OtoRhinoLaryngology News: 11/14/17

Τρίτη 14 Νοεμβρίου 2017

Erratum.

Erratum.

J Am Acad Audiol. 2017 Nov/Dec;28(10):961

Authors:

Abstract
[This corrects the article DOI: 10.3766/jaaa.15105.].

PMID: 29130444 [PubMed - in process]

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Unraveling the Mystery of Auditory Brainstem Response Corrections: The Need for Universal Standards.

Unraveling the Mystery of Auditory Brainstem Response Corrections: The Need for Universal Standards.

J Am Acad Audiol. 2017 Nov/Dec;28(10):950-960

Authors: Norrix LW, Velenovsky D

Abstract
BACKGROUND: The auditory brainstem response (ABR) is used to estimate behavioral hearing thresholds in infants and difficult-to-test populations. Differences between the toneburst ABR and behavioral thresholds exist making the correspondence between the two measures less than perfect. Some authors have suggested that corrections be applied to ABR thresholds to account for these differences. However, because there is no agreed upon universal standard, confusion regarding the use of corrections exists.
PURPOSE: The primary purpose of this article is to review the reasoning behind and use of corrections when the toneburst ABR is employed to estimate behavioral hearing thresholds. We also discuss other considerations that all audiologists should be aware of when obtaining and reporting ABR test results.
RESULTS: A review of the purpose and use of corrections reveals no consensus as to whether they should be applied or which should be used. Additionally, when ABR results are adjusted, there is no agreement as to whether additional corrections for hearing loss or the age of the client are necessary. This lack of consensus can be confusing for all individuals working with hearing-impaired children and their families.
CONCLUSIONS: Toneburst ABR thresholds do not perfectly align with behavioral hearing thresholds. Universal protocols for the use of corrections are needed. Additionally, evidence-based procedures must be employed to obtain valid ABRs that will accurately estimate hearing thresholds.

PMID: 29130443 [PubMed - in process]

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Outcomes of Hearing Aid Use by Individuals with Unilateral Sensorineural Hearing Loss (USNHL).

Outcomes of Hearing Aid Use by Individuals with Unilateral Sensorineural Hearing Loss (USNHL).

J Am Acad Audiol. 2017 Nov/Dec;28(10):941-949

Authors: Bishop CE, Hamadain E, Galster JA, Johnson MF, Spankovich C, Windmill I

Abstract
BACKGROUND: Unilateral sensorineural hearing loss (USNHL) can have a negative impact on functions associated with the advantages of balanced, binaural hearing. Although single-sided deafness, which is a complete loss of audibility in one ear, has gained increased interest in the published research, there is a gap in the literature concerning hearing aid outcomes for individuals with residual, or otherwise "aidable," hearing in the affected ear.
PURPOSE: To assess hearing aid outcomes for a group of individuals with USNHL with residual, aidable function.
RESEARCH DESIGN: A quasi-experimental study of hearing aid outcomes with paired comparisons made between unaided and aided test conditions.
STUDY SAMPLE: A convenience sample of twenty-two individuals with USNHL, with sufficient residual hearing in the affected ear as to receive audibility from use of a hearing aid, were recruited into the study from September 2011 to August 2012.
INTERVENTION: Each participant was fit with a digital behind-the-ear hearing aid coupled to a custom ear mold.
DATA COLLECTION AND ANALYSIS: Assessments were performed at baseline (unaided) and after a three-month field trial (aided) with primary outcomes involving objective measures in sound field yielding signal-to-noise ratio loss (SNR Loss) via the Quick Speech-in-Noise Test and word recognition scores (WRS) via the Northwestern University Auditory Test, No. 6. Outcomes also involved the administration of two well-established subjective benefit questionnaires: The Abbreviated Profile of Hearing Aid Benefit (APHAB) and the 49-item Speech, Spatial, and Qualities of Hearing Scale (SSQ49).
RESULTS: As a group, participants showed significantly improved median SNR Loss thresholds when aided in a test condition that included spatial separation of speech and noise, with speech stimuli directed toward the worse ear and noise stimuli directed toward the better ear (diff. = -4.5; p < 0.001). Hearing aid use had a small, though statistically significant, negative impact on median SNR Loss thresholds, when speech and noise stimuli originated from the same 0° azimuth (diff. = 1.0; p = 0.018). This was also evidenced by the median WRS in sound field (diff. = -6.0; p = 0.006), which was lowered from 98% in the unaided state to 92% in the aided state. Results from the SSQ49 showed statistically significant improvement on all subsection means when participants were aided (p < 0.05), whereas results from the APHAB were generally found to be unremarkable between unaided and aided conditions as benefit was essentially equal to the 50th percentile of the normative data. At the close of the study, it was observed that only slightly more than half of all participants chose to continue use of a hearing aid after their participation.
CONCLUSIONS: We observed that hearing aid use by individuals with USNHL can improve the SNR Loss associated with the interference of background noise, especially in situations when there is spatial separation of the stimuli and speech is directed toward the affected ear. In addition, hearing aid use by these individuals can provide subjective benefit, as evidenced by the APHAB and SSQ49 subjective benefit questionnaires.

PMID: 29130442 [PubMed - in process]

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Is the Device-Oriented Subjective Outcome (DOSO) Independent of Personality?

Is the Device-Oriented Subjective Outcome (DOSO) Independent of Personality?

J Am Acad Audiol. 2017 Nov/Dec;28(10):932-940

Authors: Wu YH, Dumanch K, Stangl E, Miller C, Tremblay K, Bentler R

Abstract
BACKGROUND: Self-report questionnaires are a frequently used method of evaluating hearing aid outcomes. Studies have shown that personality can account for 5-20% of the variance in response to self-report measures. As a result, these influences can impact results and limit their generalizability when the purpose of the study is to examine the technological merit of hearing aids. To reduce personality influences on self-report outcome data, the Device-Oriented Subjective Outcome (DOSO) was developed. The DOSO is meant to demonstrate outcomes of the amplification device relatively independent of the individual's personality. Still, it is unknown if the DOSO achieves its original goal.
PURPOSE: The purpose of this study was to examine the relationship between personality and the DOSO. The relationship between personality and several widely used hearing-related questionnaires was also examined.
RESEARCH DESIGN: This is a nonexperimental study using a correlational design.
STUDY SAMPLE: A total of 119 adult hearing aid wearers participated in the study.
DATA COLLECTION AND ANALYSIS: The NEO Five-Factor Inventory was used to measure five personality traits (Neuroticism, Extraversion, Openness, Agreeableness, and Conscientiousness). The initial (unaided) hearing disablement, residual (aided) hearing disablement, and hearing aid benefit and satisfaction was measured using the DOSO, Hearing Handicap Inventory for the Elderly/Adult, Abbreviated Profile of Hearing Aid Benefit, and Satisfaction with Amplification in Daily Life. The relationship between personality and each questionnaire was examined using a correlation analysis.
RESULTS: All of the DOSO subscales were found to be significantly correlated to personality, regardless of whether age and better-ear hearing thresholds were controlled. Individuals who reported poorer hearing aid outcomes tended to have higher Neuroticism scores, while those who scored higher in Extraversion, Openness, and Agreeableness were more likely to report better outcomes. Across DOSO subscales, the maximum variance explained by personality traits ranged from 6% to 11%. Consistent with the literature, ∼3-18% of the variance of other hearing-related questionnaires was attributable to personality.
CONCLUSIONS: The degree to which personality affects the DOSO is similar to other hearing-related questionnaires. Although the variance accounted for by personality is not large, researchers and clinicians should not assume that the results of the DOSO are independent of personality.

PMID: 29130441 [PubMed - in process]

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Development and Pilot Evaluation of a Novel Theory-Based Intervention to Encourage Help-Seeking for Adult Hearing Loss.

Development and Pilot Evaluation of a Novel Theory-Based Intervention to Encourage Help-Seeking for Adult Hearing Loss.

