chemotherapy in the presence of dementia. Cancer Epidemiol Biomarkers Prev; 26(10); 1558–63. ©2017 AACR.

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Serum Insulin, Glucose, Indices of Insulin Resistance, and Risk of Lung Cancer

Background: Although insulin may increase the risk of some cancers, few studies have examined fasting serum insulin and lung cancer risk.

Methods: We examined serum insulin, glucose, and indices of insulin resistance [insulin:glucose molar ratio and homeostasis model assessment of insulin resistance (HOMA-IR)] and lung cancer risk using a case-cohort study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish men. A total of 196 cases and 395 subcohort members were included. Insulin and glucose were measured in fasting serum collected 5 to 12 years before diagnosis. Cox proportional hazards models were utilized to estimate the relative risk of lung cancer.

Results: The average time between blood collection and lung cancer was 9.6 years. Fasting serum insulin levels were 8.7% higher in subcohort members than cases. After multivariable adjustment, men in the fourth quartile of insulin had a significantly higher risk of lung cancer than those in the first quartile [HR = 2.10; 95% confidence interval (CI), 1.12–3.94]. A similar relationship was seen with HOMA-IR (HR = 1.83; 95% CI, 0.99–3.38). Risk was not strongly associated with glucose or the insulin:glucose molar ratio (P_trend = 0.55 and P_trend = 0.27, respectively).

Conclusions: Higher fasting serum insulin concentrations, as well as the presence of insulin resistance, appear to be associated with an elevated risk of lung cancer development.

Impact: Although insulin is hypothesized to increase risk of some cancers, insulin and lung cancer remain understudied. Higher insulin levels and insulin resistance were associated with increased lung cancer risk. Although smoking cessation is the best method of lung cancer prevention, other lifestyle changes that affect insulin concentrations and sensitivity may reduce lung cancer risk. Cancer Epidemiol Biomarkers Prev; 26(10); 1519–24. ©2017 AACR.

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Explaining the Obesity Paradox--Letter

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Tobacco Product Use Patterns, and Nicotine and Tobacco-Specific Nitrosamine Exposure: NHANES 1999-2012

Background: Few studies have examined differences in product consumption patterns and nicotine and tobacco-specific nitrosamines (TSNA) exposure between single versus dual- and poly-tobacco users. We applied the Tobacco Product Use Patterns (T-PUPs) model to fill this gap in the literature.

Methods: Data from adults (age ≥18 years) who used any tobacco products during the 5 days prior to participating in the 1999–2012 National Health and Nutrition Examination Survey (NHANES) were analyzed. Participants were classified into seven T-PUPs: (1) cigarettes only, (2) noncigarette combustibles only, (3) noncombustibles only, (4) dual noncigarette combustibles and noncombustibles, (5) dual cigarettes and noncombustibles, (6) dual cigarettes and noncigarette combustibles, and (7) poly-tobacco use. Weighted regression models were used to compare product consumption, serum cotinine, and urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (i.e., NNAL) levels between single-, dual-, and poly-tobacco T-PUPs.

Results: Dual- and poly-tobacco T-PUPs were associated with lower product consumption compared with single-product T-PUPs only in some cases (e.g., dual cigarette and noncombustible users smoked cigarettes on 0.6 fewer days in the past 5 days compared with cigarette-only users; P < 0.05). Dual- and poly-tobacco T-PUPs had either nondistinguishable or higher levels of serum cotinine and urinary total NNAL than corresponding single-product T-PUPs.

Conclusions: Product consumption, and nicotine and TSNAs exposure of dual- and poly-tobacco product category users somewhat differ from those of single-product category users as defined by the T-TUPs model.

Impact: Higher levels of cotinine and NNAL among dual- and poly-tobacco T-TUPs users compared with the single-product T-TUPs users may indicate health concerns. Cancer Epidemiol Biomarkers Prev; 26(10); 1525–30. ©2017 AACR.

