Citations

ABSTRACT Bisphosphonates (BPs) are the most commonly used medications for osteoporosis. This ASBMR report provides guidance on BP therapy duration with a risk-benefit perspective. Two trials provided evidence for long-term BP use. In the Fracture Intervention Trial Long-term Extension (FLEX), postmenopausal women receiving alendronate for 10 years had fewer clinical vertebral fractures than those switched to placebo after 5 years. In the HORIZON extension, women who received 6 annual infusions of zoledronic acid had fewer morphometric vertebral fractures compared with those switched to placebo after 3 years. Low hip T-score, between –2 and –2.5 in FLEX and below –2.5 in HORIZON extension, predicted a beneficial response to continued therapy. Hence, the Task Force suggests that after 5 years of oral BP or 3 years of intravenous BP, reassessment of risk should be considered. In women at high risk, for example, older women, those with a low hip T-score or high fracture risk score, those with previous major osteoporotic fracture, or who fracture on therapy, continuation of treatment for up to 10 years (oral) or 6 years (intravenous), with periodic evaluation, should be considered. The risk of atypical femoral fracture, but not osteonecrosis of the jaw, clearly increases with BP therapy duration, but such rare events are outweighed by vertebral fracture risk reduction in high-risk patients. For women not at high fracture risk after 3 to 5 years of BP treatment, a drug holiday of 2 to 3 years can be considered. The suggested approach for long-term BP use is based on limited evidence, only for vertebral fracture reduction, in mostly white postmenopausal women, and does not replace the need for clinical judgment. It may be applicable to men and patients with glucocorticoid-induced osteoporosis, with some adaptations. It is unlikely that future trials will provide data for formulating definitive recommendations. © 2015 American Society for Bone and Mineral Research.

1. If gastric acid is necessary for the absorption of dietary calcium, the total absence of gastric acid secretion that occurs in pernicious anaemia could result in bone loss. To investigate this, we measured calcium absorption and bone density in 21 postmenopausal women (ages 51–76 years) with pernicious anaemia and in 24 normal postmenopausal women (ages 51–79 years). 2. Relative to the normal women, in the women with pernicious anaemia the bone mineral density of the lumbar spine was decreased by 16% (P < 0.001). 3. After adjustment for age and body weight, lumbar spine bone mineral density correlated with the serum concentration of group 1 pepsinogens (a group of proteins produced by the gastric fundus) (r= 0.61, P < 0.01). 4. Despite achlorhydria, the women with pernicious anaemia had normal true fractional calcium absorption and normal serum levels of parathyroid hormone and 1,25-dihydroxyvitamin D. 5. We conclude that gastric acid is not required for the absorption of dietary calcium. Thus, the loss of cancellous bone must be caused by some mechanism yet to be identified.

Abstract Glioblastoma (GBM), a highly invasive primary brain tumour, remains an incurable disease (1). Angiogenesis, the formation of new blood vessels, is a defining feature of GBM (2). Targeting GBM angiogenesis with Bevacizumab (Bev) is associated with improved progression free survival, but may also significantly enhance local tumour invasion (3). RhoGTPases and their activators, guanine nucleotide exchange factors (GEFs), play central roles in the invasive process (4). Herein, we sought to identify and target GEFs of importance in meditating GBM invasion with a view to improving Bev response. We report a novel strategy by which GBM tumours invade and proliferate via overexpression of the GEF beta-PIX which was shown to be increased at the invasive edge in 74% of GBM tumours assessed (n = 19) compared with tumour core (5). We have further shown that siRNA-mediated knockdown of beta-PIX in GBM patient-derived xenograft cell cultures and cell lines resulted in decreased cell invasion in 3D, cell proliferation and survival assays in vitro. Furthermore, we have uncovered a role for beta-PIX expression in endothelial cell function, as knockdown of beta-PIX inhibits HUVEC cell migration in vitro. To interrogate in vivo effects, we established an imagable orthotopic model of invasive GBM in mice, by stereotactically implanting GBM cells stably overexpressing firefly luciferase (U87R-GFP-luc2). beta-PIX-(human and mouse) specific siRNA or scrambled control siRNA (2 × 10 μg i.c.) were delivered to tumours using an alphaVbeta3 integrin targeting-(RGD peptide conjugated)-nanoparticle (InVivoPlex Aparna Bio Corp, Rockville, MD). Animals were treated with- or without- Bev (6 × 10mg/kg i.p. over 12 days). Initial data has shown that animals treated with beta-PIX siRNA nanoparticles in combination with Bev had an improved median survival of 100 days compared with Bev- alone treated mice (median: 88 days). Our data may support the future clinical use of a beta-PIX-targeting nanoparticle therapeutic, to improve Bev outcomes in GBM. 1. Kohler BA et al J Natl Cancer Inst. 2011; 103, 714-736 2. Jain RK et al Nat Rev Neurosci. 2007; 8(8):610-22 3. Norden AD et al Neurology 2008; 70: 779-787 4. Murray D et al Brit J Can 2014; 110(5):1307-15 5. Hoelzinger DB et al Neoplasia 2005; 7(1): 7-16 Citation Format: David W. Murray, Philip O'Halloran, Monika Jarzabek, Brian MacCarthy, Jann N. Sarkaria, Raymond M. Schiffelers, Marc Symons, Annette T. Byrne. Pre-clinical assessment of a novel anti-invasion nanoparticle therapeutic in combination with bevacizumab for the treatment of glioblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5093. doi:10.1158/1538-7445.AM2015-5093

