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AbstractIntroductionAlzheimer's Disease Neuroimaging Initiative (ADNI) is now in its 10th year. The primary objective of the magnetic resonance imaging (MRI) core of ADNI has been to improve methods for clinical trials in Alzheimer's disease (AD) and related disorders.MethodsWe review the contributions of the MRI core from present and past cycles of ADNI (ADNI‐1, ‐Grand Opportunity and ‐2). We also review plans for the future‐ADNI‐3.ResultsContributions of the MRI core include creating standardized acquisition protocols and quality control methods; examining the effect of technical features of image acquisition and analysis on outcome metrics; deriving sample size estimates for future trials based on those outcomes; and piloting the potential utility of MR perfusion, diffusion, and functional connectivity measures in multicenter clinical trials.DiscussionOver the past decade the MRI core of ADNI has fulfilled its mandate of improving methods for clinical trials in AD and will continue to do so in the future.

OBJECT The primary goals of this study were: 1) to examine the influence of disease and treatment on headache in patients with sporadic vestibular schwannoma (VS); and 2) to identify clinical predictors of long-term headache disability. METHODS This was a cross-sectional observational study with international multicenter enrollment. Patients included those with primary sporadic < 3-cm VS and a separate group of general population control subjects without tumors. Interventions included a postal survey incorporating the Headache Disability Inventory (HDI), the Hospital Anxiety and Depression Scale, and a VS symptom questionnaire. The main outcome measures were univariate and multivariable associations with HDI total score. RESULTS The overall survey response rate was 79%. Data from 538 patients with VS were analyzed. The mean age at time of survey was 64 years, 56% of patients were female, and the average duration between treatment and survey was 7.7 years. Twenty-seven percent of patients received microsurgery, 46% stereotactic radiosurgery, and 28% observation. Patients with VS who were managed with observation were more than twice as likely to have severe headache disability compared with 103 control subjects without VS. When accounting for baseline differences, there was no statistically significant difference in HDI outcome between treatment modalities at time of survey. Similarly, among the microsurgery cohort, the long-term risk of severe headache disability was not different between surgical approaches. Multivariable regression demonstrated that younger age, greater anxiety and depression, and a preexisting diagnosis of headache were the primary predictors of severe long-term headache disability, while tumor size and treatment modality had little influence. CONCLUSIONS At a mean of almost 8 years following treatment, approximately half of patients with VS experience headaches of varying frequency and severity. Patient-driven factors including age, sex, mental health, and preexisting headache syndrome are the strongest predictors of long-term severe headache disability. Tumor size and treatment modality have less impact. These data may assist with patient counseling regarding long-term expectations following diagnosis and treatment.

ObjectiveSeveral studies have demonstrated small but statistically significant differences in quality‐of‐life (QOL) scores among vestibular schwannoma (VS) treatment modalities. However, does a several‐point difference on a 100‐point scale really matter? The minimal clinically important difference (MCID)—defined as the smallest difference in scores that patients perceive as important and that could lead to a change in management—was developed to answer this important question. While the MCID has been determined for QOL measures used in other diseases, it remains undefined in the VS literature.Study DesignDistribution‐ and anchor‐based techniques were utilized to define the MCID for the Penn Acoustic Neuroma Quality of Life (PANQOL) and 36‐Item Short Form Health Survey (SF‐36).SettingTwo academic referral centers.PatientsPatients with VS (N = 538).InterventionCross‐sectional postal survey.Main Outcome MeasuresMCID for PANQOL domains and total score and SF‐36 Physical and Mental Health Component Summary scores.ResultsThe MCID (median, interquartile range) for the PANQOL total score was 11 points (10‐12); the MCIDs for individual domains were as follows: hearing, 6 (5‐8); balance, 16 (14‐19); facial, 10 (no interquartile range); pain, 11 (10‐13); energy, 13 (10‐17); anxiety, 11 (5‐22); and general, 15 (11‐19). The MCID was 7 points (6‐11) for the SF‐36 Mental Health Component Summary score and 8 points (6‐10) for the Physical Health Component Summary score.ConclusionsThe MCIDs determined in the current study generally exceed differences reported in previous prospective studies, in which conclusions about QOL benefit (or harm) among VS treatment modalities were based on statistical significance alone. Moving forward, these MCIDs should be considered when interpreting results of VS QOL studies.

