Harry P W Kozakewich

Harvard Medical School, Boston, Massachusetts, United States

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Publications (186)

  • Article · Jun 2016 · The American Journal of Human Genetics
  • Pradeep Goyal · Ahmad I Alomari · Harry P Kozakewich · [...] · Gulraiz Chaudry
    [Show abstract] [Hide abstract] ABSTRACT: Background Kaposiform lymphangiomatosis is a rare, aggressive lymphatic disorder. The imaging and presenting features of kaposiform lymphangiomatosis can overlap with those of central conducting lymphatic anomaly and generalized lymphatic anomaly. Objective To analyze the imaging findings of kaposiform lymphangiomatosis disorder and highlight features most suggestive of this diagnosis. Materials and methods We retrospectively identified and characterized 20 children and young adults with histopathological diagnosis of kaposiform lymphangiomatosis and radiologic imaging referred to the vascular anomalies center between 1995 and 2015. Results The median age at onset was 6.5 years (range 3 months to 27 years). The most common presenting features were respiratory compromise (dyspnea, cough, chest pain; 55.5%), swelling/mass (25%), bleeding (15%) and fracture (5%). The thoracic cavity was involved in all patients; all patients had mediastinal involvement followed by lung parenchymal disease (90%) and pleural (85%) and pericardial (50%) effusions. The most common extra-thoracic sites of disease were the retroperitoneum (80%), bone (60%), abdominal viscera (55%) and muscles (45%). There was characteristic enhancing and infiltrative soft-tissue thickening in the mediastinum and retroperitoneum extending along the lymphatic distribution. Conclusion Kaposiform lymphangiomatosis has overlapping imaging features with central conducting lymphatic anomaly and generalized lymphatic anomaly. Presence of mediastinal or retroperitoneal enhancing and infiltrative soft-tissue disease along the lymphatic distribution, hemorrhagic effusions and moderate thrombocytopenia (50–100,000/μl) should favor diagnosis of kaposiform lymphangiomatosis.
    Article · Apr 2016 · Pediatric Radiology
  • [Show abstract] [Hide abstract] ABSTRACT: Congenital hemangioma is a rare vascular tumor that forms in utero. Postnatally, the tumor either involutes quickly (i.e., rapidly involuting congenital hemangioma [RICH]) or partially regresses and stabilizes (i.e., non-involuting congenital hemangioma [NICH]). We hypothesized that congenital hemangiomas arise due to somatic mutation and performed massively parallel mRNA sequencing on affected tissue from eight participants. We identified mutually exclusive, mosaic missense mutations that alter glutamine at amino acid 209 (Glu209) in GNAQ or GNA11 in all tested samples, at variant allele frequencies (VAF) ranging from 3% to 33%. We verified the presence of the mutations in genomic DNA using a combination of molecular inversion probe sequencing (MIP-seq) and digital droplet PCR (ddPCR). The Glu209 GNAQ and GNA11 missense variants we identified are common in uveal melanoma and have been shown to constitutively activate MAPK and/or YAP signaling. When we screened additional archival formalin-fixed paraffin-embedded (FFPE) congenital cutaneous and hepatic hemangiomas, 4/8 had GNAQ or GNA11 Glu209 variants. The same GNAQ or GNA11 mutation is found in both NICH and RICH, so other factors must account for these tumors' different postnatal behaviors.
