Pierre Bedossa

Paris Diderot University, Lutetia Parisorum, Île-de-France, France

Are you Pierre Bedossa?

Claim your profile

Publications (482)2957.03 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background and aims: Although potentially very useful in optimizing patient selection and follow-up, the individual response to transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) is generally unpredictable. The aim of this study was to identify tissue predictors of tumor resistance to TACE for use in clinical practice on pre-treatment biopsies. Methods: We investigated the association of residual tumor in post-TACE-resected HCC with pathological and immunophenotypical features, mainly related to hypoxia and angiogenesis. Comparison of tumor phenotype between post-TACE HCC and both paired pre-TACE biopsies and control TACE-untreated HCC was performed. Cases showing >50% residual tumor (RT) were defined as TACE-resistant. Results: A consecutive series of 108 HCC from 41 patients was studied. Overall, 45/108 (44%) HCC were classified as TACE-resistant. Among these, 32 (71%) and 40 (89%) showed diffuse CD34 vascular staining and negative VEGF staining, respectively (p<0.05). The association of these 2 parameters in a weighted score (TRIP) was able to predict TACE resistance with 81% accuracy, 89% sensitivity and 59% specificity. The effectiveness of TRIP was validated in an independent series of 28 HCC biopsies from patients subsequently treated with TACE and for whom radiologic follow-up was available. Conclusion: This study demonstrates the potential value of pre-treatment tumor biopsy as predictors of TACE resistance in HCC. This article is protected by copyright. All rights reserved.
    Liver International 10/2015; DOI:10.1111/liv.12844.
  • Pancreas 05/2015; 44(4):672-674. DOI:10.1097/MPA.0000000000000319 · 3.01 Impact Factor
  • Keyur Patel, Pierre Bedossa, Laurent Castera
    [Show abstract] [Hide abstract]
    ABSTRACT: The diagnostic assessment of liver fibrosis, a major determinant of disease severity, is an important step in the management of patients with chronic liver diseases. Liver biopsy is still considered the gold standard for the assessment of necroinflammation and fibrosis; however, recent technical advances have resulted in the development of numerous serum biomarkers and imaging tools as noninvasive alternatives to biopsy. These tests include biological (serum biomarker algorithms), physical (imaging assessment of tissue stiffness), and physiological (breath test) methods. Accumulating evidence shows that noninvasive tests provide prognostic information of clinical relevance, which has led to their incorporation into clinical guidelines and everyday practice. Here, the authors review and compare invasive and noninvasive tests for the diagnosis of liver fibrosis. They discuss emerging functional genomic, microparticle, protein-profiling, and bioimaging tools, focusing on novel sensitive tools that are able to assess the dynamic nature of fibrogenesis, a key requirement for the assessment of the efficacy of antifibrotic compounds in the future. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
    Seminars in Liver Disease 05/2015; 35(2):166-83. DOI:10.1055/s-0035-1550059 · 5.12 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although potentially very useful in optimizing patient selection and follow-up, the individual response to transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) is generally unpredictable. The aim of this study was to identify tissue predictors of tumor resistance to TACE for use in clinical practice on pre-treatment biopsies. We investigated the association of residual tumor in post-TACE-resected HCC with pathological and immunophenotypical features, mainly related to hypoxia and angiogenesis. Comparison of tumor phenotype between post-TACE HCC and both paired pre-TACE biopsies and control TACE-untreated HCC was performed. Cases showing >50% residual tumor (RT) were defined as TACE-resistant. A consecutive series of 108 HCC from 41 patients was studied. Overall, 45/108 (44%) HCC were classified as TACE-resistant. Among these, 32 (71%) and 40 (89%) showed diffuse CD34 vascular staining and negative VEGF staining, respectively (p<0.05). The association of these 2 parameters in a weighted score (TRIP) was able to predict TACE resistance with 81% accuracy, 89% sensitivity and 59% specificity. The effectiveness of TRIP was validated in an independent series of 28 HCC biopsies from patients subsequently treated with TACE and for whom radiologic follow-up was available. This study demonstrates the potential value of pre-treatment tumor biopsy as predictors of TACE resistance in HCC. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 04/2015; DOI:10.1111/liv.12844 · 4.41 Impact Factor