J Am Acad Audiol. 2017 Nov/Dec;28(10):920-931

Authors: Saunders GH, Frederick MT, Silverman SC, Nielsen C, Laplante-Lévesque A

Abstract
BACKGROUND: Health behavior theories can provide an understanding of hearing health behaviors and, more importantly, can be used to develop theoretically based strategies to change these health behaviors.
PURPOSE: To develop a theory-based brief intervention to increase help-seeking for adult hearing loss and to conduct a pilot study to evaluate its feasibility, effectiveness, and impact on hearing beliefs and behaviors.
RESEARCH DESIGN: An intervention was designed that could be easily administered by a health-care provider who does not have expertise in audiology-such as a primary care physician, community nurse, or social worker. The intervention aims to alter perceived benefit, severity, cues to action, and self-efficacy for seeking help by providing experiential/affective messaging and simultaneously providing intrinsic motivation for the recipient to seek hearing help. To first determine whether this intervention changed beliefs and increased help-seeking behavior, this study was conducted in a hearing research laboratory setting.
STUDY SAMPLE: A total of 101 adults aged 50-89 yr were recruited within 6 months of having attended an appointment at a primary care clinic at the VA Portland Health Care System. All were sent a letter inviting them to participate in a study if they had trouble with their hearing but had not had a scheduled hearing test or worn hearing aids in the prior 5 yr and also had functional oral and written English. Data from 87 individuals were available for analysis.
INTERVENTION: The intervention is designed for use in any health-care setting in which a health-care provider can facilitate a conversation about hearing. On arrival at a health-care facility, recipients are provided with nine emotionally evocative color photographs to prompt reflection on ways in which hearing difficulties impact them. A discussion with a health-care provider (facilitator) follows, during which recipients may identify the negative impacts of their hearing loss. If the recipient identifies negative impacts, the facilitator suggests that he or she consider having a hearing test and provides a list of local hearing-health professionals.
DATA COLLECTION AND ANALYSIS: Participants completed baseline questionnaires assessing hearing beliefs and attitudes. They were then randomly assigned either to the group receiving the study intervention or to a control group. Six months after study enrollment, participants reported whether they had sought help for their hearing and completed a second set of questionnaires.
RESULTS: Twelve of 41 individuals (29.3%) in the intervention group and 7 of 46 individuals (15.2%) in the control group sought help within the 6-month follow-up period. A χ² test showed these numbers did not differ significantly; however, the odds ratio of having had a hearing test were 2.3 times greater for those who received the intervention than for those who did not.
CONCLUSIONS: Despite not reaching statistical significance, the odds ratio suggests that the theory-based brief intervention is worthy of additional examination. We intend to work with health-care providers to conduct a larger study to investigate whether the intervention has value in the real world.

PMID: 29130440 [PubMed - in process]

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Cochlear Implantation in Children with Postlingual Progressive Steeply Sloping High-Frequency Hearing Loss.

Cochlear Implantation in Children with Postlingual Progressive Steeply Sloping High-Frequency Hearing Loss.

J Am Acad Audiol. 2017 Nov/Dec;28(10):913-919

Authors: Meredith MA, Rubinstein JT, Sie KCY, Norton SJ

Abstract
BACKGROUND: Children with steeply sloping sensorineural hearing loss (SNHL) lack access to critical high-frequency cues despite the use of advanced hearing aid technology. In addition, their auditory-only aided speech perception abilities often meet Food and Drug Administration criteria for cochlear implantation.
PURPOSE: The objective of this study was to describe hearing preservation and speech perception outcomes in a group of young children with steeply sloping SNHL who received a cochlear implant (CI).
RESEARCH DESIGN: Retrospective case series.
STUDY SAMPLE: Eight children with steeply sloping postlingual progressive SNHL who received a unilateral traditional CI at Seattle Children's Hospital between 2009 and 2013 and had follow-up data available up to 24 mo postimplant were included.
DATA COLLECTION AND ANALYSIS: A retrospective chart review was completed. Medical records were reviewed for demographic information, preoperative and postoperative behavioral hearing thresholds, and speech perception scores. Paired t tests were used to analyze speech perception data. Hearing preservation results are reported.
RESULTS: Rapid improvement of speech perception scores was observed within the first month postimplant for all participants. Mean monosyllabic word scores were 76% and mean phoneme scores were 86.7% at 1-mo postactivation compared to mean preimplant scores of 19.5% and 31.0%, respectively. Hearing preservation was observed in five participants out to 24-mo postactivation. Two participants lost hearing in both the implanted and unimplanted ear, and received a sequential bilateral CI in the other ear after progression of the hearing loss. One participant had a total loss of hearing in only the implanted ear. Results reported in this article are from the ear implanted first. Bilateral outcomes are not reported.
CONCLUSIONS: CIs provided benefit for children with steeply sloping bilateral hearing loss for whom hearing aids did not provide adequate auditory access. In our cohort, significant improvements in speech understanding occurred rapidly postactivation. Preservation of residual hearing in children with a traditional CI electrode is possible.

PMID: 29130439 [PubMed - in process]

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Segmental and Suprasegmental Perception in Children Using Hearing Aids.

Segmental and Suprasegmental Perception in Children Using Hearing Aids.

J Am Acad Audiol. 2017 Nov/Dec;28(10):901-912

Authors: Wenrich KA, Davidson LS, Uchanski RM

Abstract
BACKGROUND: Suprasegmental perception (perception of stress, intonation, "how something is said" and "who says it") and segmental speech perception (perception of individual phonemes or perception of "what is said") are perceptual abilities that provide the foundation for the development of spoken language and effective communication. While there are numerous studies examining segmental perception in children with hearing aids (HAs), there are far fewer studies examining suprasegmental perception, especially for children with greater degrees of residual hearing. Examining the relation between acoustic hearing thresholds, and both segmental and suprasegmental perception for children with HAs, may ultimately enable better device recommendations (bilateral HAs, bimodal devices [one CI and one HA in opposite ears], bilateral CIs) for a particular degree of residual hearing. Examining both types of speech perception is important because segmental and suprasegmental cues are affected differentially by the type of hearing device(s) used (i.e., cochlear implant [CI] and/or HA). Additionally, suprathreshold measures, such as frequency resolution ability, may partially predict benefit from amplification and may assist audiologists in making hearing device recommendations.
PURPOSE: The purpose of this study is to explore the relationship between audibility (via hearing thresholds and speech intelligibility indices), and segmental and suprasegmental speech perception for children with HAs. A secondary goal is to explore the relationships among frequency resolution ability (via spectral modulation detection [SMD] measures), segmental and suprasegmental speech perception, and receptive language in these same children.
RESEARCH DESIGN: A prospective cross-sectional design.
STUDY SAMPLE: Twenty-three children, ages 4 yr 11 mo to 11 yr 11 mo, participated in the study. Participants were recruited from pediatric clinic populations, oral schools for the deaf, and mainstream schools.
DATA COLLECTION AND ANALYSIS: Audiological history and hearing device information were collected from participants and their families. Segmental and suprasegmental speech perception, SMD, and receptive vocabulary skills were assessed. Correlations were calculated to examine the significance (p < 0.05) of relations between audibility and outcome measures.
RESULTS: Measures of audibility and segmental speech perception are not significantly correlated, while low-frequency pure-tone average (unaided) is significantly correlated with suprasegmental speech perception. SMD is significantly correlated with all measures (measures of audibility, segmental and suprasegmental perception and vocabulary). Lastly, although age is not significantly correlated with measures of audibility, it is significantly correlated with all other outcome measures.
CONCLUSIONS: The absence of a significant correlation between audibility and segmental speech perception might be attributed to overall audibility being maximized through well-fit HAs. The significant correlation between low-frequency unaided audibility and suprasegmental measures is likely due to the strong, predominantly low-frequency nature of suprasegmental acoustic properties. Frequency resolution ability, via SMD performance, is significantly correlated with all outcomes and requires further investigation; its significant correlation with vocabulary suggests that linguistic ability may be partially related to frequency resolution ability. Last, all of the outcome measures are significantly correlated with age, suggestive of developmental effects.

PMID: 29130438 [PubMed - in process]

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Remote Hearing Aid Support: The Next Frontier.

Remote Hearing Aid Support: The Next Frontier.

J Am Acad Audiol. 2017 Nov/Dec;28(10):893-900

Authors: Angley GP, Schnittker JA, Tharpe AM

Abstract
BACKGROUND: In an effort to reduce health-care disparities, there has been a recent surge of interest in the remote provision of care. Audiologists have begun to provide screening, diagnostic, and rehabilitative services via telehealth technologies.
PURPOSE: To evaluate the feasibility and perceived benefits of providing remote hearing aid follow-up appointments in a controlled clinical environment and in participants' homes.
RESEARCH DESIGN: A descriptive quasi-experimental study was completed.
STUDY SAMPLE: The study consisted of two phases. The in-clinic phase included 50 adults with hearing loss who participated in remote hearing aid follow-up appointments at Vanderbilt University Medical Center. A subgroup of 21 adults from the original in-clinic phase plus one additional participant completed the in-home appointments.
DATA COLLECTION AND ANALYSIS: All participants completed the Montreal Cognitive Assessment and study-designed questionnaires. All participants were asked to install proprietary distance support (DS) client software on a laptop or desktop computer and participate in hearing aid follow-up appointments.
RESULTS: The majority of participants in both groups installed the DS client software with no assistance other than written instructions, and indicated a preference for DS appointments over face-to-face appointments.
CONCLUSION: On average, participants and the study audiologist were satisfied with remote hearing aid follow-up visits. Additional support might be needed for older patients with little confidence in their ability to interact with technology.