Abstract Intro: Male BC is a rare disease (&lt;1% male tumors); knowledge is limited and management extrapolated from female BC. An international consortium, coordinated by EORTC and TBCRC, was created to better characterize and manage this disease, with 3 parts: 1) retrospective joint analysis 2) prospective registry 3) clinical trial(s). We report 1st results of part 1. Methods: Joint analysis of male BC pts with available FU & FFPE samples, treated in 1990-2010, in 23 centers from 9 countries. Clinical data, long term outcomes, local pathology were centrally analyzed at EORTC. FFPE samples were analyzed at 3 central labs (UK, NL, US) for histology, grade, ER, PR, AR, HER-2, Ki67. Cut-off for positivity: Allred score ≥ 3 for ER/ AR/PR; 20% for Ki67; ASCO-CAP for HER2. Outcome data (OS & RFS) analyzed per Kaplan Meier, p-values correspond to logrank test, CI’s by Brookmeyer & Crowley. Reported % use number of non-missing values as denominator. Results: 1822 pts enrolled; 349 (19%) ineligible (no valid central lab assessment); of 1473 eligible pts (1384 from EU, 89 from US) 63% diagnosed in 2001-2010. Median age at diagnosis (Dx) was 68.5 ys. Of pts with known M status at Dx, 56 (5.1%) were M1; of 1046 M0 cases, 60% were N0 and 51% had T1 tumors at Dx; 4% of pts had BCS and 18% had SLNB; half received adjuvant RT. (Neo)adjuvant CT was used in 30% of M0 pts, most (44%) anthracycline-only; 77% of M0 pts received adjuvant ET, most tamoxifen (88.4%). Central pathology: 697 cases with central histology & grade (full series ongoing): 87% ductal, 53% grade 2. In 1473 pts, at least 1 biomarker centrally assessed; 92% ER highly+ (Allred 7-8), PR had wider variation (35% highly+); 87% AR highly+; 25% Ki67 high; 5% HER2pos. Using IHC surrogates: 58% Luminal A-like, 35% LuminalB-like/HER2neg, 6% LuminalB-like/HER2pos; 0.1% HER2pos/non-Luminal; 1% TNBC (16% not classified). Outcome: For 1046 M0 pts, median FU was 5.7 yrs (0-19.2); 63% alive at analysis; in 88% cause of death was reported, mainly 33% non-cancer and 28% progression(PD)/toxicity. Significant OS improvement over time is seen. 75% (42/56) M1 pts died, mainly due PD. In M0 pts, median OS (yrs) was significantly correlated with ER+ p=0.001 [Allred 0-2: 3.9 (0.1, 6.0); 3-6: 7.1 (4.7, 11.7); 7-8: 8.8 (8.3, 10.0)] & with PR+ p=0.022 [Allred 0-2: 7.3 (6.1, 10.3), 3-6: 8.0 (7.0, 9.3), 7-8: 9.5 (8.4, 12.8)]; less correlation for AR; no major differences for HER2 or Ki67. Median OS & grade (394 cases; full series ongoing): Grade1: 12.8 yrs (6.1-15.6); Grade2: 7.9 (6.5-10.7); Grade3: 9.3 (4.9-21.1). Median OS for IHC surrogates: 8.7 (7.8-9.7) for Luminal A; 8.3 (6.9-9.4) for Luminal B/HER-2neg; 9.3 years (5.9-21.1) for Luminal B/HER-2+. Similar results were seen for RFS. ER/PR/AR using histoscores will be presented. Conclusions: a) 56% pts had T1 tumors at Dx but only 4% had BCS; b) ER was highly + in &gt;90% but adjuvant ET given in only 77% pts; c) Male BC is usually ER+, PR+ & AR+ and of Luminal A-like subtype (5% HER2pos & 1% TNBC); d) Significant improvement in OS over time; e) ER and PR (Allred) are prognostic (high expression/better prognosis), less for AR, not for Ki67 nor IHC surrogates; f) In-depth characterization of samples is ongoing. Funding: BCRF, EBCC Council, Pink Ribbon NL, BRO. Citation Format: Fatima Cardoso, John Bartlett, Leen Slaets, Carolien van Deurzen, Elise van Leewen-Stok, Peggy Porter, Barbro Linderholm, Ingrid Hedenfalk, Carolien Schroder, John Martens, Jane Bayani, Christi van Asperen, Melissa Murray, Clifford Hudis, Lavinia Middleton, Joanna Vermeij, Stephanie Peeters, Judith Fraser, Monica Nowaczyk, Isabel Rubio, Stefan Aebi, Catherine Kelly, Kathryn Ruddy, Eric Winer, Cecilia Nilsson, Lissandra Dal Lago, Larissa Korde, Kim Benstead, Danielle Van Den Weyngaert, Oliver Bogler, Theodora Goulioti, Nicolas Dif, Carlo Messina, Konstantinos Tryfonidis, Jan Bogaerts, Sharon Giordano. Characterization of male breast cancer: First results of the EORTC10085/TBCRC/BIG/NABCG International Male BC Program [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S6-05.