  • Gastroenterology 04/2015; 148(4):S-935. DOI:10.1016/S0016-5085(15)33185-1 · 13.93 Impact Factor
  • Gastroenterology 04/2015; 148(4):S-928. DOI:10.1016/S0016-5085(15)33156-5 · 13.93 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Macrophages play an important role in non-alcoholic fatty liver disease (NAFLD). Soluble CD163 (sCD163) is a specific marker of macrophage activation. We aimed to measure sCD163 in morbidly obese patients with varying degrees of NAFLD before and after bariatric surgery (BS). Demographic, clinical and biochemical data, and plasma sCD163 measured by ELISA, of 196 patients were collected preoperatively and 3, 6 and 12 months after BS leading to significant weight loss. Peroperative liver biopsies were assessed for the NAFLD Activity Score (NAS), Kleiner fibrosis score and the FLIP algorithm. In a subset, CD163 immunohistochemistry and real-time quantitative PCR for CD163 mRNA were performed. sCD163 was higher in patients with NAS≥5 compared to those with NAS<5 (2.4(2.0-3.1) vs. 1.9(1.5-2.3) mg/L, p<0.001) and in patients with bridging fibrosis (F≥3) compared to lower fibrosis stages (2.6(2.0-4.9) vs. 2.0(1.5-2.4) mg/L, p=0.001). Preoperative sCD163 was independently associated with both the NAS (p=0.002) and the fibrosis score (p=0.024). sCD163 decreased after BS and was greatly reduced after 12 months, more rapidly so in patients with NAS≥5 (p<0.001) and NASH according to the FLIP algorithm (p=0.03). Immunohistochemistry showed CD163-positive macrophages aligning fat-laden hepatocytes and forming microgranulomas in patients with NASH. CD163 mRNA expression did not vary with NAS. sCD163 increased in parallel with the severity of NAFLD in morbid obesity, indicating macrophage activation. Bariatric surgery reduced sCD163 even in patients with severe liver injury and fibrosis, suggesting full reversibility of macrophage activation associated with improved insulin sensitivity. This article is protected by copyright. All rights reserved.
    Journal of Gastroenterology and Hepatology 03/2015; DOI:10.1111/jgh.12943 · 3.63 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Contextc-Met is an emerging biomarker in pancreatic ductal adenocarcinoma (PDAC); its immunostaining scoring method is not consensual.Materials and methodsc-Met immunostaining was graded using the validated MetMab score, a classic visual scale combining surface and intensity (SI score), or a simplified score (high c-Met: ≥20% of cancer cells with strong membrane staining) in stage I-II PDAC. Computer-assisted classification (Aperio® software) was developed. Clinicopathological parameters were correlated with disease-free (DFS) and overall (OS) survival.Results149 patients were analyzed retrospectively in a two-step process. Thirty-seven samples (whole slides) were analyzed as a pre-run test. Reproducibility values were optimal with the simplified score (kappa=0.773); high c-Met expression (7/37) was associated with shorter DFS (HR=3.456, p=0.0036) and OS (HR=4.257, p=0.0004). c-Met expression was concordant on whole slides and tissue microarrays in 87.9% of samples, and quantifiable using a specific computer-assisted algorithm. In the whole cohort (n=131), patients with c-Methigh tumors (36/131) had significantly shorter DFS (9.3 versus 20.0 months, HR=2.165, p=0.0005) and OS (18.2 versus 35.0 months, HR=1.832, p=0.0098) in univariate and multivariate analysis.Conclusion Simplified c-Met expression is an independent prognostic marker in stage I-II PDAC that may help identify patients with high risk of tumor relapse and poor survival.This article is protected by copyright. All rights reserved.