PMID: 29130437 [PubMed - in process]

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Hearing Technology Use and Management in School-Age Children: Reports from Data Logs, Parents, and Teachers.

Hearing Technology Use and Management in School-Age Children: Reports from Data Logs, Parents, and Teachers.

J Am Acad Audiol. 2017 Nov/Dec;28(10):883-892

Authors: Gustafson SJ, Ricketts TA, Tharpe AM

Abstract
BACKGROUND: Consistency of hearing aid and remote microphone system use declines as school-age children with hearing loss age. One indicator of hearing aid use time is data logging, another is parent report. Recent data suggest that parents overestimate their children's hearing aid use time relative to data logging. The potential reasons for this disparity remain unclear. Because school-age children spend the majority of their day away from their parents and with their teachers, reports from teachers might serve as a valuable and additional tool for estimating hearing aid use time and management.
PURPOSE: This study expands previous research on factors influencing hearing aid use time in school-age children using data logging records. Discrepancies between data logging records and parent reports were explored using custom surveys designed for parents and teachers. Responses from parents and teachers were used to examine hearing aid use, remote microphone system use, and hearing aid management in school-age children.
STUDY SAMPLE: Thirteen children with mild-to-moderate hearing loss between the ages of 7 and 10 yr and their parents participated in this study. Teachers of ten of these children also participated.
DATA COLLECTION AND ANALYSIS: Parents and teachers of children completed written surveys about each child's hearing aid use, remote microphone system use, and hearing aid management skills. Data logs were read from hearing aids using manufacturer's software. Multiple linear regression analysis and an intraclass correlation coefficient were used to examine factors influencing hearing aid use time and parent agreement with data logs. Parent report of hearing aid use time was compared across various activities and school and nonschool days. Survey responses from parents and teachers were compared to explore areas requiring potential improvement in audiological counseling.
RESULTS: Average daily hearing aid use time was ∼6 hr per day as recorded with data logging technology. Children exhibiting greater degrees of hearing loss and those with poorer vocabulary were more likely to use hearing aids consistently than children with less hearing loss and better vocabulary. Parents overestimated hearing aid use by ∼1 hr per day relative to data logging records. Parent-reported use of hearing aids varied across activities but not across school and nonschool days. Overall, parents and teachers showed excellent agreement on hearing aid and remote microphone system use during school instruction but poor agreement when asked about the child's ability to manage their hearing devices independently.
CONCLUSIONS: Parental reports of hearing aid use in young school-age children are largely consistent with data logging records and with teacher reports of hearing aid use in the classroom. Audiologists might find teacher reports helpful in learning more about children's hearing aid management and remote microphone system use during their time at school. This supplementary information can serve as an additional counseling tool to facilitate discussion about remote microphone system use and hearing aid management in school-age children with hearing loss.

PMID: 29130436 [PubMed - in process]

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Remote Hearing Healthcare.

Remote Hearing Healthcare.

J Am Acad Audiol. 2017 Nov/Dec;28(10):882

Authors: McCaslin DL

PMID: 29130435 [PubMed - in process]

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Glial control of neurogenesis

Publication date: December 2017
Source:Current Opinion in Neurobiology, Volume 47
Author(s): Sven Falk, Magdalena Götz
Glial cells are central components of all neurogenic niches in the embryonic as well as in the adult central nervous system. While neural stem cells (NSCs) themselves exhibit glial features the behavior of NSCs is also strongly influenced by niche glial cells. Recently, studies have begun to uncover a large variety of glial cell-extrinsic as well as intrinsic factors that play crucial roles in the control of NSCs and the regulation of the cellular output from the neurogenic niches. In this review, we focus on mechanisms underlying the formation of adult NSCs by embryonic radial glia cells, discuss the influence of niche glia cells on adult NSCs and examine how the neurogenic potential of glial cells is controlled.

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Clinical features, surgical management, and prognostic factors of secretory meningiomas: a single-center case series of 149 patients

Abstract

Secretory meningioma (SM) is a rare histological subtype of the meningioma family. Few reports investigating SM have been published due to its extremely low incidence; thus, the current understanding of this disease is poor. We analyzed the incidence and clinical, radiological, pathological, and prognostic features of SM. Approximately 12,380 intracranial meningiomas were surgically resected at Beijing Tiantan Hospital between April 2008 and January 2017. All pathologically confirmed SM cases were identified. SMs accounted for approximately 1.2% of the intracranial meningiomas (149 of 12,380). The patients with SM had a mean age of 51.0 years and were predominantly female (112 female and 37 male). Radiologically, peritumoral brain edema was observed in 49 (32.9%) patients. Gross total resection was achieved in 115 (77.2%) cases. At the 35-months median follow-up (range 4–109 months), six patients had tumor recurrence, and one patient died from the tumor recurrence. The 5-year progression-free survival rates were 95.9%, and the 5-year overall survival rate was 99.3%. A skull base location and a tumor size ≥ 3.5 cm were significantly associated with poor short-term outcomes, and a skull base location was significantly associated with an increased risk of poor long-term outcomes (P < 0.05). A skull base location (OR 3.797; 95% CI 1.071–13.468; P = 0.039) and tumor size ≥ 3.5 cm (OR 2.616; 95% CI 1.107–6.181; P = 0.028) were independent risk factors for non-gross total resection. A son-skull base location (OR 0.070; 95% CI 0.028–0.177; P = 0.001) was the only independent risk factor that correlated with more severe peritumoral brain edema. SM is a rare subtype of meningiomas with a female predominance and low recurrence. Our results highlight the risk factors for short- and long-term outcomes, which can be useful for selecting treatments and predicting prognosis. Microsurgical treatment of a skull base SM remains a formidable challenge due to a large tumor size and critical neurovascular structure encasement.

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Meningioma recurrence rates following treatment: a systematic analysis

Abstract

Recurrence rates of meningiomas have been widely reported in the literature, but it remains challenging for clinicians to predict recurrence rate depending on treatment, patient demographics and tumor characteristics. To address these needs, we performed a systematic analysis of the literature to determine the recurrence rate ranges of meningiomas following surgery or radiation. Our search yielded 13 studies that met all criteria for inclusion, allowing us to include 1539 patients in the assessment. Recurrence rates ranged from 0.00 to 2.36 per 100-person-years for WHO grade I meningiomas; and from 7.35 to 11.46 per 100-person-years for WHO grade II meningiomas. Our findings suggest that (1) reported recurrence rates are variable and complicated by the heterogeneity of study populations; (2) as expected, WHO grade II meningiomas generally have a higher recurrence rate than WHO grade I, when controlling for time of diagnosis (by employing person-years); and (3) there is a need for more rigorous reporting of recurrence rates, WHO grade, and Simpson grading for individual patients in order to determine a robust mean of recurrence across WHO grades.

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Preliminary results of immune modulating antibody MDV9300 (pidilizumab) treatment in children with diffuse intrinsic pontine glioma

Abstract

Diffuse intrinsic pontine glioma (DIPG) is an incurable disease with a median overall survival of 10 months. Immune modulating antibodies have recently emerged as a highly promising treatment modality in multiple cancer types. We present results from the first study to evaluate the immune modulating antibody MDV9300 (pidilizumab) in pediatric patients with DIPG. All patients aged 3 years and older, diagnosed with DIPG between February 2014 and June 2015 in Israel, were offered to participate in the study. Enrolled patients were started on biweekly 6 mg/kg MDV9300 after radiation completion. Treatment was continued until disease progression on imaging. Patients were followed biweekly for the occurrence of neurological deficit toxicities and side effects. Secondary endpoints were event free survival and overall survival. Of 13 children diagnosed with DIPG during the study period, nine were enrolled in the study. The patients underwent radiotherapy and none had chemotherapy. A total of 83 cycles of MDV9300 (range 2–16) were applied. The main side effects were neutropenia (CTCAE grade 1–3), mild to moderate fatigue, and acute elevation of blood pressure. Four patients died within 1 year of the diagnosis, another three died within 2 years and two children are still alive nearly 30 months from diagnosis, with stable disease. The median event free survival is 9.3 months (range 6.8–24) and the median overall survival is 15.6 months (range 6.9–28). Preliminary results demonstrate that MDV9300 treatment is safe and may be effective in the treatment of children with DIPG.