This review presents principles of glycosylation, describes the relevant glycosylation pathways and their related disorders, and highlights some of the neurological aspects and issues that continue to challenge researchers. More than 100 rare human genetic disorders that result from deficiencies in the different glycosylation pathways are known today. Most of these disorders impact the central and/or peripheral nervous systems. Patients typically have developmental delays/intellectual disabilities, hypotonia, seizures, neuropathy, and metabolic abnormalities in multiple organ systems. Among these disorders there is great clinical diversity because all cell types differentially glycosylate proteins and lipids. The patients have hundreds of misglycosylated products, which afflict a myriad of processes, including cell signaling, cell-cell interaction, and cell migration. This vast complexity in glycan composition and function, along with the limited availability of analytic tools, has impeded the identification of key glycosylated molecules that cause pathologies. To date, few critical target proteins have been pinpointed.

Key Points CLL stereotyped subset #2 (IGHV3-21/IGLV3-21) is uniformly aggressive independently of somatic hypermutation status. The prognosis for non–subset #2/IGHV3-21 CLL resembles that of the remaining CLL cases with similar somatic hypermutation status.

CD38 is a cell-surface protein involved in calcium signaling and contractility of airway smooth muscle. It has a role in normal airway responsiveness and in airway hyperresponsiveness (AHR) developed following airway exposure to IL-13 and TNF-α but appears not to be critical to airway inflammation in response to the cytokines. CD38 is also involved in T cell-mediated immune response to protein antigens. In this study, we assessed the contribution of CD38 to AHR and inflammation to two distinct allergens, ovalbumin and the epidemiologically relevant environmental fungus Alternaria. We also generated bone marrow chimeras to assess whether Cd38+/+inflammatory cells would restore AHR in the CD38-deficient ( Cd38−/−) hosts following ovalbumin challenge. Results show that wild-type (WT) mice develop greater AHR to inhaled methacholine than Cd38−/−mice following challenge with either allergen, with comparable airway inflammation. Reciprocal bone marrow transfers did not change the native airway phenotypic differences between WT and Cd38−/−mice, indicating that the lower airway reactivity of Cd38−/−mice stems from Cd38−/−lung parenchymal cells. Following bone marrow transfer from either source and ovalbumin challenge, the phenotype of Cd38−/−hosts was partially reversed, whereas the airway phenotype of the WT hosts was preserved. Airway inflammation was similar in Cd38−/−and WT chimeras. These results indicate that loss of CD38 on hematopoietic cells is not sufficient to prevent AHR and that the magnitude of airway inflammation is not the predominant underlying determinant of AHR in mice.

