Citations

Abstract The Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The initial study, ADNI‐1, enrolled 400 subjects with early mild cognitive impairment (MCI), 200 with early AD, and 200 cognitively normal elderly controls. ADNI‐1 was extended by a 2‐year Grand Opportunities grant in 2009 and by a competitive renewal, ADNI‐2, which enrolled an additional 550 participants and will run until 2015. This article reviews all papers published since the inception of the initiative and summarizes the results to the end of 2013. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are largely consistent with disease trajectories predicted by β‐amyloid cascade (Hardy, J Alzheimer's Dis 2006;9(Suppl 3):151–3) and tau‐mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers select and combine optimum features from multiple modalities, including MRI, [ 18 F]‐fluorodeoxyglucose‐PET, amyloid PET, CSF biomarkers, and clinical tests; (4) the development of blood biomarkers for AD as potentially noninvasive and low‐cost alternatives to CSF biomarkers for AD diagnosis and the assessment of α‐syn as an additional biomarker; (5) the development of methods for the early detection of AD. CSF biomarkers, β‐amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects and are leading candidates for the detection of AD in its preclinical stages; (6) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Multimodal methods incorporating APOE status and longitudinal MRI proved most highly predictive of future decline. Refinements of clinical tests used as outcome measures such as clinical dementia rating‐sum of boxes further reduced sample sizes; (7) the pioneering of genome‐wide association studies that leverage quantitative imaging and biomarker phenotypes, including longitudinal data, to confirm recently identified loci, CR1, CLU , and PICALM and to identify novel AD risk loci; (8) worldwide impact through the establishment of ADNI‐like programs in Japan, Australia, Argentina, Taiwan, China, Korea, Europe, and Italy; (9) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker and clinical data to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease‐modifying drugs for AD; and (10) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world.

Primary sclerosing cholangitis (PSC) is a chronic, idiopathic, fibroinflammatory cholangiopathy. The role of the microbiota in PSC etiopathogenesis may be fundamentally important, yet remains obscure. We tested the hypothesis that germ‐free (GF) mutltidrug resistance 2 knockout (mdr2 −/− ) mice develop a distinct PSC phenotype, compared to conventionally housed (CV) mdr2 −/− mice. Mdr2 −/− mice (n = 12) were rederived as GF by embryo transfer, maintained in isolators, and sacrificed at 60 days in parallel with age‐matched CV mdr2 −/− mice. Serum biochemistries, gallbladder bile acids, and liver sections were examined. Histological findings were validated morphometrically, biochemically, and by immunofluorescence microscopy (IFM). Cholangiocyte senescence was assessed by p16 INK4a in situ hybridization in liver tissue and by senescence‐associated β‐galactosidase staining in a culture‐based model of insult‐induced senescence. Serum biochemistries, including alkaline phosphatase, aspartate aminotransferase, and bilirubin, were significantly higher in GF mdr2 −/− ( P < 0.01). Primary bile acids were similar, whereas secondary bile acids were absent, in GF mdr2 −/− mice. Fibrosis, ductular reaction, and ductopenia were significantly more severe histopathologically in GF mdr2 −/− mice ( P < 0.01) and were confirmed by hepatic morphometry, hydroxyproline assay, and IFM. Cholangiocyte senescence was significantly increased in GF mdr2 −/− mice and abrogated in vitro by ursodeoxycholic acid (UDCA) treatment. Conclusions : GF mdr2 −/− mice exhibit exacerbated biochemical and histological features of PSC and increased cholangiocyte senescence, a characteristic and potential mediator of progressive biliary disease. UDCA, a commensal microbial metabolite, abrogates senescence in vitro . These findings demonstrate the importance of the commensal microbiota and its metabolites in protecting against biliary injury and suggest avenues for future studies of biomarkers and therapeutic interventions in PSC. (H epatology 2016;63:185–196)

SUMMARYBackgroundClinical factors were previously identified as predictors of short‐term treatment efficacy in Crohn's disease (CD). The PRECiSE 3 (P3) 7‐year trial provides an opportunity to study predictors of short‐ and long‐term clinical remission among CD patients treated with certolizumab pegol (CZP).AimTo identify factors that influence long‐term remission of CD with CZP treatment.MethodsPatients who had completed placebo‐controlled studies (PRECiSE 1/PRECiSE 2, P1/P2) enrolled in P3 and received open‐label CZP 400 mg every 4 weeks up to 7 years. Baseline predictors included, but were not limited to, smoking status, disease duration, prior inflammatory bowel disease (IBD) surgery, Harvey–Bradshaw Index (HBI), albumin, haematocrit and CZP exposure; association with time to initial remission (HBI ≤4) was tested for patients who received CZP in P1/P2; time to loss of remission/frequency of maintenance of remission was also tested. Univariate analyses and multivariate Cox or logistic regression models were used.ResultsPredictors for initial remission (N = 377) included age, haematocrit, prior IBD surgery and entry HBI (P < 0.05 for all). Predictors for loss of remission (N = 437) included HBI, serum albumin concentration, haematocrit, smoking status and exposure. Predictors of maintenance of remission (N = 437) included haematocrit, IBD surgery, HBI, disease duration, serum albumin concentration and exposure. Significant predictors were confirmed with stepwise multivariate regression models.ConclusionsThese analyses identified several influential parameters for short‐and long‐term remission of Crohn's disease with certolizumab pegol treatment. The data yield valuable hypotheses regarding factors that influence certolizumab pegol treatment. More investigation is needed.(ClinicalTrials.gov identifier NCT00552058).