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Treatment utilization and outcomes in elderly patients with locally advanced esophageal carcinoma: a review of the National Cancer Database

Abstract

For elderly patients with locally advanced esophageal cancer, therapeutic approaches and outcomes in a modern cohort are not well characterized. Patients ≥70 years old with clinical stage II and III esophageal cancer diagnosed between 1998 and 2012 were identified from the National Cancer Database and stratified based on treatment type. Variables associated with treatment utilization were evaluated using logistic regression and survival evaluated using Cox proportional hazards analysis. Propensity matching (1:1) was performed to help account for selection bias. A total of 21,593 patients were identified. Median and maximum ages were 77 and 90, respectively. Treatment included palliative therapy (24.3%), chemoradiation (37.1%), trimodality therapy (10.0%), esophagectomy alone (5.6%), or no therapy (12.9%). Age ≥80 (OR 0.73), female gender (OR 0.81), Charlson–Deyo comorbidity score ≥2 (OR 0.82), and high-volume centers (OR 0.83) were associated with a decreased likelihood of palliative therapy versus no treatment. Age ≥80 (OR 0.79) and Clinical Stage III (OR 0.33) were associated with a decreased likelihood, while adenocarcinoma histology (OR 1.33) and nonacademic cancer centers (OR 3.9), an increased likelihood of esophagectomy alone compared to definitive chemoradiation. Age ≥80 (OR 0.15), female gender (OR 0.80), and non-Caucasian race (OR 0.63) were associated with a decreased likelihood, while adenocarcinoma histology (OR 2.10) and high-volume centers (OR 2.34), an increased likelihood of trimodality therapy compared to definitive chemoradiation. Each treatment type demonstrated improved survival compared to no therapy: palliative treatment (HR 0.49) to trimodality therapy (HR 0.25) with significance between all groups. Any therapy, including palliative care, was associated with improved survival; however, subsets of elderly patients with locally advanced esophageal cancer are less likely to receive aggressive therapy. Care should be taken to not unnecessarily deprive these individuals of treatment that may improve survival.

Through analysis of the NCDB, we found both definitive and palliative therapy results in improved survival over no therapy in the elderly. Specific groups are less likely to receive aggressive therapy suggesting that nonclinical factors in treatment selection may compromise outcomes.

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MET-GRB2 Signaling-Associated Complexes Correlate with Oncogenic MET Signaling and Sensitivity to MET Kinase Inhibitors

Purpose: Targeting MET in cancer is hampered by lack of diagnostics that accurately reflect high MET signaling and dependence. We hypothesized that assays reflecting MET signaling associated protein complexes could redefine tumors dependent on MET and could add additional precision beyond genomic assessments.

Experimental Design: We used biochemical approaches, cellular viability studies, and proximity ligation assays to assess MET dependence. We examined MET signaling complexes in lung cancer patient specimens (N = 406) and patient-derived xenograft (PDX) models of solid tumors (N = 308). We evaluated response to crizotinib in a MET-amplified cohort of PDX models of lung cancer (N = 6) and provide a case report of a lung cancer patient harboring a exon14 MET splice variant.

Results: We found the interaction of MET with the adaptor protein GRB2 is necessary for oncogenic survival signaling by MET. MET-GRB2 complexes were identified only within MET-amplified PDX models and patient specimens but exhibit substantial variability. Lack of MET-GRB2 complexes was associated with lack of response to MET TKI in cell lines and PDX models. Presence of MET-GRB2 complexes can further subtype tumors with exon14 MET splice variants. Presence of these complexes correlated with response to crizotinib in one patient with exon14 MET lacking MET gene amplification.

Conclusions: Proximity assays measuring MET-GRB2 signaling complexes provide novel insights into MET-mediated signaling and could complement current clinical genomics-based assay platforms. Clin Cancer Res; 23(22); 7084–96. ©2017 AACR.

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FDA Drug Approval: Elotuzumab in Combination with Lenalidomide and Dexamethasone for the Treatment of Relapsed or Refractory Multiple Myeloma

On November 30, 2015, the FDA approved elotuzumab (Empliciti; Bristol-Myers Squibb) in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who received one to three prior therapies. FDA approval was based primarily on the results of a phase III, randomized, open-label, multicenter trial, CA204004, which evaluated elotuzumab in combination with lenalidomide and dexamethasone (E-Ld) compared with lenalidomide and dexamethasone (Ld) alone in patients with relapsed or refractory multiple myeloma. Coprimary endpoints were progression-free survival (PFS) and overall response rate (ORR). The key secondary endpoint was overall survival, but these data were not mature at the time of clinical database cutoff. The trial demonstrated a statistically significant improvement in PFS, with an estimated HR of 0.70 for E-Ld over Ld [95% confidence interval (CI), 0.57–0.85; P = 0.0004). Estimated median PFS was 19.4 months in the E-Ld arm and 14.9 months in the Ld arm. ORR was 75.8% in the E-Ld arm compared with 65.5% in the Ld arm. Serious adverse reactions were reported in 65% of patients in the E-Ld arm compared with 57% in the Ld arm. The FDA approved elotuzumab with the following warnings and precautions: infusion reactions, infections, second primary malignancies, hepatotoxicity, and interference with the determination of complete response. Clin Cancer Res; 23(22); 6759–63. ©2017 AACR.

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Enhanced Cancer Immunotherapy by Chimeric Antigen Receptor-Modified T Cells Engineered to Secrete Checkpoint Inhibitors

Purpose: Despite favorable responses of chimeric antigen receptor (CAR)-engineered T-cell therapy in patients with hematologic malignancies, the outcome has been far from satisfactory in the treatment of solid tumors, partially owing to the development of an immunosuppressive tumor microenvironment. To overcome this limitation, we engineered CAR T cells secreting checkpoint inhibitors (CPI) targeting PD-1 (CAR.αPD1-T) and evaluated their efficacy in a human lung carcinoma xenograft mouse model.

Experimental Design: To evaluate the effector function and expansion capacity of CAR.αPD1-T cells in vitro, we measured the production of IFN and T-cell proliferation following antigen-specific stimulation. Furthermore, the antitumor efficacy of CAR.αPD1-T cells, CAR T cells, and CAR T cells combined with anti–PD-1 antibody was determined using a xenograft mouse model. Finally, the underlying mechanism was investigated by analyzing the expansion and functional capacity of TILs.

Results: Human anti–PD-1 CPIs secreted by CAR.αPD1-T cells efficiently bound to PD-1 and reversed the inhibitory effect of PD-1/PD-L1 interaction on T-cell function. PD-1 blockade by continuously secreted anti–PD-1 attenuated the inhibitory T-cell signaling and enhanced T-cell expansion and effector function both in vitro and in vivo. In the xenograft mouse model, we demonstrated that the secretion of anti–PD-1 enhanced the antitumor activity of CAR T cells and prolonged overall survival.

Conclusions: With constitutive anti–PD-1 secretion, CAR.αPD1-T cells are more functional and expandable, and more efficient at tumor eradication than parental CAR T cells. Collectively, our study presents an important and novel strategy that enables CAR T cells to achieve better antitumor immunity, especially in the treatment of solid tumors. Clin Cancer Res; 23(22); 6982–92. ©2017 AACR.

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Immunotherapy of Prostate Cancer: Facts and Hopes

In the last few years, immunotherapy has become an important cancer treatment modality, and although the principles of immunotherapy have evolved over many decades, the FDA approvals of sipuleucel-T and ipilimumab began a new wave in immuno-oncology. Despite the current enthusiasm, it is unlikely that any of the immunotherapeutics alone can dramatically change prostate cancer outcomes, but combination strategies are more promising and provide a reason for optimism. Several completed and ongoing studies have shown that the combination of cancer vaccines or checkpoint inhibitors with different immunotherapeutic agents, hormonal therapy (enzalutamide), radiotherapy (radium 223), DNA-damaging agents (olaparib), or chemotherapy (docetaxel) can enhance immune responses and induce more dramatic, long-lasting clinical responses without significant toxicity. The goal of prostate cancer immunotherapy does not have to be complete eradication of advanced disease but rather the return to an immunologic equilibrium with an indolent disease state. In addition to determining the optimal combination of treatment regimens, efforts are also ongoing to discover biomarkers of immune response. With such concerted efforts, the future of immunotherapy in prostate cancer looks brighter than ever. Clin Cancer Res; 23(22); 6764–70. ©2017 AACR.