OBJECT The optimal treatment for sporadic vestibular schwannoma (VS) is highly controversial. To date, the majority of studies comparing treatment modalities have focused on a narrow scope of technical outcomes including facial function, hearing status, and tumor control. Very few publications have investigated health-related quality of life (HRQOL) differences between individual treatment groups, and none have used a disease-specific HRQOL instrument. METHODS All patients with sporadic small- to medium-sized VSs who underwent primary microsurgery, stereotactic radiosurgery (SRS), or observation between 1998 and 2008 were identified. Subjects were surveyed via postal questionnaire using the 36-Item Short Form Health Survey (SF-36), the 10-item Patient-Reported Outcomes Measurement Information System short form (PROMIS-10), the Glasgow Benefit Inventory (GBI), and the Penn Acoustic Neuroma Quality-of-Life (PANQOL) scale. Additionally, a pool of general population adults was surveyed, providing a nontumor control group for comparison. RESULTS A total of 642 respondents were analyzed. The overall response rate for patients with VS was 79%, and the mean time interval between treatment and survey was 7.7 years. Using multivariate regression, there were no statistically significant differences between management groups with respect to the PROMIS-10 physical or mental health dimensions, the SF-36 Physical or Mental Component Summary scores, or the PANQOL general, anxiety, hearing, or energy subdomains. Patients who underwent SRS or observation reported a better total PANQOL score and higher PANQOL facial, balance, and pain subdomain scores than the microsurgical cohort (p < 0.02). The differences in scores between the nontumor control group and patients with VS were greater than differences observed between individual treatment groups for the majority of measures. CONCLUSIONS The differences in HRQOL outcomes following SRS, observation, and microsurgery for VS are small. Notably, the diagnosis of VS rather than treatment strategy most significantly impacts quality of life. Understanding that a large number of VSs do not grow following discovery, and that intervention does not confer a long-term HRQOL advantage, small- and medium-sized VS should be initially observed, while intervention should be reserved for patients with unequivocal tumor growth or intractable symptoms that are amenable to treatment. Future studies assessing HRQOL in VS patients should prioritize use of validated disease-specific measures, such as the PANQOL, given the significant limitations of generic instruments in distinguishing between treatment groups and tumor versus nontumor subjects.

Objectives/HypothesisTo investigate the influence of posttreatment audiovestibular symptoms, facial neuropathy, and headache on long‐term quality‐of‐life outcomes in patients with sporadic vestibular schwannoma (VS) utilizing the Short Form 36 (SF‐36) Health Survey and the Penn Acoustic Neuroma Quality of Life (PANQOL) scale.Study DesignCross‐sectional observation study.MethodsPatients with sporadic small‐ or medium‐sized VS (< 3.0 cm) who were evaluated between 1998 and 2008 at two independent tertiary academic referral centers were surveyed. Multivariable associations with the PANQOL total score and the SF‐36 physical and mental component scores evaluated using regression analysis.ResultsA total of 538 surveyed patients returned a completed questionnaire, providing a response rate of 79%. Two hundred forty‐seven (46%) patients underwent stereotactic radiosurgery, 143 (27%) microsurgery, and 148 (28%) observation. Multivariable regression analysis revealed that ongoing dizziness was associated with the greatest reduction in PANQOL total score, followed by headache. After adjusting for all examined features, ongoing dizziness and ongoing headache were the only two variables that were associated with both the SF‐36 physical and mental component scores. Patient sex and treatment modality did not significantly influence PANQOL or SF‐36 scores.ConclusionsOngoing dizziness and headache are the strongest predictors of long‐term quality‐of‐life reduction in patients with sporadic VS, while the impact of hearing loss, facial nerve function, and tinnitus are less by comparison. This information may be valuable for patient counseling, refinement of VS quality‐of‐life assessment instruments, and determining high‐yield targets for therapy in efforts to further improve patient outcomes.Level of Evidence4. Laryngoscope, 125:1697–1702, 2015