    Article · Apr 2016 · The American Journal of Human Genetics
  • [Show abstract] [Hide abstract] ABSTRACT: Fatty acid-binding proteins (FABP) are small molecular mass intracellular lipid chaperones that are expressed in a tissue-specific manner with some overlaps. FABP4 and FABP5 share ~55 % amino acid sequence homology and demonstrate synergistic effects in regulation of metabolic and inflammatory responses in adipocytes and macrophages. Recent studies have shown that FABP4 and FABP5 are also co-expressed in a subset of endothelial cells (EC). FABP4, which has a primarily microvascular distribution, enhances angiogenic responses of ECs, including proliferation, migration, and survival. However, the vascular expression of FABP5 has not been well characterized, and the role of FABP5 in regulation of angiogenic responses in ECs has not been studied to date. Herein we report that while FABP4 and FABP5 are co-expressed in microvascular ECs in several tissues, FABP5 expression is also detected in ECs of larger blood vessels. In contrast to FABP4, EC-FABP5 levels are not induced by VEGF-A or bFGF. FABP5 deficiency leads to a profound impairment in EC proliferation and chemotactic migration. These effects are recapitulated in an ex vivo assay of angiogenesis, the aortic ring assay. Interestingly, in contrast to FABP4-deficient ECs, FABP5-deficient ECs are significantly more resistant to apoptotic cell death. The effect of FABP5 on EC proliferation and survival is mediated, only in part, by PPARδ-dependent pathways. Collectively, these findings demonstrate that EC-FABP5, similar to EC-FABP4, promotes angiogenic responses under certain conditions, but it can also exert opposing effects on EC survival as compared to EC-FABP4. Thus, the balance between FABP4 and FABP5 in ECs may be important in regulation of angiogenic versus quiescent phenotypes in blood vessels.
    Article · Dec 2015 · Angiogenesis
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    [Show abstract] [Hide abstract] ABSTRACT: Pediatric hepatic angiosarcoma (PHAS) is extremely rare, with only five reported tumor-free survivors. Aggressive surgical resection and chemotherapy have been the management in all documented survivors of this disease, however no specific treatment guidelines are established. We present a case of PHAS with the longest reported tumor-free survival at over six years off therapy.
    Full-text available · Article · Sep 2015 · Journal of Pediatric Surgery Case Reports
  • [Show abstract] [Hide abstract] ABSTRACT: Many benign and malignant soft tissue tumors in children are challenging and their diagnosis requires knowledge of their vast diversity, histopathological complexity, and immunohistochemical, cytogenetic, and molecular characteristics. The importance of clinical and imaging features cannot be overstated. Soft tissue sarcomas account for 15% of all pediatric malignancies after leukemia/lymphoma, central nervous system tumors, neuroblastoma and Wilms tumor. This article discusses selected challenging pediatric soft tissue tumors with an update on recently described entities. Copyright © 2015 Elsevier Inc. All rights reserved.
    Article · Sep 2015
  • [Show abstract] [Hide abstract] ABSTRACT: We report 33 pure yolk sac tumors of the testis from boys 5 to 71 months of age (mean 20.7 mo) diagnosed from 1918 to 2014. All except 1 underwent orchiectomy, with lymph node dissections (all negative) performed in 18; 21 also received chemotherapy and 12 radiotherapy. The tumors were 1.6 to 7.0 cm (mean 3.7 cm) and were nonencapsulated, with a gray to yellow, often mucoid, cut surface. The commonest pattern was reticular-microcystic, but macrocystic, papillary, endodermal sinus (Schiller-Duval bodies), labyrinthine, myxomatous, glandular, and solid patterns were also observed. Follow-up was available for 32 patients (mean 100.5 mo; range, 3 to 456 mo). Twenty-four patients (including 4 who did not receive adjuvant therapy) were without evidence of disease, 8 had metastatic disease; 5 of the latter died of tumor and 1 of treatment complications. Two patients with metastasis were cured with radiation with or without chemotherapy. Two or more of the following were associated with a poor outcome in patients presenting with stage I cases: tumor size >4.5 cm (4/6 tumors [67%]), invasion of rete testis and/or epididymis (3/7 tumors [43%]), and necrosis (6/17 tumors [35%]). In the nonmetastasizing group, 2 or more unfavorable features occurred in only 3/24 tumors (13%) (P=0.0001). It is crucial that this tumor be distinguished from the juvenile granulosa cell tumor, which occurs at a slightly younger age and has distinctive features, although there may be some morphologic overlap. The survival of young boys with testicular yolk sac tumor is very good because of both effective chemotherapy and likely, the inherent characteristics of the tumor in this age group.