AbstractBackgroundStudies point to a direct association between social support and better cancer outcomes. This study examined whether baseline social support is associated with better survival and fewer chemotherapy‐related adverse events in older, early‐stage breast cancer patients.MethodsThis study is a pre‐planned secondary analysis of CALGB 49907/Alliance A171301, a randomized trial that compared standard adjuvant chemotherapy versus capecitabine in breast cancer patients 65 years of age or older. A subset reported on the extent of their social support with questionnaires that were completed 6 times over 2 years.ResultsThe median age of this 331‐patient cohort was 72 years (range: 65, 90); 179 (55%) were married, and 210 (65%) lived with someone. One hundred forty‐five patients (46%) described a social network of 0–10 people; 110 (35%) of 11–25; and 58 (19%) of 26 or more. The Medical Outcomes Study (MOS) social support survey revealed that the median scores (range) for emotional/informational, tangible, positive social interaction, and affectionate social support were 94 (3, 100), 94 (0, 100), 96 (0, 100), and 100 (8, 100), respectively. Social support scores appeared stable over 2 years and higher (more support) than in other cancer settings. No statistically significant associations were observed between social support and survival and adverse events in multivariate analyses. However, married patients had smaller tumors, and those with arthritis reported less social support.ConclusionAlthough social support did not predict survival and adverse events, the exploratory but plausible inverse associations with larger tumors and arthritis suggest that social support merits further study. Copyright © 2015 John Wiley & Sons, Ltd.

Selective serotonin reuptake inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs, thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at www.pharmgkb.org ).

Abstract The clinical efficacies of molecularly targeted glioblastomas therapies have been vastly disappointing. The multitudes of resistance mechanisms suggest that glioblastomas possess highly dynamic molecular circuits grounded in functional redundancy. Emerging data suggests that the expression of functionally redundant oncogenes induced similar forms of cellular stress, requiring hyper-activation of common compensatory pathways to ensure cell viability. Targeting these pathways, therefore, afford potential opportunities for tumor ablation while by-passing the redundancy of oncogenic circuitry. To explore this paradigm, we carried out a siRNA screen to identify synthetic lethal partners of the oncogenic Epidermal Growth Factor Receptor variant III (EGFRvIII) in glioblastoma cells and identified Polo-Like Kinase 1 (PLK1). Treatment using a PLK1 inhibitor, BI2536, or siRNAs induced preferential toxicity to the EGFRvIII expressing glioblastoma cells in multiple in vitro (serum and neurosphere lines) and in vivo models (heterotopic and orthotopic xenograft models). Consistent with the heightened PLK1 requirement, EGFRvIII expressing glioblastomas harbored increased levels of the p-Thr210 PLK1 (an activated form of PLK1). Inhibition of PLK1 by BI2536 treatment induced an increase in the proportion of cells that co-stained for p-Histone H3 and γH2AX foci, suggesting accumulation of mitotic DNA damage. This effect was exacerbated by EGFRvIII expression, implicating induction of mitotic DNA damage as a major contributor to the observed synthetic lethality. Consistent with this observation, EGFRvIII expression induced the formation of aberrant mitosis as well as prolonged mitotic progression. Further supporting an essential role for PLK1 in suppressing DNA damage accumulation, BI2536 treatment significantly enhanced the tumoricidal effect of the DNA damaging chemotherapy, temozolomide. Mechanistically, inhibition of PLK1 suppressed the expression of Rad51, the accumulation of pS14 Rad51 (an active form of Rad51), as well as overall homologous recombination efficiency in vitro. We validated the clinical pertinence of these results using three clinically annotated glioblastoma databases (TCGA, REMEBMRANDT, CGGA). In all three datasets, increased expression of a PLK1 signature consistently associated with increased expression of HR genes and lowered gene expression signature associated with DNA damage accumulation. Supporting our proposed paradigm, the tumoricidal effect of BI2536 was universally observed in a panel of eight murine ink4a/arf (-/-) EGFRvIII expressing glioblastoma clones that developed resistance to EGFR inhibitors by distinct and independent mechanisms. In aggregate, our results support the essential role of PLK1 in suppressing mitotic DNA damage and provide a novel framework for glioblastoma therapy. Citation Format: Ying Shen, Masayuki Nitta, Jie Li, Diahnn Futalan, Tyler Steed, Zack Taich, Jeffrey M. Treiber, Deanna Stevens, Mark A. Schroeder, Jann N. Sarkaria, Hong-Zhuan Chen, Tao Jiang, Bob S. Carter, Fumiko Esashi, Jill Wakosky, Frank Furnari, Webster K. Cavenee, Arshad Desai, Clark C. Chen. Modulation of mitotic DNA damage as a paradigm for glioblastoma therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2737. doi:10.1158/1538-7445.AM2014-2737