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Personalized Medicine-Based Approach to Model Patterns of Chemoresistance and Tumor Recurrence Using Ovarian Cancer Stem Cell Spheroids

Purpose: Chemoresistant ovarian cancers grow in suspension within the ascites fluid. To screen the effect of chemotherapeutics and biologics on resistant ovarian cancers with a personalized basis, we developed a 3D hanging drop spheroid platform.

Experimental Design: We initiated spheroids with primary aldehyde dehydrogenase–positive (ALDH⁺) CD133⁺ ovarian cancer stem cells (OvCSC) from different patient samples and demonstrated that stem cell progeny from harvested spheroids was similar to the primary tumor. OvCSC spheroids were utilized to initiate tumors in immunodeficient mice. Drug responses to cisplatin and ALDH-targeting compound or JAK2 inhibitor determined whether the OvCSC population within the spheroids could be targeted. Cells that escaped therapy were isolated and used to initiate new spheroids and model tumor reemergence in a personalized manner.

Results: OvCSC spheroids from different patients exhibited varying and personalized responses to chemotherapeutics. Xenografts were established from OvCSC spheroids, even with a single spheroid. Distinct responses to therapy were observed in distinct primary tumor xenografts similar to those observed in spheroids. Spheroids resistant to cisplatin/ALDH inhibitor therapy had persistent, albeit lower ALDH expression and complete loss of CD133 expression, whereas those resistant to cisplatin/JAK2 inhibitor therapy were enriched for ALDH⁺ cells.

Conclusions: Our 3D hanging drop suspension platform can be used to propagate primary OvCSCs that represent individual patient tumors effectively by differentiating in vitro and initiating tumors in mice. Therefore, our platform can be used to study cancer stem cell biology and model tumor reemergence to identify new targeted therapeutics from an effective personalized medicine standpoint. Clin Cancer Res; 23(22); 6934–45. ©2017 AACR.

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Low-Dose Cyclophosphamide Induces Antitumor T-Cell Responses, which Associate with Survival in Metastatic Colorectal Cancer

Purpose: Anticancer T-cell responses can control tumors, but immunosuppressive mechanisms in vivo prevent their function. The role of regulatory T cells (Tregs) in metastatic colorectal cancer is unclear. We have previously shown depletion of Tregs enhances colorectal cancer–specific effector T-cell responses. Low-dose cyclophosphamide targets Tregs in animal models and some human studies; however, the effect of cyclophosphamide in metastatic colorectal cancer is unknown.

Experimental Design: Fifty-five patients with metastatic colorectal cancer were enrolled in a phase I/II trial and randomly assigned to receive 2-week-long courses of low-dose (50 mg twice a day) cyclophosphamide or not. The absolute number, phenotype, and antitumor function of peripheral blood–derived lymphocyte subsets were monitored throughout treatment, as well as during 18-month follow-up.

Results: Initially, cyclophosphamide reduced proliferation in all lymphocyte subsets; however, a rapid mobilization of effector T cells overcame this decrease, leading to increased absolute T-cell numbers. In contrast, a reduction in proportional and absolute Treg, B-cell, and NK-cell numbers occurred. The expansion and subsequent activation of effector T cells was focused on tumor-specific T cells, producing both granzyme B and IFN. Cyclophosphamide-treated patients demonstrating the most enhanced IFN⁺ tumor-specific T-cell responses exhibited a significant delay in tumor progression [HR = 0.29; 95% confidence interval (CI), 0.12–0.69; P = 0.0047), compared with nonresponders and no-treatment controls.

Conclusions: Cyclophosphamide-induced Treg depletion is mirrored by a striking boost in antitumor immunity. This study provides the first direct evidence of the benefit of naturally primed T cells in patients with metastatic colorectal cancer. Our results also support the concept that nonmutated self-antigens may act as useful targets for immunotherapies. Clin Cancer Res; 23(22); 6771–80. ©2017 AACR.

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Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression

Purpose: VEGF-targeted therapies have modest efficacy in cancer patients, but acquired resistance is common. The mechanisms underlying such resistance are poorly understood.

Experimental Design: To evaluate the potential role of immune cells in the development of resistance to VEGF blockade, we first established a preclinical model of adaptive resistance to anti-VEGF therapy. Additional in vitro and in vivo studies were carried out to characterize the role of macrophages in such resistance.

Results: Using murine cancer models of adaptive resistance to anti-VEGF antibody (AVA), we found a previously unrecognized role of macrophages in such resistance. Macrophages were actively recruited to the tumor microenvironment and were responsible for the emergence of AVA resistance. Depletion of macrophages following emergence of resistance halted tumor growth and prolonged survival of tumor-bearing mice. In a macrophage-deficient mouse model, resistance to AVA failed to develop, but could be induced by injection of macrophages. Downregulation of macrophage VEGFR-1 and VEGFR-3 expression accompanied upregulation of alternative angiogenic pathways, facilitating escape from anti-VEGF therapy.

Conclusions: These findings provide a new understanding of the mechanisms underlying the modest efficacy of current antiangiogenesis therapies and identify new opportunities for combination approaches for ovarian and other cancers. Clin Cancer Res; 23(22); 7034–46. ©2017 AACR.

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Genomic Characterization of Vulvar (Pre)cancers Identifies Distinct Molecular Subtypes with Prognostic Significance

Purpose: Vulvar cancer (VC) can be subclassified by human papillomavirus (HPV) status. HPV-negative VCs frequently harbor TP53 mutations; however, in-depth analysis of other potential molecular genetic alterations is lacking. We comprehensively assessed somatic mutations in a large series of vulvar (pre)cancers.

Experimental Design: We performed targeted next-generation sequencing (17 genes), p53 immunohistochemistry and HPV testing on 36 VC and 82 precursors (sequencing cohort). Subsequently, the prognostic significance of the three subtypes identified in the sequencing cohort was assessed in a series of 236 VC patients (follow-up cohort).

Results: Frequent recurrent mutations were identified in HPV-negative vulvar (pre)cancers in TP53 (42% and 68%), NOTCH1 (28% and 41%), and HRAS (20% and 31%). Mutation frequency in HPV-positive vulvar (pre)cancers was significantly lower (P = 0.001). Furthermore, a substantial subset of the HPV-negative precursors (35/60, 58.3%) and VC (10/29, 34.5%) were TP53 wild-type (wt), suggesting a third, not-previously described, molecular subtype. Clinical outcomes in the three different subtypes (HPV⁺, HPV^–/p53wt, HPV^–/p53abn) were evaluated in a follow-up cohort consisting of 236 VC patients. Local recurrence rate was 5.3% for HPV⁺, 16.3% for HPV^–/p53wt and 22.6% for HPV^–/p53abn tumors (P = 0.044). HPV positivity remained an independent prognostic factor for favorable outcome in the multivariable analysis (P = 0.020).

Conclusions: HPV^– and HPV⁺ vulvar (pre)cancers display striking differences in somatic mutation patterns. HPV^–/p53wt VC appear to be a distinct clinicopathologic subgroup with frequent NOTCH1 mutations. HPV⁺ VC have a significantly lower local recurrence rate, independent of clinicopathological variables, opening opportunities for reducing overtreatment in VC. Clin Cancer Res; 23(22); 6781–9. ©2017 AACR.

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Antagonism of EG-VEGF Receptors as Targeted Therapy for Choriocarcinoma Progression In Vitro and In Vivo

Purpose: Choriocarcinoma (CC) is the most malignant gestational trophoblastic disease that often develops from complete hydatidiform moles (CHM). Neither the mechanism of CC development nor its progression is yet characterized. We recently identified endocrine gland–derived vascular endothelial growth factor (EG-VEGF) as a novel key placental growth factor that controls trophoblast proliferation and invasion. EG-VEGF acts via two receptors, PROKR1 and PROKR2. Here, we demonstrate that EG-VEGF receptors can be targeted for CC therapy.

Experimental Design: Three approaches were used: (i) a clinical investigation comparing circulating EG-VEGF in control (n = 20) and in distinctive CHM (n = 38) and CC (n = 9) cohorts, (ii) an in vitro study investigating EG-VEGF effects on the CC cell line JEG3, and (iii) an in vivo study including the development of a novel CC mouse model, through a direct injection of JEG3-luciferase into the placenta of gravid SCID-mice.

