Christine Sempoux

The Catholic University of America, Washington, Washington, D.C., United States

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Publications (244)1176.52 Total impact

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    ABSTRACT: Activated hepatic stellate cells (HSCs) are the main collagen-producing cells in liver fibrogenesis. With the purpose to analyze their presence and relevance in predicting liver allograft fibrosis development, 162 liver biopsies of 54 pediatric liver transplant (LT) recipients were assessed at 6 months, 3 and 7 years post-LT. Methods: The proportion of activated HSCs, identified by α-smooth muscle actin (ASMA) immunostaining and the amount of fibrosis, identified by PicroSirious-red staining (PSR%), were determined by computer-based morphometric analysis. Fibrosis was also staged by using the semiquantitative liver allograft fibrosis score (LAFSc), specifically designed to score fibrosis in the pediatric LT population. Results: Liver allograft fibrosis displayed progression along the time by PSR%, (p< 0.001) and by LAFSc, (p< 0.001). The ASMA expression decreased in the long-term, with inverse evolution respect to fibrosis (p< 0.01). Patients with ASMA-positive HSCs area ≥ 8% at 6 months (n=20) developed higher fibrosis proportion compared to those with ASMA-positive HSCs area ≤ 8% (n=34) at the same period of time and in the long-term (p= 0.03 and p<0.01, respectively), but not at 3 years (p= 0.8). ASMA expression ≥ 8% at 6 months, was found as independent risk factor for 7 years-fibrosis development by PSR% (r2 =0.5, p< 0.01) and by LAFSc (r2 =0.3, p= 0.03). Further, ASMA expression ≥ 8% at 3 years showed association with the development of fibrosis at 7 years (p= 0.02). Conclusion: There is a high proportion of activated HSCs in pediatric LT recipients. ASMA ≥ 8% at 6 months seems to be a risk factor for early and long-term fibrosis development. In addition, Activated HSCs showed inverse evolution respect to fibrosis in the long-term. This article is protected by copyright. All rights reserved.
    No preview · Article · Feb 2016 · Liver Transplantation
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    ABSTRACT: A fair to moderate concordance in grading the total mesorectal excision (TME) surgical specimen by local pathologists and a central review panel has been observed in the PROCARE (Project on Cancer of the Rectum) project. In the present study the difference in the accuracy of prediction of oncological outcome through TME grading by local pathologists or by the review panel has been evaluated. The quality of TME specimen was reviewed in 482 surgical specimens registered on a prospective database between 2006 and 2011. Patients with a stage IV tumour, with unknown incidence date or without follow-up information were excluded, resulting in a study population of 383 patients. Quality assessment of the specimen was based on three grades including mesorectal (MRR), intramesorectal (IMR) and muscularis propria resection (MPR). Using univariable Cox regression models local and review panel histopathological gradings of the quality of TME were assessed as predictors of local recurrence, distant metastasis and disease-free and overall survival. Differences in the predictions between local and review grading were determined. Resection planes were concordant in 215 (56.1%) specimens. Downgrading from MRR to MPR was noted in 23 (6.0%). There were no significant differences in the prediction error between the two models; local and central review TME grading predicted the outcome equally well. Any difference in grading of the TME specimen between local histopathologists and the review panel had no significant impact on the prediction of oncological outcome for this patient cohort. Grading of the quality of TME as reported by local histopathologists can therefore be used for outcome analysis. Quality control of TME grading is not warranted provided the histopathologist is adequately trained. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Colorectal Disease
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    ABSTRACT: Background: Optimal preoperative treatment before colorectal cancer metastases (CRCM) resection remains unclear. This study evaluated pathological responses (pR) in CRCM resected after chemotherapy alone or combined with angiogenesis or epidermal growth factor receptor (EGFR) inhibitors. Methods: Pathological response was retrospectively evaluated on 264 resected metastases from 99 patients. The proportion of responding metastases after different preoperative treatments was reported and compared. Patient's progression-free survival (PFS) and overall survival (OS) were compared based on pR. Results: The combination of anti-angiogenics with oxaliplatin-based chemotherapy resulted in more pR than when they were combined with irinotecan-based chemotherapy (80% vs 50%; P<0.001). Inversely, the combination of EGFR inhibitors with oxaliplatin-based chemotherapy seemed to induce fewer pR than when they were combined with irinotecan-based treatment (53% vs 72%; P=0.049). Overall survival at 5 years was improved for patients with a pR in all resected metastases compared with those who did not achieve a pR (68.5% vs 32.6%; P=0.023) and this response was the only factor predicting OS in a multivariate analysis. Conclusion: The chemotherapy partner combined with angiogenesis or EGFR inhibitors influenced pR in resected CRCM. In our exploratory analysis anti-angiogenic/oxaliplatin-based regimens and anti-EGFR/irinotecan-based regimens were associated with the highest pR. Prospective randomised trials should be performed to validate these observations.British Journal of Cancer advance online publication 13 October 2015; doi:10.1038/bjc.2015.321 www.bjcancer.com.