    Article · Mar 2015 · The American journal of surgical pathology
  • Javier A Couto · Matthew P Vivero · Harry P W Kozakewich · [...] · Arin K Greene
    [Show abstract] [Hide abstract] ABSTRACT: Verrucous venous malformation (VVM), also called "verrucous hemangioma," is a non-hereditary, congenital, vascular anomaly comprised of aberrant clusters of malformed dermal venule-like channels underlying hyperkeratotic skin. We tested the hypothesis that VVM lesions arise as a consequence of a somatic mutation. We performed whole-exome sequencing (WES) on VVM tissue from six unrelated individuals and looked for somatic mutations affecting the same gene in specimens from multiple persons. We observed mosaicism for a missense mutation (NM_002401.3, c.1323C>G; NP_002392, p.Iso441Met) in mitogen-activated protein kinase kinase kinase 3 (MAP3K3) in three of six individuals. We confirmed the presence of this mutation via droplet digital PCR (ddPCR) in the three subjects and found the mutation in three additional specimens from another four participants. Mutant allele frequencies ranged from 6% to 19% in affected tissue. We did not observe this mutant allele in unaffected tissue or in affected tissue from individuals with other types of vascular anomalies. Studies using global and conditional Map3k3 knockout mice have previously implicated MAP3K3 in vascular development. MAP3K3 dysfunction probably causes VVM in humans. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    Article · Feb 2015 · The American Journal of Human Genetics
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    [Show abstract] [Hide abstract] ABSTRACT: To test the hypothesis that somatic phosphatidylinositol-4,5-bisphospate 3-kinase, catalytic subunit alpha (PIK3CA) mutations would be found in patients with more common disorders including isolated lymphatic malformation (LM) and Klippel-Trenaunay syndrome (KTS). We used next generation sequencing, droplet digital polymerase chain reaction, and single molecule molecular inversion probes to search for somatic PIK3CA mutations in affected tissue from patients seen at Boston Children's Hospital who had an isolated LM (n = 17), KTS (n = 21), fibro-adipose vascular anomaly (n = 8), or congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies syndrome (n = 33), the disorder for which we first identified somatic PIK3CA mutations. We also screened 5 of the more common PIK3CA mutations in a second cohort of patients with LM (n = 31) from Seattle Children's Hospital. Most individuals from Boston Children's Hospital who had isolated LM (16/17) or LM as part of a syndrome, such as KTS (19/21), fibro-adipose vascular anomaly (5/8), and congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies syndrome (31/33) were somatic mosaic for PIK3CA mutations, with 5 specific PIK3CA mutations accounting for ∼80% of cases. Seventy-four percent of patients with LM from Seattle Children's Hospital also were somatic mosaic for 1 of 5 specific PIK3CA mutations. Many affected tissue specimens from both cohorts contained fewer than 10% mutant cells. Somatic PIK3CA mutations are the most common cause of isolated LMs and disorders in which LM is a component feature. Five PIK3CA mutations account for most cases. The search for causal mutations requires sampling of affected tissues and techniques that are capable of detecting low-level somatic mosaicism because the abundance of mutant cells in a malformed tissue can be low. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text available · Article · Feb 2015 · Journal of Pediatrics
  • Nick M Shillingford · Monica L Calicchio · Lisa A Teot · [...] · Harry P W Kozakewich
    [Show abstract] [Hide abstract] ABSTRACT: Microvillus inclusion disease (MVID) is a rare congenital disorder that manifests early in infancy as intractable watery diarrhea. The entity is characterized morphologically by a deficient brush border and apical cytoplasmic inclusions within absorptive cells (enterocytes) due to misplaced assembly of brush border proteins. The diagnosis is based upon histopathology, special stains, immunohistochemistry (IHC), and ultimately upon electron microscopy. Currently, the periodic acid-Schiff stain (PAS) and CD10 IHC are commonly used as adjuncts, but in addition to brush border structures, they stain a variety of apical cytoplasmic inclusions and organelles, thereby interfering with recognition of microvillus inclusions. Villin is a protein that specifically binds to the actin core bundle of microvilli. We utilized villin IHC in formalin-fixed paraffin-embedded gastrointestinal biopsies from 6 patients with MVID, 5 with celiac disease, and 17 children with normal intestinal biopsies and compared the results with those obtained with CD10 IHC and PAS staining. All MVID cases had confirmatory electron microscopy at the time of diagnosis. Villin immunoreactivity was restricted to the brush border in the control groups. In MVID, villin IHC showed attenuation or loss of the surface brush border and also highlighted the cytoplasmic microvillus inclusions with clarity. In MVID, CD10 IHC and the PAS stain also showed attenuation or loss of the surface brush border, but staining of a variety of cytoplasmic structures largely obscured the microvillus inclusions. In sum, villin IHC is a reliable and superior adjunct in the diagnosis of MVID. Study of additional cases will determine whether villin IHC would obviate the need for electron microscopic confirmation.
