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Osteoporos IntDOI 10.1007/s00198-011-1528-y Skeletal mineralization defects in adulthypophosphatasia—a clinical and histological analysis F. Barvencik & F. Timo Beil & M. Gebauer & B. Busse &T. Koehne & S. Seitz & J. Zustin & P. Pogoda & T. Schinke &M. Amling Received: 14 April 2010 / Accepted: 3 January 2011 # International Osteoporosis Foundation and National Osteoporosis Foundation 2011 ALPL gene, encoding tissue non-specific alkaline phospha- Summary Histomorphometry and quantitative backscat- tase. While it is commonly accepted that the increased fracture tered electron microscopy of iliac crest biopsies from risk of the patients is the consequence of osteomalacia, there patients with adult hypophosphatasia not only confirmed are only few studies describing a complete histomorphometric the expected enrichment of non-mineralized osteoid, but analysis of bone biopsies from affected individuals. There- also demonstrated an altered trabecular microarchitecture, fore, we analyzed iliac crest biopsies from eight patients and an increased number of osteoblasts, and an impaired set them in direct comparison to biopsies from healthy donors calcium distribution within the mineralized bone matrix.
or from individuals with other types of osteomalacia.
Introduction Adult hypophosphatasia is an inherited disorder Methods Histomorphometric analysis was performed on non- of bone metabolism caused by inactivating mutations of the decalcified sections stained either after von Kossa/van Giesonor with toluidine blue. Bone mineral density distribution wasquantified by backscattered electron microscopy.
Florian Barvencik and Frank Timo Beil contributed equally to thiswork and therefore share first authorship.
Results Besides the well-documented enrichment of non-mineralized bone matrix in individuals suffering from adult F. Barvencik F. T. Beil M. Gebauer B. Busse T. Koehne S. Seitz P. Pogoda T. Schinke M. Amling (*) hypophosphatasia, our histomorphometric analysis revealed Department of Osteology and Biomechanics, alterations of the trabecular microarchitecture and an University Medical Center Hamburg-Eppendorf, increased number of osteoblasts compared to healthy Martinistrasse 52, controls or to individuals with other types of osteomalacia.
20246, Hamburg, Germanye-mail: amling@uke.uni-hamburg.de Moreover, the analysis of the mineralized bone matrixrevealed significantly decreased calcium content in patients F. T. Beil S. Seitz with adult hypophosphatasia.
Department of Orthopaedics, Conclusions Taken together, our data show that adult University Medical Center Hamburg-Eppendorf,Hamburg, Germany hypophosphatasia does not solely result in an enrichmentof osteoid, but also in a considerable degradation of bone quality, which might contribute to the increased fracture Materials Sciences Division, Lawrence Berkeley National risk of the affected individuals.
Laboratory, University of California,Berkeley, USA Keywords Alkaline phosphatase . Histomorphometry .
Osteoid . Osteomalacia . qBEI Institute of Bone Pathology,University Medical Center Hamburg-Eppendorf,Hamburg, Germany P. PogodaDepartment of Trauma-, Hand- and Reconstructive Surgery, Hypophosphatasia is an inherited disorder primarily char- University Medical Center Hamburg-Eppendorf,Hamburg, Germany acterized by defective mineralization of bones and teeth, which is caused by inactivating mutations of the gene since there are no larger studies being performed after the ALPL, encoding the tissue non-specific alkaline phospha- standardization of bone histomorphometry by the American tase Depending on the type of mutation and the Society for Bone and Mineral Research we decided to mode of inheritance, the disease is highly variable in its analyze iliac crest biopsies from eight individuals suffering clinical expression and can be classified into six major from adult hypophosphatasia using non-decalcified histology, forms (perinatal lethal, prenatal benign, infantile, child- which were compared to biopsies from age-matched indi- hood, adult, and odontohypophosphatasia) [Given the viduals without skeletal abnormalities or to biopsies from severe skeletal hypomineralization, the perinatal form either individuals with other types of osteomalacia. In addition, we results in stillbirth or in early postnatal lethality [, ].
have applied quantitative backscattered electron microscopy The clinical course of the infantile form starts in the first to determine the calcium distribution within the mineralized 6 months of life and is characterized by rickets, craniosy- bone matrix.
nostosis, nephrocalcinosis, and premature death ]. Afterthe first year, the childhood form of hypophosphatasia ischaracterized by short stature, bone deformities of the lower extremities, and premature loss of primary teeth , ].