Results: Both placental and circulating EG-VEGF levels were increased in CHM and CC (x5) patients. EG-VEGF increased JEG3 proliferation, migration, and invasion in two-dimensional (2D) and three-dimensional (3D) culture systems. JEG3 injection in the placenta caused CC development with large metastases compared with their injection into the uterine horn. Treatment of the animal model with EG-VEGF receptor's antagonists significantly reduced tumor development and progression and preserved pregnancy. Antibody-array and immunohistological analyses further deciphered the mechanism of the antagonist's actions.

Conclusions: Our work describes a novel preclinical animal model of CC and presents evidence that EG-VEGF receptors can be targeted for CC therapy. This may provide safe and less toxic therapeutic options compared with the currently used multi-agent chemotherapies. Clin Cancer Res; 23(22); 7130–40. ©2017 AACR.

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Single Dose of the CXCR4 Antagonist BL-8040 Induces Rapid Mobilization for the Collection of Human CD34+ Cells in Healthy Volunteers

Purpose: The potential of the high-affinity CXCR4 antagonist BL-8040 as a monotherapy-mobilizing agent and its derived graft composition and quality were evaluated in a phase I clinical study in healthy volunteers (NCT02073019).

Experimental Design: The first part of the study was a randomized, double-blind, placebo-controlled dose escalation phase. The second part of the study was an open-label phase, in which 8 subjects received a single injection of BL-8040 (1 mg/kg) and approximately 4 hours later underwent a standard leukapheresis procedure. The engraftment potential of the purified mobilized CD34⁺ cells was further evaluated by transplanting the cells into NSG immunodeficient mice.

Results: BL-8040 was found safe and well tolerated at all doses tested (0.5–1 mg/kg). The main treatment-related adverse events were mild to moderate. Transient injection site and systemic reactions were mitigated by methylprednisolone, paracetamol, and promethazine pretreatment. In the first part of the study, BL-8040 triggered rapid and substantial mobilization of WBCs and CD34⁺ cells in all tested doses. Four hours postdose, the count rose to a mean of 8, 37, 31, and 35 cells/μL (placebo, 0.5, 0.75, and 1 mg/kg, respectively). FACS analysis revealed substantial mobilization of immature dendritic, T, B, and NK cells. In the second part, the mean CD34⁺ cells/kg collected were 11.6 x 10⁶ cells/kg. The graft composition was rich in immune cells.

Conclusions: The current data demonstrate that BL-8040 is a safe and effective monotherapy strategy for the collection of large amounts of CD34⁺ cells and immune cells in a one-day procedure for allogeneic HSPC transplantation. Clin Cancer Res; 23(22); 6790–801. ©2017 AACR.

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Combined CDK4/6 and mTOR Inhibition Is Synergistic against Glioblastoma via Multiple Mechanisms

Purpose: Glioblastoma (GBM) is a deadly brain tumor marked by dysregulated signaling and aberrant cell-cycle control. Molecular analyses have identified that the CDK4/6-Rb-E2F axis is dysregulated in about 80% of GBMs. Single-agent CDK4/6 inhibitors have failed to provide durable responses in GBM, suggesting a need to combine them with other agents. We investigate the efficacy of the combination of CDK4/6 inhibition and mTOR inhibition against GBM.

Experimental Design: Preclinical in vitro and in vivo assays using primary GBM cell lines were performed.

Results: We show that the CDK4/6 inhibitor palbociclib suppresses the activity of downstream mediators of the mTOR pathway, leading to rebound mTOR activation that can be blocked by the mTOR inhibitor everolimus. We further show that mTOR inhibition with everolimus leads to activation of the Ras mediator Erk that is reversible with palbociclib. The combined treatment strongly disrupts GBM metabolism, resulting in significant apoptosis. Further increasing the utility of the combination for brain cancers, everolimus significantly increases the brain concentration of palbociclib.

Conclusions: Our findings demonstrate that the combination of CDK4/6 and mTOR inhibition has therapeutic potential against GBM and suggest it should be evaluated in a clinical trial. Clin Cancer Res; 23(22); 6958–68. ©2017 AACR.

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Impact of Therapy on Genomics and Transcriptomics in High-Risk Prostate Cancer Treated with Neoadjuvant Docetaxel and Androgen Deprivation Therapy

Purpose: The combination of docetaxel chemotherapy and androgen deprivation therapy (ADT) has become a standard treatment for patients with metastatic prostate cancer. The recently accrued phase III CALGB 90203 trial was designed to investigate the clinical effectiveness of this treatment approach earlier in the disease. Specimens from this trial offer a unique opportunity to interrogate the acute molecular response to docetaxel and ADT and identify potential biomarkers.

Experimental Design: We evaluated baseline clinical data, needle biopsies, and radical prostatectomy (RP) specimens from 52 (of 788) patients enrolled on CALGB 90203 at one high volume center. Pathology review, tumor and germline-targeted DNA sequencing (n = 72 genes), and expression profiling using NanoString platform (n = 163 genes) were performed to explore changes in critical prostate cancer pathways linked to aggression and resistance.

Results: Three of 52 patients had only microfocal residual cancer at prostatectomy. The most common alterations included TMPRSS2-ERG fusion (n = 32), TP53 mutation or deletion (n = 11), PTEN deletion (n = 6), FOXA1 (n = 6), and SPOP (n = 4) mutation, with no significant enrichment in posttreated specimens. We did not observe AR amplification or mutations. The degree of AR signaling suppression varied among treated tumors and there was upregulation of both AR and AR-V7 expression as well as a subset of neuroendocrine and plasticity genes.

Conclusions: These data support the feasibility of targeted and temporal genomic and transcriptome profiling of neoadjuvant-treated prostate cancer with limited formalin-fixed paraffin embedded tissue requirement. Characterization of the heterogeneity of treatment response and molecular outliers that arise posttreatment provides new insight into potential early markers of resistance. Clin Cancer Res; 23(22); 6802–11. ©2017 AACR.

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Defective Cyclin B1 Induction in Trastuzumab-emtansine (T-DM1) Acquired Resistance in HER2-positive Breast Cancer

Purpose: Trastuzumab-emtansine (T-DM1) is a standard treatment in advanced HER2-positive breast cancer. However, resistance inevitably occurs. We aimed to identify mechanisms of acquired T-DM1 resistance.

Experimental Design: HER2-positive breast cancer cells (HCC1954, HCC1419, SKBR3, and BT474) were treated in a pulse-fashion with T-DM1 to induce a resistant phenotype. Cellular and molecular effects of T-DM1 in parental versus resistant cells were compared. CDK1 kinase activity and cyclin B1 expression were assayed under various conditions. Genetic modifications to up- or downregulate cyclin B1 were conducted. Effects of T-DM1 on cyclin B1 levels, proliferation, and apoptosis were assayed in human HER2-positive breast cancer explants.

Results: We obtained three cell lines with different levels of acquired T-DM1 resistance (HCC1954/TDR, HCC1419/TDR, and SKBR3/TDR cells). HER2 remained amplified in the resistant cells. Binding to HER2 and intracellular uptake of T-DM1 were maintained in resistant cells. T-DM1 induced cyclin B1 accumulation in sensitive but not resistant cells. Cyclin B1 knockdown by siRNA in parental cells induced T-DM1 resistance, while increased levels of cyclin B1 by silencing cdc20 partially sensitized resistant cells. In a series of 18 HER2-positive breast cancer fresh explants, T-DM1 effects on proliferation and apoptosis paralleled cyclin B1 accumulation.

Conclusions: Defective cyclin B1 induction by T-DM1 mediates acquired resistance in HER2-positive breast cancer cells. These results support the testing of cyclin B1 induction upon T-DM1 treatment as a pharmacodynamic predictor in HER2-positive breast cancer. Clin Cancer Res; 23(22); 7006–19. ©2017 AACR.

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Expression of PD-L1 in Hormone-naïve and Treated Prostate Cancer Patients Receiving Neoadjuvant Abiraterone Acetate plus Prednisone and Leuprolide

Purpose: Programmed cell death ligand-1 (PD-L1)/programmed cell death-1 (PD-1) blockade has been unsuccessful in prostate cancer, with poor immunogenicity and subsequent low PD-L1 expression in prostate cancer being proposed as an explanation. However, recent studies indicate that a subset of prostate cancer may express significant levels of PD-L1. Furthermore, the androgen antagonist enzalutamide has been shown to upregulate PD-L1 expression in prostate cancer preclinical models. In this study, we evaluated the effect of neoadjuvant androgen deprivation therapy with abiraterone acetate plus prednisone and leuprolide (Neo-AAPL) on PD-L1 expression in prostate cancer.