Abstract Background: Tumor-infiltrating lymphocytes (TILs) at diagnosis are reported to be prognostic in triple-negative breast cancer (BC). Analysis of a small subset of 209 HER2+ patients (pts) with 49 events concluded that higher levels of S-TILs are associated with increased trastuzumab benefit (Loi, 2014). Here we report the largest study to date evaluating S-TILs and their prognostic and predictive association with clinical outcome in N9831 pts treated with either chemotherapy or chemotherapy plus trastuzumab. Methods: Samples assessed were from primary tumors of pts on N9831 arm A (standard AC→T chemotherapy) and arm C (concurrent chemotherapy with trastuzumab) (Perez, 2011). S-TILs were evaluated on H&E whole tumor slides by a single pathologist with ∼10% of cases read by two pathologists in tandem. The percent of stromal lymphocytic infiltrates (S-TILs) was quantitated in deciles; ≥60% S-TILs was used for the categorical cutoff (Denkert, 2010). The association between S-TILs, treatment (tx) and recurrence-free survival (RFS) was studied and the interaction between S-TILs, trastuzumab benefit and RFS was calculated. Results: 489 pts from arm A (chemo) and 456 pts from arm C (chemo with trastuzumab) were assessed and were similar to pts in the overall trial; all had RFS information and a median follow-up of 4.4yr. Tumors from 54% of pts in arms A and C were HR+; 14% were node-negative. Tumors with high S-TILs were more likely to be hormone receptor-negative (p&lt; 0.0001). In multivariable analyses including nodal status, hormone receptor status, tx arm, tumor size, tumor grade, and age, ≥60% S-TILs was significantly associated with RFS (HR 0.20; 95%CI 0.064–0.65, p=0.007) in arm A but not in arm C (HR 1.1; 95%CI 0.42–2.8, p=0.87); the interaction term of arm and ≥60% S-TILs was significant (p=0.042). Semi-continuous deciles were associated with RFS in arm A (p&lt;0.0002) but not in C (p=0.37). Hormone receptor status was an independent prognostic factor in arm A (HR 0.61; 95%CI 0.41-0.93, p=0.02) but not in C (HR 0.79; 95%CI 0.44-1.41, p=0.42). In arm A the 10yr Kaplan-Meier estimates for RFS were 90.9% and 64.5% for high S-TILs and low S-TILs pts, respectively (HR 0.23; 95%CI 0.073–0.73, p=0.013). In arm C the 10yr Kaplan-Meier estimates for RFS were 80.0% and 80.1% for high S-TILs and low S-TILs pts, respectively (HR 1.26; 95%CI 0.5–3.2, p=0.63). Arm A (N=489)Arm C (N=456)VariableHR (95% CI)p-valueHR (95% CI)p-valueNodal statusLymph node(-)1.00 (ref)&lt;0.00011.00 (ref)0.0131-3+0.58 (0.25, 1.35) 2.99 (0.40, 22.70) 4-91.46 (0.64, 3.35) 3.29 (0.42, 25.80) 10+2.42 (1.04, 5.64) 8.22 (1.06, 63.60) HR statusnegative1.00 (ref)0.01981.00 (ref)0.42positive0.61 (0.41, 0.93) 0.79 (0.44, 1.41) S-TILs status&lt;60%1.00 (ref)0.0071.00 (ref)0.87≥60%0.2 (0.06, 0.65) 1.08 (0.42, 2.79) Tumor gradeGrade 1 or 21.00 (ref)0.501.00 (ref)0.51Grade 31.18 (0.73, 1.91) 1.24 (0.65, 2.39) Tumor size1.08 (0.98, 1.19)0.121.00 (0.93, 1.07)0.92Age0.99 (0.97, 1.00)0.131 (0.98, 1.03)0.87 Conclusions: In exploratory analyses from this subset HER2+ population from N9831, S-TILs were associated with RFS in patients treated with chemotherapy alone, and were not shown to be associated with RFS in patients treated with chemotherapy plus trastuzumab. Citation Format: Edith A Perez, Karla V Ballman, S Keith Anderson, E Aubrey Thompson, Sunil S Badve, Helen Bailey, Frederick L Baehner. Stromal tumor-infiltrating lymphocytes(S-TILs): In the alliance N9831 trial S-TILs are associated with chemotherapy benefit but not associated with trastuzumab benefit [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 S1-06.