    Histopathology 03/2015; DOI:10.1111/his.12691 · 3.30 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: The roles of intravisceral and subcutaneous fat are unknown and the prevalence of precancerous lesions in obese patients was never evaluated. Aims- To assess the frequency and severity of pancreatic intraepithelial neoplasia (PanIN), to correlate pathological findings with metabolic abnormalities, type of fat and fatty pancreatic infiltration. Experimental Design: Normal pancreatic tissue from surgical specimens was analyzed. Fatty infiltration and fibrosis in intra- and extralobular locations, PanIN were assessed. General characteristics were collected: body mass index (BMI), diabetes and tobacco intake. Liver steatosis, subcutaneous and intravisceral fat were assessed by CT scan (ImageJ software). Results- 110 patients were included (median age: 53.8 [17-85] years). Arterial hypertension, diabetes, tobacco intake were found in 19, 9 and 23%, respectively. Median BMI was 24 [16-37], (BMI<25: 45%, 25-<30: 24%, ≥30: 11%). Overall, PanIN lesions were found in 65% (Type 1, 2 and 3 PanIN in 62, 38 and 1%, respectively). Fibrosis and fatty pancreas (intra- and extralobular locations) were found in 1% and 24% and in 30% and 51%, respectively. A correlation was observed between PanIN lesions and fatty pancreas [extra- (0.01) and intralobular (<0.0001)], intralobular fibrosis (0.003), high BMI (p=0.02), subcutaneous (p=0.02) and intravisceral fat (p=0.02). The number of PanIN lesions was correlated with the intravisceral fat (r=0,22, p=0,04) but not with the subcutaneous fat (r=0.14, p=0.22). In multivariate analysis, PanIN were associated with intralobular fibrosis (OR=5.61 [1.18-42.99]) and the intralobular fat (OR=17.86 [4.935-88.12]). Conclusions: Obesity (android obesity, especially) and pancreatic fatty infiltration are risk factors for pancreatic precancerous lesions. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 02/2015; DOI:10.1158/1078-0432.CCR-14-2385 · 8.19 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Assessing fibrosis is essential in patients with chronic hepatitis B (CHB). The objective was to investigate the relationship between fibrosis, host and viral factors to identify non-invasive markers of significant fibrosis in a large cohort of unselected, well-characterized, treatment-naïve CHB patients. Three hundred and seventy-seven HBsAg positive patients (97 HBeAg-positive and 280 HBeAg-negative, genotypes A to E) who had liver biopsy were consecutively included. Host and viral factors (ALT, HBsAg and HBV-DNA levels, HBV genotype and precore (PC) / basal core promoter (BCP) variants) were determined on the day of the biopsy. Fibrosis stage was assessed using METAVIR score. 38% of the patients had significant fibrosis (METAVIR F≥2). On univariate analysis, the stages of fibrosis F≥2 were associated with older age (P<0.0001), male gender (P=0.01), higher ALT and HBV-DNA levels (P<0.0001 and P=0.0003, respectively), the presence of BCP (P<0.0001) and BCP/PC variants (P<0.0001). On multivariate analysis, age (P<0.0001), the presence of HBV variants (P<.0001), HBV-DNA level (P=0.0006) and ALT level (P=0.02) were independently associated with significant fibrosis. The diagnostic accuracy of the combination (age, ALT, HBV-DNA, HBV variants) in predicting fibrosis F≥2 was evidenced by a c-index of 0.76 [CI 95% 0.71-0.81]. We identified strong independent risk factors (age, ALT, HBV-DNA, HBV variants) predicting significant fibrosis (F≥2) independently of HBeAg status in patients with CHB. Patients with BCP variants have a higher risk of severe liver disease. The detection of these mutants may help to predict significant fibrosis (F≥2). This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 01/2015; DOI:10.1111/liv.12787 · 4.41 Impact Factor
  • Pierre Bedossa
    [Show abstract] [Hide abstract]
    ABSTRACT: The end point of liver fibrosis in almost all chronic liver diseases including HBV chronic hepatitis is cirrhosis. Progression to cirrhosis is associated with annular deposition of fibrous tissue and vascular remodeling with a shift from a lobular to nodular organization. Although advanced liver fibrosis was previously thought to be irreversible, today there is compelling evidence that cirrhosis can be reversed if the underlying cause of liver injury is eliminated. Indeed, most clinical trials with antiviral therapy and histological follow-up have shown that fibrosis can regress and that in some cases even cirrhosis can reverse following long-term HBV-DNA suppression, although the return to a fully normal liver is rarely observed and difficult to prove. Nevertheless, a marked percentage of cirrhosis will not reverse even after effective antiviral therapy. Generally cirrhosis is more likely to regress if it is recent, there is effective and long-lasting viral suppression, an internal capacity to regenerate and no vascular thrombosis. HBV treatment in patients with cirrhosis is associated with an improved clinical outcome although there may still be a risk of hepatocellular carcinoma. Nevertheless it has not yet been determined if a favorable outcome depends on histological regression or whether the reversal of cirrhosis is merely a surrogate marker of viral suppression. The significance of the reversal of cirrhosis is still a subject of debate because neither the histological scoring systems nor non-invasive markers to evaluate the reversal of cirrhosis have been validated.