    Article · Dec 2014 · American Journal of Surgical Pathology
  • Kristy L Rialon · Rudy Murillo · Rebecca D Fevurly · [...] · Steven J Fishman
    [Show abstract] [Hide abstract] ABSTRACT: Multifocal and diffuse hepatic hemangiomas are true infantile hemangiomas, which likely exist in a continuum. We reviewed our hepatic hemangioma registry to identify prognostic indicators for mortality. Registry records entered between 1995 and 2012 were reviewed. Clinical characteristics were evaluated for prognostic significance using the multivariable Cox proportional hazards model. Survival data were analyzed using the Kaplan-Meier product-limit method. We identified 123 patients with multifocal (n=91) and diffuse (n=32) hepatic hemangiomas. Mortality was 16% (n=20); 40% (n=8) had multifocal and 60% (n=12) had diffuse lesions. A diagnosis of diffuse disease (hazard ratio: 9.9, 95% CI: 2.0-50.8, P=.002) and congestive heart failure (CHF) (hazard ratio: 3.9, 95% CI: 1.3-14.2, P=.031) were significant risk factors for mortality across the continuum; age at presentation, cardiomegaly, presence of shunts, and hypothyroidism were not statistically significant independent risk factors. Among patients with diffuse lesions, eight (67%) who died had abdominal compartment syndrome, which was also associated with mortality (P=.002). Hepatic hemangioma patients with CHF or diffuse disease are at higher risk for mortality. Patients with multifocal lesions without CHF may go undetected until lesions become diffuse. Aggressive treatment of symptomatic patients and close follow-up of asymptomatic patients may improve mortality. Copyright © 2014. Published by Elsevier Inc.
    Article · Dec 2014 · Journal of Pediatric Surgery
  • [Show abstract] [Hide abstract] ABSTRACT: Uncommon congenital hemangiomas differ from common infantile hemangiomas in their appearance, postnatal behavior, histopathology, and immunohistologic staining. Two types are well described in the literature: noninvoluting congenital hemangioma (NICH) and rapidly involuting congenital hemangioma (RICH). We report a series of infants with another presentation of congenital hemangioma that arises prenatally and is nearly regressed at birth. This was a retrospective case series. We describe six infants with unusual congenital vascular tumors. Each lesion presented at birth as a violaceous, atrophic plaque with a surrounding pale halo. The lesions involuted in infancy, fading in color and becoming atrophic, with prominent central veins, similar to RICH in the final stage of regression. The distinctive morphology and behavior suggests that these tumors undergo a life cycle of proliferation and involution during fetal life. We describe a new variant of congenital hemangioma that we refer to as rapidly involuting congenital hemangioma with fetal involution.