    No preview · Article · Oct 2015 · British Journal of Cancer
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    ABSTRACT: In many organs, including the intestine and skin, cancers originate from cells of the stem or progenitor compartment. Despite its nomenclature, the cellular origin of hepatocellular carcinoma (HCC) remains elusive. In contrast to most organs, the liver lacks a defined stem cell population for organ maintenance. Previous studies suggest that both hepatocytes and facultative progenitor cells within the biliary compartment are capable of generating HCC. As HCCs with a progenitor signature carry a worse prognosis, understanding the origin of HCC is of clinical relevance. Here, we used complementary fate-tracing approaches to label the progenitor/biliary compartment and hepatocytes in murine hepatocarcinogenesis. In genotoxic and genetic models, HCCs arose exclusively from hepatocytes but never from the progenitor/biliary compartment. Cytokeratin 19-, A6- and α-fetoprotein-positive cells within tumors were hepatocyte derived. In summary, hepatocytes represent the cell of origin for HCC in mice, and a progenitor signature does not reflect progenitor origin, but dedifferentiation of hepatocyte-derived tumor cells.
    Full-text · Article · Sep 2015 · The Journal of clinical investigation

  • No preview · Article · Sep 2015
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    ABSTRACT: Because of its known malignant potential, precise histologic diagnosis of intraductal papillary mucinous neoplasm of the pancreas (IPMN) during intraoperative pancreatoscopy (IOP) is essential for complete surgical resection. The impact of IOP on perioperative IPMN patient management was reviewed over 20 years of practice at Cliniques universitaires Saint-Luc, Brussels, Belgium. Among 86 IPMN patients treated by pancreatectomy between 1991 and 2013, 21 patients had a dilated main pancreatic duct enabling IOP and were retrospectively reviewed. The IOP was performed using an ultrathin flexible endoscope and biopsy forceps, and specimens of all suspicious lesions underwent frozen section examination. Complete IOP with intraductal biopsies was easily and safely performed in 21 patients, revealing 8 occult IPMN lesions. In 5 cases (23.8%), initially planned surgical resection was modified secondary to IOP: 3 for carcinoma in situ and 2 for invasive carcinoma. The postoperative morbidity rate at 3 months was 25.0% (5 of 20); 1 patient died from septic shock postoperatively and was excluded. Median follow-up was 93 months (range 13 to 248 months). Nineteen of 21 patients were still alive and free of disease at last follow-up (90.5%); there was 1 patient with invasive carcinoma at initial pathology (pT3 N1) who died of pulmonary recurrence 21 months after surgery. Intraoperative pancreatoscopy of the main pancreatic duct combined with intraductal biopsies plays a significant role in the surgical management of IPMN patients and should be used in all patients presenting a sufficiently dilated main pancreatic duct. Copyright © 2015 American College of Surgeons. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Aug 2015 · Journal of the American College of Surgeons
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    Elizabeth M Brunt · Valerie Paradis · Christine Sempoux · Neil D Theise

    Full-text · Article · Jul 2015
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    ABSTRACT: Insulinomas are β-cell tumors that cause hypoglycemia through inappropriate secretion of insulin. Characterization of the in vitro dynamics of insulin secretion by perifused fragments of ten human insulinomas permitted their subdivision in three functional groups with similar insulin content. Group A (4 cases with fasting and/or postprandial hypoglycemias) showed qualitatively normal responses to glucose, leucine, diazoxide, tolbutamide and extracellular CaCl2 omission or excess. The effect of glucose was concentration-dependent but, compared to normal islets, insulin secretion was excessive in both low and high glucose. Group B (3 cases with fasting hypoglycemias) was mainly characterized by large insulin responses to 1mmol/l glucose, resulting in very high basal secretion rates that were inhibited by diazoxide and restored by tolbutamide, but not further augmented by other agents except high CaCl2. Group C (3 cases with fasting hypoglycemias) displayed very low rates of insulin secretion and virtually no response to stimuli (including high CaCl2) and inhibitors (CaCl2 omission being paradoxically stimulatory). In group B, the presence of low-Km hexokinase-I in insulinoma β-cells (not in adjacent islets) was revealed by immunochemistry. Human insulinomas thus show distinct, though not completely heterogeneous, defects in insulin secretion that are attributed to undue expression of hexokinase-I in 3/10 cases. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    No preview · Article · Jun 2015 · Diabetes