    Liver international: official journal of the International Association for the Study of the Liver 01/2015; 35(s1). DOI:10.1111/liv.12710 · 4.41 Impact Factor
  • Human pathology 12/2014; 46(4). DOI:10.1016/j.humpath.2014.10.030 · 2.81 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: There are very few studies on the incidence and risk factors of hepatitis C virus (HCV)-induced hepatocellular carcinoma (HCC) in the absence of advanced fibrosis. Our objective was to identify the clinical-pathological features of these patients. We retrospectively reviewed 162 patients admitted to our hospital for HCV-related HCC between 2000 and 2010. Patients with hepatitis of other aetiologies, human immunodeficiency virus co-infection, or treated with interferon were excluded. We compared demographic, laboratory, clinical and outcome parameters of patients with and without advanced fibrosis. 137 patients had advanced fibrosis (85%). Median age was higher in the advanced fibrosis vs. the non-advanced fibrosis group (62 vs. 65 years, respectively; p=0.025). Steatosis was significantly more frequent in patients with advanced fibrosis compared to those without advanced fibrosis (43% vs. 20%, respectively; p=0.032). Independent predictors associated to the occurrence of HCC in patients without advanced fibrosis were hepatitis B core antigen (odds ratio: 3.86; p=0.044) and duration of hepatitis C infection (odds ratio: 1.21; p=0.003). Risk factors such as steatosis or diabetes were not frequent in patients without advanced fibrosis. Further studies are needed to evaluate the role of occult hepatitis B and the duration of hepatitis infection in patients with HCC and chronic hepatitis C without advanced fibrosis. Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
    Digestive and Liver Disease 12/2014; 47(4). DOI:10.1016/j.dld.2014.12.010 · 2.89 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Context: Liver and white adipose tissue (WAT) develop inflammation and fibrosis. Objective: The aim of the study was to evaluate the bioclinical relevance of WAT fibrosis in morbid obesity and diabetes and the relationships with tissue stiffness measured using a novel device. Design and Setting: Observational and longitudinal studies were conducted in a hospital nutrition department. Patients: Biopsies of liver and subcutaneous WAT (scWAT) and omental adipose tissue were collected from 404 obese bariatric surgery candidates, of whom 243 were clinically characterized before surgery and 3, 6, and 12 months after surgery. In 123 subjects, liver and scWAT stiffness was assessed noninvasively using vibration-controlled transient elastography (VCTE). Interventions: Bariatric surgery was performed for some patients. Main Outcome Measure: Adipose tissue fibrosis and stiffness and their link to obesity phenotypes were measured. Results: scWAT fibrosis was positively associated with liver fibrosis (fibrosis score ≥ 2) ([GRAPHIC] = 0.14; P = .01). VCTE-evaluated liver and scWAT stiffness was positively correlated with immunohistochemistry-determined liver ([GRAPHIC] = 0.46; P = .0009) and scWAT fibrosis ([GRAPHIC] = 0.48; P = .0001). VCTE-evaluated scWAT stiffness measures negatively associated with dual-energy x-ray absorptiometry-evaluated body fat mass (R = -0.25; P = .009) and were correlated with metabolic variables. Diabetic subjects showed increased scWAT stiffness. Participants less responsive to gastric bypass were older and more frequently diabetic, and they had increased body mass index, serum IL-6, and scWAT and liver fibrosis. Subjects with no diabetes and normal liver had higher fat mass and lower tissue fibrosis and stiffness. Conclusion: scWAT stiffness was associated with tissue fibrosis, obesity, and diabetes-related traits. Noninvasive evaluation of scWAT stiffness might be useful in clinical practice.