    Article · Dec 2014 · Pediatric Dermatology
  • Wibke Uller · Harry P Kozakewich · Cameron C Trenor · [...] · Ahmad I Alomari
    Article · Aug 2014 · Journal of Pediatrics
  • Article: Abstract 63
    Article · Apr 2014 · Plastic & Reconstructive Surgery
  • [Show abstract] [Hide abstract] ABSTRACT: The mechanism for the growth of infantile hemangioma and vascular malformations is unknown. Follicle-stimulating hormone secretion mirrors the life cycle of infantile hemangioma and increases during adolescence, when vascular malformations often progress. The purpose of this study was to determine whether vascular anomalies express the receptor for follicle-stimulating hormone. Human vascular tumors (i.e., infantile hemangioma, congenital hemangioma, kaposiform hemangioendothelioma, and pyogenic granuloma) and vascular malformations (i.e., capillary, lymphatic, venous, and arteriovenous) were subjected to immunofluorescence for follicle-stimulating hormone receptor. Control specimens included normal skin/subcutis, mucosa, liver, spleen, Crohn disease, granulation, pancreatitis, rheumatoid arthritis, and synovitis. Receptor and microvessel density were quantified using imaging software. Follicle-stimulating hormone receptor was found in the endothelium of all vascular anomalies but was not present in control specimens. Expression was greater in proliferating infantile hemangioma (6.0 percent) compared with other vascular tumors (congenital hemangioma, 0.61 percent; kaposiform hemangioendothelioma, 0.55 percent; pyogenic granuloma, 0.56 percent; p < 0.0001), despite similar microvessel density (p = 0.1). Follicle-stimulating hormone receptor was elevated in arteriovenous malformations (2.65 percent) compared with other types of vascular malformations (capillary, 1.02 percent; lymphatic, 0.38 percent; venous, 0.76 percent; p < 0.0001). Vascular anomalies express follicle-stimulating hormone receptor on their endothelium, in contrast to vascular control tissues. Vascular anomalies are the only benign, pathologic tissue known to express this receptor. Because the secretion of follicle-stimulating hormone correlates with the growth pattern of infantile hemangioma and vascular malformations, follicle-stimulating hormone might be involved in the pathogenesis of these lesions.
    Article · Mar 2014 · Plastic and Reconstructive Surgery
  • Article: Abstract 75
    Article · Mar 2014 · Plastic & Reconstructive Surgery
  • [Show abstract] [Hide abstract] ABSTRACT: Glomuvenous malformation (GVM) is an inherited autosomal dominant trait. The lesions, which appear as bluish nodules or plaque-like cutaneous elevations, are usually tender and more firm than sporadic venous malformations. Conventionally, the lesions are thought to be limited to the cutaneous and subcutaneous tissue planes. The objective was to characterize the depth of involvement of GVM lesions. Magnetic resonance imaging (MRI) findings in GVM were retrospectively evaluated by two radiologists. The signal characteristics, tissue distribution, pattern of contrast enhancement of the lesions in GVM were documented. Thirty patients (19 female) aged 1-35 years (mean 18 years) were diagnosed with GVM based on clinical features (n = 20) and/or histopathological findings (n = 10). The lesions were present in the lower extremity (n = 15), upper extremity (n = 6), cervico-facial region (n = 6), pelvis (n = 2), and chest wall (n = 1). All patients had skin and subcutaneous lesions. Fifty percent of the patients (n = 15) demonstrated subfascial intramuscular (n = 15), intra-osseous (n = 1), and intra-articular involvement (n = 1). Contrary to the conventional belief that GVMs are generally limited to the skin and subcutaneous tissue, deep subfascial extension of the lesions is common.
    Article · Feb 2014 · Skeletal Radiology
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    Simone Hettmer · Lisa A Teot · Harry Kozakewich · [...] · Amy J Wagers
    [Show abstract] [Hide abstract] ABSTRACT: In mice, activated Hedgehog (Hh) signaling induces tumors with myogenic differentiation. In humans, hyperactive Hh signaling due to germline PATCHED1 (PTCH1) mutations has been linked to nevoid basal cell carcinoma syndrome (NBCCS). We report an embryonal rhabdomyosarcoma in a 16-month-old girl with NBCCS and review the literature on myogenic neoplasms in NBCCS, including 8 fetal rhabdomyomas and 3 rhabdomyosarcomas. Of note, 3 population studies, including 255 individuals with NBCCS aged 4 months to 87 years, did not identify any myogenic tumors. Thus, myogenic tumors in NBCCS are rare and include both rhabdomyosarcomas and fetal rhabdomyomas.