Experimental Design: Radical prostatectomy (RP) tissues were collected from 44 patients with intermediate- to high-risk prostate cancer who underwent RP after Neo-AAPL treatment. Untreated prostate cancer tissues were collected from 130 patients, including 44 matched controls for the Neo-AAPL cases. Tumor PD-L1 expression was detected by IHC using validated anti-PD-L1 antibodies. Tumor-infiltrating CD8⁺ cells were analyzed in trial cases and matched controls. Expression of DNA mismatch repair genes was examined in PD-L1–positive tumors.

Results: Neo-AAPL–treated tumors showed a trend toward decreased PD-L1 positivity compared with matched controls (7% vs. 21% having ≥1% positive tumor cells; P = 0.062). Treated tumors also harbored significantly fewer tumor-infiltrating CD8⁺ cells (P = 0.029). In 130 untreated prostate cancers, African American ethnicity, elevated serum PSA, and small prostate independently predicted tumor PD-L1 positivity. Loss of MSH2 expression was observed in 1 of 21 PD-L1–positive tumors.

Conclusions: A subset of prostate cancer expresses PD-L1, which is not increased by Neo-AAPL treatment, indicating that combining Neo-AAPL treatment with PD-L1/PD-1 blockade may not be synergistic. Clin Cancer Res; 23(22); 6812–22. ©2017 AACR.

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Macropinocytosis of Bevacizumab by Glioblastoma Cells in the Perivascular Niche Affects their Survival

Purpose: Bevacizumab, a humanized monoclonal antibody to VEGF, is used routinely in the treatment of patients with recurrent glioblastoma (GBM). However, very little is known regarding the effects of bevacizumab on the cells in the perivascular space in tumors.

Experimental Design: Established orthotopic xenograft and syngeneic models of GBM were used to determine entry of monoclonal anti-VEGF-A into, and uptake by cells in, the perivascular space. Based on the results, we examined CD133⁺ cells derived from GBM tumors in vitro. Bevacizumab internalization, trafficking, and effects on cell survival were analyzed using multilabel confocal microscopy, immunoblotting, and cytotoxicity assays in the presence/absence of inhibitors.

Results: In the GBM mouse models, administered anti-mouse-VEGF-A entered the perivascular tumor niche and was internalized by Sox2⁺/CD44⁺ tumor cells. In the perivascular tumor cells, bevacizumab was detected in the recycling compartment or the lysosomes, and increased autophagy was found. Bevacizumab was internalized rapidly by CD133⁺/Sox2⁺-GBM cells in vitro through macropinocytosis with a fraction being trafficked to a recycling compartment, independent of FcRn, and a fraction to lysosomes. Bevacizumab treatment of CD133⁺ GBM cells depleted VEGF-A and induced autophagy thereby improving cell survival. An inhibitor of lysosomal acidification decreased bevacizumab-induced autophagy and increased cell death. Inhibition of macropinocytosis increased cell death, suggesting macropinocytosis of bevacizumab promotes CD133⁺ cell survival.

Conclusions: We demonstrate that bevacizumab is internalized by Sox2⁺/CD44⁺-GBM tumor cells residing in the perivascular tumor niche. Macropinocytosis of bevacizumab and trafficking to the lysosomes promotes CD133⁺ cell survival, as does the autophagy induced by bevacizumab depletion of VEGF-A. Clin Cancer Res; 23(22); 7059–71. ©2017 AACR.

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A Phase II Trial of Neoadjuvant MK-2206, an AKT Inhibitor, with Anastrozole in Clinical Stage II or III PIK3CA-Mutant ER-Positive and HER2-Negative Breast Cancer

Purpose: Hyperactivation of AKT is common and associated with endocrine resistance in estrogen receptor–positive (ER⁺) breast cancer. The allosteric pan-AKT inhibitor MK-2206 induced apoptosis in PIK3CA-mutant ER⁺ breast cancer under estrogen-deprived condition in preclinical studies. This neoadjuvant phase II trial was therefore conducted to test the hypothesis that adding MK-2206 to anastrozole induces pathologic complete response (pCR) in PIK3CA mutant ER⁺ breast cancer.

Experimental Design: Potential eligible patients with clinical stage II/III ER⁺/HER2^– breast cancer were preregistered and received anastrozole (goserelin if premenopausal) for 28 days in cycle 0 pending tumor PIK3CA sequencing. Patients positive for PIK3CA mutation in the tumor were eligible to start MK-2206 (150 mg orally weekly, with prophylactic prednisone) on cycle 1 day 2 (C1D2) and to receive a maximum of four 28-day cycles of combination therapy before surgery. Serial biopsies were collected at preregistration, C1D1 and C1D17.

Results: Fifty-one patients preregistered and 16 of 22 with PIK3CA-mutant tumors received study drug. Three patients went off study due to C1D17 Ki67 >10% (n = 2) and toxicity (n = 1). Thirteen patients completed neoadjuvant therapy followed by surgery. No pCRs were observed. Rash was common. MK-2206 did not further suppress cell proliferation and did not induce apoptosis on C1D17 biopsies. Although AKT phosphorylation was reduced, PRAS40 phosphorylation at C1D17 after MK-2206 persisted. One patient acquired an ESR1 mutation at surgery.

Conclusions: MK-2206 is unlikely to add to the efficacy of anastrozole alone in PIK3CA-mutant ER⁺ breast cancer and should not be studied further in the target patient population. Clin Cancer Res; 23(22); 6823–32. ©2017 AACR.

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Downregulation of SAFB Sustains the NF-{kappa}B Pathway by Targeting TAK1 during the Progression of Colorectal Cancer

Purpose: To investigate the role and the underlying mechanism of scaffold attachment factor B (SAFB) in the progression of colorectal cancer (CRC).

Experimental Design: SAFB expression was analyzed in the Cancer Outlier Profile Analysis of Oncomine and in 175 paraffin-embedded archived CRC tissues. Gene Ontology analyses were performed to explore the mechanism of SAFB in CRC progression. Western blot, RT-PCR, luciferase assay, and chromatin immunoprecipitation (ChIP) were used to detect the regulation of transforming growth factor-β–activated kinase 1 (TAK1) and NF-B signaling by SAFB. The role of SAFB in invasion, metastasis, and angiogenesis was investigated using in vitro and in vivo assays. The relationship between SAFB and TAK1 was analyzed in CRC tissues.

Results: SAFB was downregulated in CRC tissues, and low expression of SAFB was significantly associated with an aggressive phenotype and poorer survival of CRC patients. The downregulation of SAFB activated NF-B signaling by targeting the TAK1 promoter. Ectopic expression of SAFB inhibited the development of aggressive features and metastasis of CRC cells both in vitro and in vivo. The overexpression of TAK1 could rescue the aggressive features in SAFB-overexpressed cells. Furthermore, the expression of SAFB in CRC tissues was negatively correlated with the expression of TAK1- and NF-B–related genes.

Conclusions: Our results show that SAFB regulated the activity of NF-B signaling in CRC by targeting TAK1. This novel mechanism provides a comprehensive understanding of both SAFB and the NF-B signaling pathway in the progression of CRC and indicates that the SAFB–TAK1–NF-B axis is a potential target for early therapeutic intervention in CRC progression. Clin Cancer Res; 23(22); 7108–18. ©2017 AACR.

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Phase I Study of a Poxviral TRICOM-Based Vaccine Directed Against the Transcription Factor Brachyury

Purpose: The transcription factor brachyury has been shown in preclinical studies to be a driver of the epithelial-to-mesenchymal transition (EMT) and resistance to therapy of human tumor cells. This study describes the characterization of a Modified Vaccinia Ankara (MVA) vector–based vaccine expressing the transgenes for brachyury and three human costimulatory molecules (B7.1, ICAM-1, and LFA-3, designated TRICOM) and a phase I study with this vaccine.

Experimental Design: Human dendritic cells (DC) were infected with MVA-brachyury-TRICOM to define their ability to activate brachyury-specific T cells. A dose-escalation phase I study (NCT02179515) was conducted in advanced cancer patients (n = 38) to define safety and to identify brachyury-specific T-cell responses.