    The Journal of Clinical Endocrinology and Metabolism 12/2014; 99(3):jc20133253. DOI:10.1210/jc.2013-3253 · 6.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cirrhosis is a lesion at risk of hepatocellular carcinoma (HCC). Identifying mechanisms associated with the transition from cirrhosis to HCC and characterizing biomarkers of cirrhosis at high risk of developing into cancer are crucial for improving early diagnosis and prognosis of HCC. We used MALDI imaging to compare mass spectra obtained from tissue sections of cirrhosis without HCC, cirrhosis with HCC and HCC, and top-down proteomics approach to characterize differential biomarkers. We identified a truncated form of monomeric ubiquitin lacking the two C-terminal glycine residues, Ubi(1–74), the level of which increased progressively, from cirrhosis without HCC to cirrhosis with HCC, to HCC. We showed that kallikrein-related peptidase 6 (KLK6) catalyzed the production of Ubi(1–74) from monomeric ubiquitin. Furthermore, we demonstrated that KLK6 was induced de novo in cirrhosis and increased in HCC in parallel with accumulation of Ubi(1–74). We investigated in vitro the possible consequences of Ubi(1–74) accumulation, and demonstrated that Ubi(1–74) interferes with the normal ubiquitination machinery in what is likely to be a kinetic process. Our data suggests that de novo KLK6 expression during early liver carcinogenesis may induce production of Ubi(1–74) by post-translational modification of ubiquitin. Given the deleterious effect of Ubi(1–74) on protein ubiquitination and the major role of ubiquitin machinery in maintenance of cell homeostasis, Ubi(1–74) might severely impacts a number of critical cellular functions during transition from cirrhosis to cancer. Ubi(1–74), and KLK6 may serve as a marker of cancer risk in patients with cirrhosis.
    The Journal of Pathology 12/2014; 234(4). DOI:10.1002/path.4398 · 7.33 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Prothrombin induced by vitamin K absence-II (PIVKA-II) is a diagnostic and surveillance marker for HCC mainly used in Asia, and has also been shown to be a predictor of microvascular invasion (MVI), a major prognostic factor in HCC. However, experience with PIVKA-II in Europe remains limited.Methods In a French cohort, we conducted a case-control study to compare the performances of α-fetoprotein (AFP) and PIVKA-II serum levels for diagnosis of early stage HCC, and we determined the value of PIVKA-II serum and tissue expression in pre-operative detection of MVI. 43 cirrhotic controls and 85 HCC cases were included, of which 54 (63.5%) had early stage HCC (n=22 very early, n=32 early). PIVKA-II tissue expression was assessed by immunohistochemistry in HCC surgical samples.ResultsFor the diagnosis of early HCC, PIVKA-II had a sensitivity of 77% and a specificity of 82% at a cutoff of 42 mAU/mL, versus 61% and 50% for AFP at a cutoff of 5.5 ng/mL (AUC 0.81 versus 0.58, respectively). A PIVKA-II level > 90 mAU/mL was an independent predictor of MVI (HR 3.5; 95% CI 1.08-11.8; p=0.043). High PIVKA-II tissue expression was significantly associated with the presence of MVI (p=0.001). When combining PIVKA-II immunostaining with the PIVKA-II serum level, sensitivity and specificity for the diagnosis of MVI increased from 70% to 87% and 63% to 90%, respectively.ConclusionsPIVKA-II was more efficient than AFP for the diagnosis of early HCC, and could be used as a predictive biomarker of MVI.