The adult form of hypophosphatasia is mainly characterized Patients and histological analysis of iliac crest biopsies by osteomalacia, pseudofractures, and pathologic fracturesafter minimal trauma, as well as by muscle and joint pain In this study, we included eight adult hypophosphatasia patients from whom iliac crest bone biopsies were assessed The clinical diagnosis of hypophosphatasia is, however, in the bone pathology department of the University Medical not only based on radiological findings or bone mineral Center Hamburg-Eppendorf. All patient records were density (BMD) measurements, but also on biochemical screened, and the relevant clinical data were extracted.
assays, such as monitoring the serum activities of alkaline The group included six women and two men between 24 phosphatase, which are reduced in the affected individuals.
and 66 years of age (average age of 47 years, average In addition, elevated levels of phosphoethanolamine in the height of 168 cm). Eight age- and sex-matched cases from urine or of pyridoxal-5-phosphate in the serum are our iliac crest archive without any bone disease were supporting the diagnosis of hypophosphatasia, since these integrated in this study as a control group (six females and substrates of alkaline phosphatase accumulate in the two males, average age of 48 years). All of these absence of the enzyme []. Moreover, the genetic individuals died in accidents or of acute disease. Reviews screening methods that are available nowadays have led of hospital records and autopsy reports were used to to the identification of more than 221 mutations of the exclude individuals with cancer, diabetes, glucocorticoid ALPL gene so far and have helped in the understanding of medication, or donors on other drugs known to affect the genetic causes underlying the variability of clinical calcium metabolism. Moreover, patients with severe liver or expression [These methods have not only allowed the kidney disease or periods of longer immobilization before performance of prenatal diagnostics of the disease, but also biopsy were excluded. In addition, we have analyzed helped to confirm the diagnosis of hypophosphatasia ].
biopsies from eight individuals with low circulating 25 However, while there is no doubt about the usefulness of (OH)-vitamin D levels (8.8±3.3 ng/ml), with an average genetic diagnosis in the case of hypophosphatasia, the age of 49 years, and from one patient suffering from X- availability of these methods certainly explains why linked hypophosphatemic rickets (male, 45 years old). This histopathological analyses of bone biopsies from affected study was carried out according to existing rules and individuals are not routinely performed anymore.
regulations of the University Medical Center Hamburg- In fact, the largest histologic study so far, describing Eppendorf and is in line with the "Hamburg Hospital Law skeletal pathologies in various forms of hypophosphatasia, (HmbKHG) April 17th, 1991: Patient Security §12." was published in 1984 ]. Through the use of non-decalcified sections from iliac crest biopsies, the authors were able to demonstrate an enrichment of osteoid in mostof the affected individuals, whose degree reflected the As previously described by Bordier, all samples from the iliac clinical severity of the disease. From the 17 cases of adult crest were dissected out 2 cm below and 2 cm behind the crista hypophosphatasia analyzed in this study, 11 were diagnosed iliaca superior anterior and fixed overnight at 4°C in 3.7% with osteomalacia, while five others were characterized by PBS-buffered formaldehyde []. After dehydration in decreased bone remodeling. Taken together, these and other ascending concentrations of ethanol, the samples were data have helped in the understanding of the skeletal embedded non-decalcified in methylmethacrylate, and 5- manifestations of hypophosphatasia [–However, μm-thick sections were cut using a Microtec rotation microtome (Techno-Med; Munich, Germany). The sections with energy dispersive X-ray analysis and qBEI to create a were stained according to standard protocols after von calibration curve. A highly linear relationship between Kossa/van Gieson, Goldner, or with toluidine blue as backscattered electron imaging gray values and the calcium described [–].
content (Ca-wt.%) has been reported previously by otherauthors [, The linear dependence (R2=0.98) of Dual-energy X-ray absorptiometry the evaluated HA gray values due to the respective calciumconcentration of the HA samples enables the calibration of BMD was measured by dual-energy X-ray absorptiometry (DXA) (Lunar Prodigy en Core 2007, GE Healthcare;Madison, WI, USA). Two skeletal areas, the left proximal Statistical analysis femur and the lumbar spine (L1–L4), were evaluated byDXA. The patients were scanned according to the manual All data are presented as means ± SD. Statistical analysis of supplied by the manufacturer and were placed in the supine histomorphometric values was compared using unpaired position. The detected BMD of the projected bone area was Student's t test. Statistical differences were considered expressed in grams per square centimeter (g/cm2), and the significant when p<0.05.
corresponding T-Score was calculated.