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    ABSTRACT: A broad range of hepatocellular nodules has been reported in hepatic vascular disorders. It is not clear whether hepatocellular adenoma (HCA) in this context share the same characteristics as conventional HCA. The aim of this study was to carry out a retrospective multicenter survey of hepatocellular nodules associated with hepatic vascular disorders. 45 cases were reviewed, including 32 Budd Chiari syndrome (BCS). Benign nodules were subtyped using the HCA immunohistochemical panel. Nodules with a HCA morphology were observed in 11 cases. Six originated in BCS: 2 were liver fatty acid binding protein (LFABP) negative (one with malignant transformation); 2 expressed glutamine synthetase (GS) and nuclear b-catenin, 2 expressed C reactive protein (CRP). Among 3 cases with portal vein agenesis, 1 nodule was LFABP negative, 2 expressed GS and nuclear b-catenin, both with malignant transformation. In a Fallot tetralogy case, there were multiple LFABP negative nodules with borderline features and in a hepatoportal sclerosis case, the nodule looked like an inflammatory HCA. Two additional cases had nodules expressing CRP, without typical characteristics of inflammatory HCA. HCA of different immunohistochemical phenotype can develop in hepatic vascular disorders; they may have a different behavior compared to conventional HCA and be more at risk of malignant transformation. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Jun 2015 · Journal of Hepatology
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    ABSTRACT: To evaluate the outcome of pediatric living donor liver transplantation (LDLT) regarding portal vein (PV) reconstruction, ABO compatibility, and impact of maternal donation on graft acceptance. LDLT and ABO-mismatched transplantation constitute feasible options to alleviate organ shortage in children. Vascular complications of portal hypoplasia in biliary atresia (BA) and acute rejection (AR) are still major concerns in this field. Data from 250 pediatric LDLT recipients, performed at Cliniques Universitaires Saint-Luc between July 1993 and June 2012, were collected retrospectively. Results were analyzed according to ABO matching and PV complications. Uni- and multivariate analyses were performed to study the impact of immunosuppression, sex matching, and maternal donation on AR rate. Overall, the 10-year patient survival rate was 93.2%. Neither patient or graft loss nor vascular rejection, nor hemolysis, was encountered in the ABO nonidentical patients (n = 58), provided pretransplant levels of relevant isoagglutinins were below 1/16. In BA recipients, the rate of PV complications was lower after portoplasty (4.6%) than after truncal PV anastomosis (9.8%) and to jump graft interposition (26.9%; P = 0.027). In parental donation, maternal grafts were associated with higher 1-year AR-free survival (55.2%) than paternal grafts (39.8%; P = 0.041), but only in BA patients. LDLT, including ABO-mismatched transplantation, constitutes a safe and efficient therapy for liver failure in children. In BA patients with PV hypoplasia, portoplasty seems to constitute the best technique for PV reconstruction. Maternal donation might be a protective factor for AR.
    No preview · Article · Jan 2015 · Annals of Surgery
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    ABSTRACT: Ibrutinib is a small molecule that has been recently developped for the treatment of B cell malignancies. Common side effects are diarrhoea, nausea, fatigue, infections, neutropenia and thrombocytopenia. Here we report the first case of Hepatitis B virus reactivation in a 80 years old chronic lymphocytic leukaemia patient receiving ibrutinib, suggesting that such treatment must be associated with HBV screening.