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Cigarette Prices and Smoking Cessation--Letter

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EGFR Downregulation after Anti-EGFR Therapy Predicts the Antitumor Effect in Colorectal Cancer

Anti-EGFR mAb is reported to induce EGFR internalization in colorectal cancer cells. However, the biological relevance of EGFR internalization with anti-EGFR mAb is unknown. Therefore, the relevance of EGFR downregulation with anti-EGFR mAb to antitumor activity in colorectal cancer cells was investigated. Quantification of EGFR on the cell surface before cetuximab treatment was assessed by flow cytometry, and its growth-inhibitory effects were measured by Trypan blue exclusion, in 10 RAS, BRAF wild-type colorectal cancer cell lines, but there was no significant correlation between EGFR number and its growth-inhibitory effect. However, a significant correlation existed between the percentage decrease in the number of EGFRs after cetuximab treatment and its growth-inhibitory effect in those cell lines. Treatment with TGFα, a ligand for EGFR, induced EGFR internalization in colorectal cancer cells, but most EGFRs subsequently recycled to the cell surface, consistent with previous studies. While cetuximab treatment induced EGFR internalization, most receptors subsequently translocated into the late endosome, leading to lysosomal degradation, as revealed by immunoblotting and double immunofluorescence. Cetuximab-sensitive colorectal cancer cells showed greater EGFR internalization, stronger cell growth inhibition, and more augmented apoptotic signals than nonsensitive cells. IHC for EGFR, performed using an EGFR pharmDx Kit (mouse anti-human EGFR mAb clone 2-18C9), in clinical specimens before and after anti-EGFR mAb therapy in 13 colorectal cancer patients showed a significant correlation between the response to anti-EGFR mAb and decreased staining after therapy.

Implications: This report clearly demonstrates that anti-EGFR mAb facilitates internalization and subsequent degradation of EGFRs in lysosomes, which is an important determinant of the efficacy of anti-EGFR mAb treatment for colorectal cancer. Mol Cancer Res; 15(10); 1445–54. ©2017 AACR.

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p120-Catenin Downregulation and PIK3CA Mutations Cooperate to Induce Invasion through MMP1 in HNSCC

Despite recent improvements in treatment for head and neck squamous cell carcinoma (HNSCC), half of all patients with a regional or advanced disease will die within 5 years from diagnosis. Therefore, identification of mechanisms driving the aggressive behavior of HNSCC is of utmost importance. Because p120-catenin (CTNND1/P120CTN) downregulation and PIK3CA mutations are commonly found in HNSCC, the objective of this study was to identify their impact on fundamental processes of metastasis, specifically, migration and invasion. Furthermore, this study aimed to identify the key effector proteins regulated by P120CTN downregulation and PIK3CA mutations. Studies using oral keratinocytes demonstrated that P120CTN downregulation and PIK3CA mutations increased migration and invasion. In addition, P120CTN downregulation and PIK3CA mutations resulted in elevated matrix metallopeptidase 1 (MMP1) levels. Inhibition of MMP1 resulted in decreased invasion, suggesting that MMP1 plays a critical role in HNSCC invasion. Moreover, analysis of HNSCC patient specimens from The Cancer Genome Atlas confirmed these findings. Tumors with low P120CTN and PI3K pathway mutations have higher levels of MMP1 compared to tumors with high P120CTN and no PI3K pathway mutations. In conclusion, this study demonstrates that P120CTN downregulation and PIK3CA mutations promote MMP1-driven invasion, providing a potential novel target for limiting metastasis in HNSCC.

Implications: Because of its role in invasion, MMP1 represents a novel, potential target for limiting metastasis in a subset of HNSCCs with P120CTN downregulation and PIK3CA mutations. Mol Cancer Res; 15(10); 1398–409. ©2017 AACR.

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A Massively Parallel Fluorescence Assay to Characterize the Effects of Synonymous Mutations on TP53 Expression

Although synonymous mutations can affect gene expression, they have generally not been considered in genomic studies that focus on mutations that increase the risk of cancer. However, mounting evidence implicates some synonymous mutations as driver mutations in cancer. Here, a massively parallel assay, based on cell sorting of a reporter containing a segment of p53 fused to GFP, was used to measure the effects of nearly all synonymous mutations in exon 6 of TP53. In this reporter context, several mutations within the exon caused strong expression changes including mutations that may cause potential gain or loss of function. Further analysis indicates that these effects are largely attributed to errors in splicing, including exon skipping, intron inclusion, and exon truncation, resulting from mutations both at exon–intron junctions and within the body of the exon. These mutations are found at extremely low frequencies in healthy populations and are enriched a few-fold in cancer genomes, suggesting that some of them may be driver mutations in TP53. This assay provides a general framework to identify previously unknown detrimental synonymous mutations in cancer genes.