    Journal of Hepatology 11/2014; 62(4). DOI:10.1016/j.jhep.2014.11.005 · 10.40 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Nonalcoholic steatohepatitis (NASH) is characterized by steatosis, lobular inflammation, hepatocyte ballooning with fibrosis in severe cases and high prevalence in obesity. We aimed at defining NASH signature in morbid obesity by mass spectrometry-based lipidomic analysis.
    Journal of Hepatology 11/2014; 62(4). DOI:10.1016/j.jhep.2014.11.002 · 10.40 Impact Factor
  • Hepatology 10/2014; 60(4 (SUPPL)):600A. · 11.19 Impact Factor
  • Hepatology 10/2014; 60(4 (SUPPL)):627A. · 11.19 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):3824-3824. DOI:10.1158/1538-7445.AM2014-3824 · 9.28 Impact Factor

Publication Stats

18k Citations
2,957.03 Total Impact Points

Institutions

  • 2006–2015
    • Paris Diderot University
      • Centre de recherche biomédicale Bichat, Beaujon (CRB3) UMR-S 773
      Lutetia Parisorum, Île-de-France, France
  • 2001–2015
    • Assistance Publique – Hôpitaux de Paris
      • • Departement de Pathologie
      • • Department of Radiology
      Lutetia Parisorum, Île-de-France, France
  • 2013
    • Pierre and Marie Curie University - Paris 6
      Lutetia Parisorum, Île-de-France, France
  • 2008–2012
    • University of Paris-Est
      La Haye-Descartes, Centre, France
    • Centre Hospitalier Universitaire de Grenoble
      Grenoble, Rhône-Alpes, France
  • 2011
    • Toronto Western Hospital
      Toronto, Ontario, Canada
  • 2007–2011
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2010
    • Università degli Studi di Palermo
      • Department of Scienze per la promozione della Salute "G. D'Alessandro"
      Palermo, Sicily, Italy
  • 2007–2010
    • Hôpital Beaujon – Hôpitaux Universitaires Paris Nord Val de Seine
      Clicy, Île-de-France, France
  • 2006–2010
    • French Institute of Health and Medical Research
      • Center of Biomedical Research Bichat-Beaujon
      Lutetia Parisorum, Île-de-France, France
  • 1997–2010
    • Université René Descartes - Paris 5
      Lutetia Parisorum, Île-de-France, France
    • University of Angers
      Angers, Pays de la Loire, France
  • 2009
    • Alphabio
      Marsiglia, Provence-Alpes-Côte d'Azur, France
    • Université de Versailles Saint-Quentin
      Versailles, Île-de-France, France
  • 1993–2008
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 2005–2006
    • Centre Hospitalier Universitaire de Dijon
      Dijon, Bourgogne, France
  • 1987–2006
    • Hôpital Antoine-Béclère – Hôpitaux universitaires Paris-Sud
      Clamart, Île-de-France, France
  • 1998–2005
    • Université Paris-Sud 11
      • Faculty of Medicine
      Orsay, Île-de-France, France
  • 1999–2004
    • Centre Hospitalier Universitaire d'Angers
      • Service d'hépatologie gastro-entérologie
      Angers, Pays de la Loire, France
    • Hôpital Bicêtre (Hôpitaux Universitaires Paris-Sud)
      Lutetia Parisorum, Île-de-France, France
  • 1995–2002
    • Hôpital La Pitié Salpêtrière (Groupe Hospitalier "La Pitié Salpêtrière - Charles Foix")
      • Service d’Hépato - Gastro - Entérologie
      Lutetia Parisorum, Île-de-France, France
  • 1994
    • University of California, San Diego
      • Department of Medicine
      San Diego, California, United States