Parameters of static histomorphometry were quantified on Clinical diagnosis of hypophosphatasia toluidine blue–or von Kossa/van Gieson-stained non-decalcified sections of iliac crest biopsies. Analyses of Diagnosis of adult hypophosphatasia was based on character- bone volume (BV/TV), trabecular thickness (Tb.Th), istic clinical and laboratory findings. Pain and discomfort in trabecular number (Tb.N), trabecular separation (Tb.Sp), the thighs and hips were often present, and pseudofractures osteoid volume (OV/BV), osteoid surface (OS/BS), as well (Looser Zones), for example of the femur, fibula, or tibia, as the determination of osteoblast (N.Ob/B.Pm), osteoclast could be verified on plain X-ray films (Fig. ). Also number (N.Oc/B.Pm), osteocyte number (Ot.N/B.Ar/mm2) bone deformities, which occur with this disease, like and surface indices (Ob.S/BS and Oc.S/BS), mineralized pathologic alteration of the joint axis (Fig. ) and bowing bone volume (Md.V/TV), and osteoclasts surface per of the femur (Fig. ), were documented on radiographs. In mineralized bone surface (Oc.S/Md.BS) were carried out addition, we observed pathologic calcium accumulation in according to the ASBMR standards using the Osteo- other organs by ultrasound, especially in the kidney (Fig. Measure histomorphometry system (Osteometrics; Atlanta, DXA performed in the femur and lumbar spine demonstrated GA, USA) connected to a Zeiss microscope (Carl Zeiss; low BMDs in adult hypophosphatasia patients (Fig. ).
Jena, Germany) [We did not perform dynamic Biochemical analysis of serum, plasma, and urine demon- histomorphometry in our study.
strated reduced levels of alkaline phosphatase (AP) (27.8±4.5 U/l; normal range, 35–104 U/l), bone-specific alkaline Bone mineral density distribution measurements phosphatase (BAP) (5.0±1.4 μg/l; normal range, 6–26 μg/l) by quantitative backscattered electron imaging and elevated levels of pyridoxal phosphate (PLP) (41.2±14.4;normal range, 7.5–18.5 μg/l). In contrast, serum levels of BMD distribution (BMDD) measurements were performed phosphate, calcium, 25-OH vitamin D3, intact parathyroid on non-decalcified, coplanar polished, carbon-coated hormone (PTH), and creatinine were in the normal range, methylmethacrylate-embedded bone biopsies. The technical which ruled out the existence of secondary hyperparathy- application is based on the work of other groups using roidism (Fig. ). Pregnancy, anemia, hypothyroidosis, qBEI and has been reported previously –]. The anorexia, and malnutrition that can also cause decreased scanning electron microscope (LEO 435 VP; Cambridge, alkaline phosphatase levels were ruled out by clinical and England) was operated at 15 kV and 665 pA at a constant working distance (BSE Detector, type 202, K.E. Develop-ments Ltd.; Cambridge, England). The pixel size amounts Histological findings to 3 μm and lies within the recommendation range ofRoschger et al. []. The standardization of the method was The light microscopic findings of the iliac crest bone accomplished by the analysis of synthetic hydroxyapatite biopsies revealed distinct differences between hypophos- (HA). Seven HA samples with increasing Ca/P ratios (D.O.