    Full-text available · Article · Feb 2014 · Journal of Pediatric Hematology/Oncology
  • Sabri Yilmaz · Harry P Kozakewich · Ahmad I Alomari · [...] · Gulraiz Chaudry
    [Show abstract] [Hide abstract] ABSTRACT: Infantile hemangiomas demonstrate a pattern of proliferative growth in infancy followed by a slow phase of involution. In contrast a rare type of vascular tumor, intramuscular capillary-type hemangioma, usually presents beyond the period of infancy with nonspecific symptoms and no evidence of involution. The purpose of this study was to characterize the clinical, imaging, histopathological characteristics and management of intramuscular capillary-type hemangioma. We performed a retrospective review of a 20-year period to identify children diagnosed with intramuscular capillary-type hemangioma. Patient demographics, imaging and histopathological findings were recorded. We included 18 children (10 boys, 8 girls) with histologically proven intramuscular capillary-type hemangioma - and adequate imaging. The mean age at presentation was 8.1 years (range 1 day to 19 years). Twelve lesions involved muscles of the extremities, 4 were located in the trunk and 2 were in the head and neck. MRI had been performed in all children and demonstrated a soft-tissue mass with flow voids, consistent with fast flow. The lesion was well-circumscribed in 16 children and intralesional fat was seen in 14. Doppler US demonstrated a heterogeneous lesion, predominantly isoechoic to surrounding muscle, with enlarged arterial feeders. Enlarged feeding arteries, inhomogeneous blush and lack of arteriovenous shunting were noted on angiography (n = 5). The most common histopathological findings were lobules of capillaries with plump endothelium and at least some adipose tissue. The lesions were excised in six children. Two children were lost to follow-up. In the remaining 10, follow-up MRI studies ranging from 3 months to 10 years showed that the lesion enlarged in proportion to the child (n = 7), demonstrated slow growth (n = 2) or remained stable (n = 1). There was no change in imaging characteristics on follow-up. Intramuscular capillary-type hemangioma is a rare benign vascular tumor of skeletal muscle. The most typical imaging features show a heterogeneous intramuscular mass with fast flow, and intralesional fat. Although the lesion is relatively stable in appearance over time, imaging does not obviate the need for a biopsy to rule out sarcoma. The diagnosis can usually be established by typical findings on histopathology.
    Article · Feb 2014 · Pediatric Radiology
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    Ahmad I Alomari · Samantha A Spencer · Ryan W Arnold · [...] · Harry P Kozakewich
    [Show abstract] [Hide abstract] ABSTRACT: The diagnosis and management of vascular anomalies of the extremities can be challenging as these disorders are uncommon and may clinically overlap. The aim of this paper is to describe the clinical, radiologic, and histopathologic features of fibro-adipose vascular anomaly (FAVA), a previously unrecognized disorder of the limb. The clinical, imaging, operative, and histopathologic data from patients with a unique intramuscular lesion of the extremities comprising dense fibrofatty tissue and slow-flow vascular malformations were retrospectively reviewed. Sixteen patients diagnosed with FAVA of the extremity (3 male and 13 female individuals) met the clinical, radiologic, and histopathologic inclusion criteria. The age at presentation ranged from the time of birth to 28 years. The locations of the lesions were: calf (n=10), forearm/wrist (n=3), and thigh (n=3). Fourteen patients presented with severe pain. Seven of the patients with calf lesions had limited ankle dorsiflexion. On imaging, the complex intramuscular lesions replaced muscle fibers with fibrofatty overgrowth and phlebectasia (dilation of the veins). The extrafascial component comprised fatty overgrowth, phlebectasia, and an occasional lymphatic malformation. The histopathologic features comprised dense fibrous tissue, fat, and lymphoplasmacytic aggregates within atrophied skeletal muscle. Adipose tissue also infiltrated skeletal muscle at the periphery of the lesion. There were large, irregular, and sometimes excessively muscularized venous channels and smaller, clustered channels. Other findings include organizing thrombi, a lymphatic component, and dense fibrous tissue-encircled nerves. The constellation of clinical, radiologic, and histopathologic features constitutes a distinct entity comprising fibrofatty infiltration of muscle, unusual phlebectasia with pain, and contracture of the affected extremity. The clinical and radiologic findings permit the diagnosis of FAVA with major therapeutic implications. Level III.
    Full-text available · Article · Jan 2014 · Journal of pediatric orthopedics

Publication Stats

7k Citations


  • 1999-2011
    • Harvard Medical School
      • Department of Pathology
      Boston, Massachusetts, United States
  • 1997-2006
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1988-2005
    • Boston Children's Hospital
      • • Department of Pathology
      • • Department of Radiology
      Boston, Massachusetts, United States
  • 2001
    • Universitair Ziekenhuis Leuven
      Louvain, Flemish, Belgium