Implications: Using a massively parallel assay, this study demonstrates that synonymous mutations in the TP53 gene affect protein expression, largely through their impact on splicing.

Visual Overview: http://ift.tt/2fK53qp. Mol Cancer Res; 15(10); 1301–7. ©2017 AACR.

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Phostine PST3.1a Targets MGAT5 and Inhibits Glioblastoma-Initiating Cell Invasiveness and Proliferation

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor and accounts for a significant proportion of all primary brain tumors. Median survival after treatment is around 15 months. Remodeling of N-glycans by the N-acetylglucosamine glycosyltransferase (MGAT5) regulates tumoral development. Here, perturbation of MGAT5 enzymatic activity by the small-molecule inhibitor 3-hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl2-oxo-25-[1,2]oxaphosphinane (PST3.1a) restrains GBM growth. In cell-based assays, it is demonstrated that PST3.1a alters the β1,6-GlcNAc N-glycans of GBM-initiating cells (GIC) by inhibiting MGAT5 enzymatic activity, resulting in the inhibition of TGFβR and FAK signaling associated with doublecortin (DCX) upregulation and increase oligodendrocyte lineage transcription factor 2 (OLIG2) expression. PST3.1a thus affects microtubule and microfilament integrity of GBM stem cells, leading to the inhibition of GIC proliferation, migration, invasiveness, and clonogenic capacities. Orthotopic graft models of GIC revealed that PST3.1a treatment leads to a drastic reduction of invasive and proliferative capacity and to an increase in overall survival relative to standard temozolomide therapy. Finally, bioinformatics analyses exposed that PST3.1a cytotoxic activity is positively correlated with the expression of genes of the epithelial–mesenchymal transition (EMT), while the expression of mitochondrial genes correlated negatively with cell sensitivity to the compound. These data demonstrate the relevance of targeting MGAT5, with a novel anti-invasive chemotherapy, to limit glioblastoma stem cell invasion. Mol Cancer Res; 15(10); 1376–87. ©2017 AACR.

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On My Shelf: Patterns of Culture

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VariantValidator: Accurate validation, mapping and formatting of sequence variation descriptions

Abstract

The Human Genome Variation Society (HGVS) variant nomenclature is widely used to describe sequence variants in scientific publications, clinical reports and databases. However, the HGVS recommendations are complex and this often results in inaccurate variant descriptions being reported. The open-source hgvs Python package (http://ift.tt/2qVpipe) provides a programmatic interface for parsing, manipulating, formatting and validating of variants according to the HGVS recommendations, but does not provide a user-friendly web interface. We have developed a web-based variant validation tool, VariantValidator (http://ift.tt/2yDubml), which utilizes the hgvs Python package and provides additional functionality to assist users who wish to accurately describe and report sequence-level variations that are compliant with the HGVS recommendations. VariantValidator was designed to ensure that users are guided through the intricacies of the HGVS nomenclature, e.g. if the user makes a mistake, VariantValidator automatically corrects the mistake if it can, or provides helpful guidance if it cannot. In addition, VariantValidator has the facility to interconvert genomic variant descriptions in HGVS and Variant Call Format (VCF) with a degree of accuracy which surpasses most competing solutions.

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Mild phenotypes and proper supercomplex assembly in human cells carrying the homoplasmic m.15557G > A mutation in cytochrome b gene

Abstract

Respiratory complex III (CIII) is the first enzymatic bottleneck of the mitochondrial respiratory chain both in its native dimeric form and in supercomplexes. The mammalian CIII comprises 11 subunits among which cytochrome b is central in the catalytic core, where oxidation of ubiquinol occurs at the Qo site. The Qo- or PEWY-motif of cytochrome b is the most conserved through species. Importantly, the highly conserved glutamate at position 271 (Glu271) has never been studied in higher eukaryotes so far and its role in the Q-cycle remains debated. Here we showed that the homoplasmic m.15557G > A/MT-CYB, which causes the p.Glu271Lys amino acid substitution predicted to dramatically affect CIII, induces a mild mitochondrial dysfunction in human transmitochondrial cybrids. Indeed, we found that the severity of such mutation is mitigated by the proper assembly of CIII into supercomplexes, which may favor an optimal substrate channeling and buffer superoxide production in vitro.

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