phatasia patients and control individuals. The von Kossa/ T. Medical Solutions; Rostock, Germany) were evaluated van Gieson- or Goldner-stained specimens of the control


Fig. 1 Typical clinical aspects of adult hypophosphatasia. a X-ray bowing of the left femur (red line) is clearly visible by X-ray (lateral (oblique view) and b MRI (axial view) of the left lateral proximal view). e Results of bone densitometry and biochemical analysis. The femur of a 32-year-old male patient diagnosed with adult hypophos- normal ranges of all parameters are given on the right. Pathological phatasia. A pseudofracture in the femoral neck is indicated by the abnormalities in the hypophosphatasia patients (n=8) are highlighted arrow. c X-ray (a.p. view) of the right ankle joint of the same patient in boldface. f X-ray (lateral view) of the tibia showing a pseudo- showing also a pseudofracture in the distal fibula. In addition, a fracture of the tibial shaft (white arrow). g Ultrasound of the kidney pathologic tilt of the ankle joint axis was observed (dotted red line, illustrating a calcification spot as an echogenic focus (white arrow) pathologic axis; dotted black line, anatomic axis). d The pronounced with posterior acoustic shadowing (black arrow) group showed a normal orientation and distribution of the outline of the trabeculae seemed to be regularly formed, but trabeculae in the cancellous bone, with only thin layers of the impaired mineralization in hypophosphatasia patients osteoid (Fig. Compared to the control group, the resulted in an irregularly formed mineralized part of iliac crest biopsies of the hypophosphatasia patients were trabeculae lying underneath the thick osteoid layer remarkably different with increased osteoid volume (Fig. In fact, the interface between mineralized bone (Fig. In the toluidine blue-stained sections, the and unmineralized osteoid was irregularly shaped in


Fig. 2 Non-decalcified histology of iliac crest biopsies from healthyb individuals and adult hypophosphatasia patients. a von Kossa/vanGieson staining (×25 magnification) and b Goldner staining (×100magnification) showing an accumulation of osteoid (stained in red) inhypophosphatasia patients. The red arrow indicates a site where acomplete trabecule is bridged by osteoid. c Toluidine blue staining(×400 magnification) confirms the existence of thick osteoid layers(red arrows) in hypophosphatasia patients and demonstrated anincreased number of osteoblasts covering these surfaces. The whitearrows indicate scalloped appearance of the cement lines, which werecharacteristic for the hypophosphatasia cases. d Polarized brightfieldmicroscopy reveals an accumulation of osteoid (red arrows) but alsodemonstrates that the lamellar structures observed in control biopsies(white arrows) are impaired in the hypophosphatasia cases. The insertshows basophilic pellets accumulating on the osteoid, which was alsocharacteristic for the sections of the hypophosphatasia patients sections from hypophosphatasia patients, which resemblesthe findings reported by Balena et al., who has introducedthe term "scalloped cement lines" [ At the cellular level, both osteoclasts and osteoblasts appeared morphologically similar in the two groups.
However, toluidine-blue staining revealed an increasednumber of osteoblasts in the hypophosphatasia patients,which were orientated in line on the thick layer ofosteoid (Fig. ). Moreover, a polarized microscopic viewrevealed striking differences between the two groups. Infact, the regular structure of bone layers is disrupted inhypophosphatasia patients by areas of unmineralizedosteoid that seem to be randomly distributed (Fig. ).
At the interface of osteoid and mineralized bone, wefurther observed basophilic pellets, which may representclusters of calcium complexes (Fig. Interestingly,these structures did not progress uniformly outward fromthe cement line, thus implying that the deficiency of ALPLrather affects the initiation of mineralization, rather thanits continuation.
To quantify the observed structural changes, we performedhistomorphometry according to the guidelines of theAmerican Society for Bone and Mineral Research (Table ).
We first determined the trabecular bone volume (BV/TV)and found a non-significant increase in the biopsies derivedfrom the hypophosphatasia patients compared to the controlgroup. In addition, we observed a significant increase of thetrabecular number (Tb.N) and a significant decrease oftrabecular separation (Tb.Sp) and thickness (Tb.Th) insections from hypophosphatasia patients. As expected, thebiopsies from hypophosphatasia patients also showed asignificant increase in osteoid volume (OV/BV) and osteoidsurface (OS/BS) compared to biopsies taken from thecontrol group. Therefore, when we determined the miner-alized bone volume per tissue volume (Md.V/TV), therewas no increase in the hypophosphatasia cases.