ObjectiveThe aim of this study was to determine whether the frequency of TAR DNA‐binding protein 43 (TDP‐43) deposition in Alzheimer's disease (AD) differs across pathologically defined AD subtypes (hippocampal sparing [HpSp]; typical and limbic) and further examine the relationship between TDP‐43, pathological subtype, and clinical features in AD.MethodsWe identified all cases with pathologically confirmed AD (NIA‐Reagan intermediate‐high probability, Braak stage IV–VI) independent of cognitive status (n = 188). Neurofibrillary tangle counts were performed using thioflavin‐S microscopy in hippocampus and three neocortical regions, and all cases were subtyped: HpSp AD pathology (n = 19); typical AD pathology (n = 136); and limbic AD pathology (n = 33). TDP‐43 immunoreactivity was performed in multiple brain regions to assess for the presence of TDP‐43 and TDP‐43 stage. All cases were clinically subclassified at presentation as amnestic AD dementia versus atypical AD dementia. Statistical analysis was performed using linear and penalized logistic regression to assess associations with pathological subtype, and the effects of TDP‐43, accounting for possible interactions between pathological subtype and TDP‐43.ResultsTDP‐43 deposition was frequent in typical (59%) and limbic AD pathologies (67%), but not HpSp AD pathology (21%; p = 0.003). The observed associations of TDP‐43 with greater memory loss, naming and functional decline, and smaller hippocampal volumes, closest to death, did not differ across AD pathological subtype. Clinical presentation was associated with pathological subtype (p = 0.01), but not TDP‐43 (p = 0.69).InterpretationAlthough the frequency of TDP‐43 deposition in AD varies by pathological subtype, the observed effects of TDP‐43 on clinical/magnetic resonance imaging features are consistent across pathological subtypes. Clinical presentation in AD is driven by pathological subtype, not by TDP‐43. Ann Neurol 2015;78:Ann Neurol 2015;78:679–696

A mouse model for ALS A G4C2 repeat expansion in C9ORF72 is known to be the major genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). However, a lack of animal models recapitulating key disease features has hindered efforts to understand and prevent c9FTD/ALS-related neurodegeneration. Until now. Chew et al. describe a mouse model that mimics both neuropathological and clinical phenotypes of c9FTD/ALS. Science , this issue p. 1151

Abstract Intro: Male BC is a rare disease (<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 >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.

Abstract The link between autoimmune diseases and primary immunodeficiency syndromes has been increasingly appreciated. Immunologic evaluation of a young man with autoimmune enterocolopathy and unexplained infections revealed evidence of immunodeficiency, including IgG subclass deficiency, impaired Ag-induced lymphocyte proliferation, reduced cytokine production by CD8+ T lymphocytes, and decreased numbers of NK cells. Genetic evaluation identified haploinsufficiency of NFAT5, a transcription factor regulating immune cell function and cellular adaptation to hyperosmotic stress, as a possible cause of this syndrome. Inhibition or deletion of NFAT5 in normal human and murine cells recapitulated several of the immune deficits identified in the patient. These results provide evidence of a primary immunodeficiency disorder associated with organ-specific autoimmunity linked to NFAT5 deficiency.