Results: MVA-brachyury-TRICOM-infected human DCs activated CD8⁺ and CD4⁺ T cells specific against the self-antigen brachyury in vitro. No dose-limiting toxicities were observed due to vaccine in cancer patients at any of the three dose levels. One transient grade 3 adverse event (AE) possibly related to vaccine (diarrhea) resolved without intervention and did not recur with subsequent vaccine. All other AEs related to vaccine were transient and ≤grade 2. Brachyury-specific T-cell responses were observed at all dose levels and in most patients.

Conclusions: The MVA-brachyury-TRICOM vaccine directed against a transcription factor known to mediate EMT can be administered safely in patients with advanced cancer and can activate brachyury-specific T cells in vitro and in patients. Further studies of this vaccine in combination therapies are warranted and planned. Clin Cancer Res; 23(22); 6833–45. ©2017 AACR.

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Highlights of This Issue

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Epidermal Growth Factor Receptor Variant III (EGFRvIII) Positivity in EGFR-Amplified Glioblastomas: Prognostic Role and Comparison between Primary and Recurrent Tumors

Purpose: Approximately 40% of all glioblastomas have amplified the EGFR gene, and about half of these tumors express the EGFRvIII variant. The prognostic role of EGFRvIII in EGFR-amplified glioblastoma patients and changes in EGFRvIII expression in recurrent versus primary glioblastomas remain controversial, but such data are highly relevant for EGFRvIII-targeted therapies.

Experimental Design: EGFR-amplified glioblastomas from 106 patients were assessed for EGFRvIII positivity. Changes in EGFR amplification and EGFRvIII status from primary to recurrent glioblastomas were evaluated in 40 patients with EGFR-amplified tumors and 33 patients with EGFR–nonamplified tumors. EGFR single-nucleotide variants (SNV) were assessed in 27 patients. Data were correlated with outcome and validated in 150 glioblastoma patients from The Cancer Genome Atlas (TCGA) consortium.

Results: Sixty of 106 EGFR-amplified glioblastomas were EGFRvIII-positive (56.6%). EGFRvIII positivity was not associated with different progression-free or overall survival. EGFRvIII status was unchanged at recurrence in 35 of 40 patients with EGFR-amplified primary tumors (87.5%). Four patients lost and one patient gained EGFRvIII positivity at recurrence. None of 33 EGFR-nonamplified glioblastomas acquired EGFR amplification or EGFRvIII at recurrence. EGFR SNVs were frequent in EGFR-amplified tumors, but were not linked to survival.

Conclusions: EGFRvIII and EGFR SNVs are not prognostic in EGFR-amplified glioblastoma patients. EGFR amplification is retained in recurrent glioblastomas. Most EGFRvIII-positive glioblastomas maintain EGFRvIII positivity at recurrence. However, EGFRvIII expression may change in a subset of patients at recurrence, thus repeated biopsy with reassessment of EGFRvIII status is recommended for patients with recurrent glioblastoma to receive EGFRvIII-targeting agents. Clin Cancer Res; 23(22); 6846–55. ©2017 AACR.

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Erratum.

Erratum.

J Am Acad Audiol. 2017 Nov/Dec;28(10):961

Authors:

Abstract
[This corrects the article DOI: 10.3766/jaaa.15105.].

PMID: 29130444 [PubMed - in process]

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Unraveling the Mystery of Auditory Brainstem Response Corrections: The Need for Universal Standards.

Unraveling the Mystery of Auditory Brainstem Response Corrections: The Need for Universal Standards.

J Am Acad Audiol. 2017 Nov/Dec;28(10):950-960

Authors: Norrix LW, Velenovsky D

PMID: 29130443 [PubMed - in process]

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Outcomes of Hearing Aid Use by Individuals with Unilateral Sensorineural Hearing Loss (USNHL).

Outcomes of Hearing Aid Use by Individuals with Unilateral Sensorineural Hearing Loss (USNHL).

J Am Acad Audiol. 2017 Nov/Dec;28(10):941-949

Authors: Bishop CE, Hamadain E, Galster JA, Johnson MF, Spankovich C, Windmill I

PMID: 29130442 [PubMed - in process]

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Is the Device-Oriented Subjective Outcome (DOSO) Independent of Personality?

Is the Device-Oriented Subjective Outcome (DOSO) Independent of Personality?

J Am Acad Audiol. 2017 Nov/Dec;28(10):932-940

Authors: Wu YH, Dumanch K, Stangl E, Miller C, Tremblay K, Bentler R

PMID: 29130441 [PubMed - in process]

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Development and Pilot Evaluation of a Novel Theory-Based Intervention to Encourage Help-Seeking for Adult Hearing Loss.

Development and Pilot Evaluation of a Novel Theory-Based Intervention to Encourage Help-Seeking for Adult Hearing Loss.

J Am Acad Audiol. 2017 Nov/Dec;28(10):920-931

Authors: Saunders GH, Frederick MT, Silverman SC, Nielsen C, Laplante-Lévesque A

PMID: 29130440 [PubMed - in process]

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Cochlear Implantation in Children with Postlingual Progressive Steeply Sloping High-Frequency Hearing Loss.

Cochlear Implantation in Children with Postlingual Progressive Steeply Sloping High-Frequency Hearing Loss.

J Am Acad Audiol. 2017 Nov/Dec;28(10):913-919

Authors: Meredith MA, Rubinstein JT, Sie KCY, Norton SJ

PMID: 29130439 [PubMed - in process]

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Segmental and Suprasegmental Perception in Children Using Hearing Aids.

Segmental and Suprasegmental Perception in Children Using Hearing Aids.

J Am Acad Audiol. 2017 Nov/Dec;28(10):901-912

Authors: Wenrich KA, Davidson LS, Uchanski RM

PMID: 29130438 [PubMed - in process]

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Remote Hearing Aid Support: The Next Frontier.

Remote Hearing Aid Support: The Next Frontier.

J Am Acad Audiol. 2017 Nov/Dec;28(10):893-900

Authors: Angley GP, Schnittker JA, Tharpe AM

PMID: 29130437 [PubMed - in process]

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Hearing Technology Use and Management in School-Age Children: Reports from Data Logs, Parents, and Teachers.

Hearing Technology Use and Management in School-Age Children: Reports from Data Logs, Parents, and Teachers.

J Am Acad Audiol. 2017 Nov/Dec;28(10):883-892

Authors: Gustafson SJ, Ricketts TA, Tharpe AM

PMID: 29130436 [PubMed - in process]

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Remote Hearing Healthcare.

Remote Hearing Healthcare.

J Am Acad Audiol. 2017 Nov/Dec;28(10):882

Authors: McCaslin DL

PMID: 29130435 [PubMed - in process]

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Syntaxin1B contributes to regulation of the dopaminergic system through GABA transmission in the CNS

Abstract

In neuronal plasma membrane, two syntaxin isoforms, HPC-1/syntaxin1A (STX1A) and syntaxin1B (STX1B), are predominantly expressed as soluble N-ethylmaleimide-sensitive fusion attachment protein receptors, also known as t-SNAREs. We previously reported that glutamatergic and GABAergic synaptic transmission is impaired in Stx1b null mutant (Stx1b^−/−) mice, but is almost normal in Stx1a null mutant (Stx1a^−/−) mice. These observations suggested that STX1A and STX1B have distinct functions in fast synaptic transmission in the central nervous system (CNS). Interestingly, recent studies indicated that Stx1a^−/− or Stx1a^+/− mice exhibit disruption in the monoaminergic system in the CNS, causing unusual behavior that is similar to neuropsychological alterations observed in psychiatric patients. Here, we studied whether STX1B contributes to the regulation of monoaminergic system and if STX1B is related to neuropsychological properties in human neuropsychological disorders similar to STX1A. We found that monoamine release in vitro was normal in Stx1b^+/− mice unlike Stx1a^−/− or Stx1a^+/− mice, but the basal extracellular dopamine (DA) concentration in the ventral striatum was increased. DA secretion in the ventral striatum is regulated by GABAergic neurons, and Stx1b^+/− mice exhibited reduced GABA release both in vitro and in vivo, disrupting the DAergic system in the CNS of these mice. We also found that Stx1b^+/− mice exhibited reduced pre-pulse inhibition (PPI), which is believed to represent one of the prominent schizotypical behavioral profiles of human psychiatric patients. The reduction in PPI was rescued by DA receptor antagonists. These observations indicated that STX1B contributes to excess activity of the DAergic system through regulation of GABAergic transmission.

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Αρχειοθήκη ιστολογίου

Τρίτη 14 Νοεμβρίου 2017

Abstract

Abstract

Abstract

Abstract

Abstract