Table 1 Histomorphometric parameters of the iliac crestbiopsies derived from healthy donors (control) and adulthypophosphatasia patients (HP) N.Ob/B.Pm (mm−1) N.Oc/B.Pm (mm−1) Shown are the mean values and standard deviation (SD) * P values below 0.05 were N.Oc/Md.BS (mm−1) considered statistically significant We next quantified the numbers of osteoblasts, osteo- To address the question, whether the increased clasts, and osteocytes. Here we found an increase of osteoblast number and the structural changes of trabec- osteoblast number (N.Ob/B.Pm) and surface (Ob.S/BS) in ular bone are generally observed in cases of osteomala- the hypophosphatasia patients, although their morphology cia, we further performed histomorphometry in biopsies appeared to be normal. In contrast, the number (N.Oc/B.
derived from eight individuals with low circulating 25 Pm) and surface of osteoclasts (Oc.S/BS) were not (OH)-vitamin D levels and from one patient suffering significantly different between the two groups, and the from X-linked hypophosphatemic rickets (Fig. In both same was the case for the osteocyte number (Ot.N/B.Ar/ cases, we found the expected pathological increases of mm2). Given the large increase of the osteoid surface in the osteoid volume and thickness, albeit both parameters were cases of adult hypophosphatasia, we further quantified the significantly lower in the cases of vitamin D deficiency osteoclast surface per mineralized bone surface (Oc.S/MS).
compared to adult hypophosphatasia. Most importantly, Here we observed a non-significant increase compared to however, the number of osteoblasts was only elevated in the control cases, which may explain, at least in part, the individuals with adult hypophosphatasia, but not in scalloped pattern of cement lines described above.
individuals with vitamin D deficiency, and the same was Fig. 3 Histomorphometricanalysis of iliac crest biopsiesderived from control individuals(CO) or from patients with adulthypophosphatasia (HP), vitaminD deficiency (VD) or X-linkedhypophosphatemic rickets(XLH). Bars represent means ±SD, and asterisks indicatestatistically significantdifferences (p<0.05) betweentwo groups (n=8)


the case for the changes in trabecular number and separation (Fig. ).
Bone mineral density distribution measurementsby quantitative backscattered electron imaging Since the histomorphometric analysis clearly confirmed thatthe major skeletal abnormality associated with an ALPLinactivation is a pathological impairment of matrix miner-alization, we finally addressed the question whether themineralized bone matrix in hypophosphatasia patientscontains the same amount and distribution of calcium,when compared to the control biopsies. This was achievedby measuring the BMDD using quantitative backscattered electron microscopy. Here we found that the mineraldistribution was indeed markedly impaired in sections fromhypophosphatasia patients, with an increased amount ofbone packets in a low mineralized state (Fig. In thehypophosphatasia sections, we further observed a reductionof bright pixels and a decrease of the mean gray valuecompared to the control cases, which is reflected by asignificantly decreased overall calcium content (Ca meanwt). The significantly lower calcium width (Ca width wt)reflects a less heterogenic structure due to the absence ofhighly mineralized bone packages (Fig. ). Again, weperformed the same measurements for the cases of vitamin D deficiency, but here we failed to detect a statisticallysignificant difference compared to the control group.
Interestingly, however, the overall calcium content (Camean wt) was decreased in the one case of X-linkedhypophosphatemic rickets, representing the influence ofPHEX inactivation on BMD, which needs to be confirmedin a larger number of affected individuals.
Fig. 4 Measurement of BMDD in non-decalcified bone biopsies fromhypophosphatasia patients and control individuals. a Quantitative Taken together, our study demonstrates that individuals backscattered electron images expressed by pseudo-colors (×25magnification). Highly mineralized bone is represented by brightly suffering from adult hypophosphatasia display specific colored pixels, whereas lower mineralized bone areas are predominant skeletal abnormalities, in addition to the previously estab- in darker colors. Completely unmineralized tissue, such as the bone lished osteomalacia. These include increased trabecular marrow, remains black. b The BMDD evaluated by the appropriate number, decreased trabecular separation, as well as gray levels characterizes the mineralization profile of the hypophos-phatasia patients (gray graph) and the control cases (black graph).
increased osteoblast number and surface compared to age- The evaluated histogram revealed an increase of mineralized bone matched control individuals and compared to individuals underlying primary mineralization in hypophosphatasia patients with osteomalacia due to low circulating vitamin D levels.
(mineralized bone beneath 17.68 wt.% Ca). c Quantification of the Moreover, we were able to show that the calcium content overall calcium content (Ca mean wt) and calcium width (Ca widthwt) for control individuals (CO) or for patients with adult hypophos- within the mineralized phase was significantly lower in the phatasia (HP), vitamin D deficiency (VD), or X-linked hypophospha- cases of hypophosphatasia, an aspect of the phenotype, temic rickets (XLH). Bars represent means ± SD, and asterisks which has not been addressed before. Although we can indicate statistically significant differences (p<0.05) between two only speculate whether these previously unrecognized skeletal abnormalities contribute to the increased fracturerate observed in hypophophatasia patients, we believe thatour data are an important contribution to our understanding of this disease, especially since there are only few control and vitamin D deficiency cases by qBEI measurement.
histomorphometric studies published so far , ].
Moreover, both the increased and decreased trabecular The largest of these studies, involving 17 patients with separations were specifically observed in the cases of adult adult hypophosphatasia, has been reported in 1984 ], hypophosphatasia, and there was also no increased number of which was 3 years before the standardization of histomor- osteoblasts in the cases of vitamin D deficiency. Taken phometric parameters by the American Society for Bone together, our findings have revealed some previously unrec- and Mineral Research [However, although there are ognized skeletal alterations in adult hypophosphatasia some structural histomorphometric parameters missing in patients, which are not generally observed in disorders with this study, the authors have clearly demonstrated an impaired skeletal mineralization.
accumulation of osteoid as the major abnormality. Thisosteomalacia was especially pronounced in the six individualswith a history of fractures (mean osteoid volume of 27.5%) The authors thank Ms. Olga Winter for excellent and less evident in individuals only displaying altered serum technical assistance in preparing the samples for qualitative and parameters, which were mostly first-degree relatives of the above-mentioned individuals (mean osteoid volume of 4.5%).
Conflicts of interest While there was no consistent change in the number ofosteoblasts observed in this collective, it was interesting thatthe five cases, where no enrichment of osteoid has been observed, displayed histological features of low bone turn-over, including a decrease of fluorescent labeling following 1. Mornet E (2008) Hypophosphatasia. Best Pract Res Clin Rheumatol 22:113–127 In this regard, we would like to point out that one major 2. Greenberg CR, Evans JA, McKendry-Smith S, Redekopp S, Haworth JC, Mulivor R, Chodirker BN (1990) Infantile weakness of our study is that the patients did not receive hypophosphatasia: localization within chromosome region tetracycline, thus excluding the possibility of dynamic 1p36.1-34 and prenatal diagnosis using linked DNA markers.
histomorphometry. However, as in our study, all hypophos- Am J Hum Genet 46:286–292 phatasia cases were characterized by a pathological accu- 3. Henthorn PS, Raducha M, Fedde KN, Lafferty MA, Whyte MP (1992) Different missense mutations at the tissue-nonspecific mulation of osteoid; we believe that it would have been alkaline phosphatase gene locus in autosomal recessively inherited difficult to demonstrate low bone turnover here, since in the forms of mild and severe hypophosphatasia. Proc Natl Acad Sci case of osteomalacia, one can only observe diffuse USA 89:9924–9928 tetracycline labeling, which cannot be utilized to determine 4. Henthorn PS, Whyte MP (1992) Missense mutations of the tissue- nonspecific alkaline phosphatase gene in hypophosphatasia. Clin the mineral apposition rate. Thus, it is probably most Chem 38:2501–2505 important that, besides the osteomalacia, we have found 5. Moore CA, Ward JC, Rivas ML, Magill HL, Whyte MP (1990) altered parameters of trabecular architecture, as well as Infantile hypophosphatasia: autosomal recessive transmission to increased numbers of osteoblasts, both of which have not two related sibships. Am J Med Genet 36:15–22 6. Orimo H, Goseki-Sone M, Sato S, Shimada T (1997) Detection of been reported for the patients analyzed by Fallon et al.
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GLI ABSTRACTS DI ALCUNE PUBBLICAZIONI SCIENTIFICHE RECENSITE NELL'ANNO 2007 DA MEDLINE, LA PIÙ IMPORTANTE BASE DI DATI DELLA LETTERATURA BIOMEDICA MONDIALE. Come si può vedere, la ricerca nel campo dell'agopuntura è molto attiva ed è orientata nei settori più disparati della scienza biomedica. Chi fosse interessato a reperire tutti i lavori

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December 5, 2014 Emerging Strategies for the Immunotherapy of Pancreatic Cancer Elizabeth M. Jaffee, M.D. Dana and Albert Broccoli Professor of Oncology Skip Viragh Pancreatic Cancer Center Sidney Kimmel Cancer Center at Johns Hopkins Disclosure Information Elizabeth M. Jaffee, M.D. I have the following financial relationships to disclose