    Full-text · Article · Jan 2015
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    ABSTRACT: A 1-year-old girl born to consanguineous parents presented with unexplained liver failure, leading to transplantation at 19 months. Subsequent partial splenectomy for persistent cytopenia showed the presence of foamy cells, and Gaucher disease was confirmed by homozygosity for the p.Leu483Pro mutation in the GBA gene. She was treated by enzyme replacement therapy (ERT). Clinical follow-up showed mild developmental delay, strabismus, nystagmus and oculomotor apraxia. Biochemical studies revealed multiple respiratory chain deficiencies and a mosaic pattern of deficient complex IV immunostaining in liver and fibroblast. Molecular analysis identified a mtDNA depletion syndrome due to the homozygous p.Pro98Leu mutation in MPV17. A younger sister unaffected by mtDNA depletion, presented with pancytopenia and hepatosplenomegaly. ERT for Gaucher disease resulted in visceral normalization without any neurological symptom. A third sister, affected by both conditions, had marked developmental delay, strabismus and ophthalmoplegia but no liver cirrhosis. In conclusion, intrafamilal variability occurs in MPV17-related disease. The combined pathological effect of Gaucher and mitochondrial diseases can negatively impact neurological and liver functions and influence the outcome in consanguineous families. The immunocytochemical staining of OXPHOS protein in tissues and cultured cells is a powerful tool revealing mosaic pattern of deficiency pointing to mtDNA-related mitochondrial disorders.
    Full-text · Article · Dec 2014 · Molecular Genetics and Metabolism Reports
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    Full-text · Article · Dec 2014 · Human pathology
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    ABSTRACT: Hepatocellular adenomas are rare benign nodules developed mainly in women taking oral contraceptives. They are solitary or multiple. Their size is highly variable. There is no consensus in the literature for their management except that once their size exceeds 5 cm nodules are taken out to prevent 2 major complications: bleeding and malignant transformation. There are exceptions particularly in men where it is recommended to remove smaller nodules. Since the beginning of this century, major scientific contributions have unveiled the heterogeneity of the disease. HCA are composed of four major subtypes. HNF1A (coding for hepatocyte nuclear factor 1a) inactivating mutations (H-HCA); inflammatory adenomas (IHCA); the β-catenin-mutated HCAs (β-HCA) and unclassified HCA (UHCA) occurring in 30–40%, 40–50%, 10–15% and 10% of all HCA, respectively. Half of β-HCAs are also inflammatory (β-IHCA). Importantly, β-catenin mutations are associated with a high risk of malignant transformation. HCA subtypes can be identified on liver tissue, including biopsies using specific immunomarkers with a good correspondence with molecular data. Recent data has shown that TERT promoter mutation was a late event in the malignant transformation of β-HCA, β-IHCA. Furthermore, in addition to β-catenin exon 3 mutations, other mutations do exist (exon 7 and 8) with a lower risk of malignant transformation. With these new scientific informations, we have the tools to better know the natural history of the different subtypes, in terms of growth, disappearance, bleeding, malignant transformation and to investigate HCA in diseased livers (vascular diseases, alcoholic cirrhosis). A better knowledge of HCA should lead to a more rational management of HCA. This can be done only if the different subspecialties, including hepatologists, liver pathologists, radiologists and surgeons work altogether in close relationship with molecular biologists. It is a long way to go.
    No preview · Article · Nov 2014 · Gastroentérologie Clinique et Biologique
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    ABSTRACT: Background: Solitary extramedullary plasmacytoma (SEP) is a rare malignant neoplasm arising from plasma cells. SEP mostly occurs in the upper respiratory tract. Thyroid gland is rarely affected (<78 cases). Methods/results: We describe the case of a 78-year-old woman presenting a rapidly enlarging palpable thyroid mass. Neck computed tomography scan showed enlargement of both thyroid lobes. Laboratory tests were normal, including serum protein level with no monoclonal gamma globulin peak. Cytology was suspicious for lymphoma. Biopsy showed an infiltrating neoplasm composed of atypical tumor cells with abundant cytoplasm and eccentric nuclei. These revealed diffuse immunoreactivity for CD138 and predominant staining for immunoglobulin kappa light chains. Clinical workup for multiple myeloma was negative. Conclusions: SEP should be considered in the differential diagnosis of a rapidly enlarging thyroid nodule and be distinguished from involvement of thyroid in multiple myeloma, mucosa-associated lymphoid tissue lymphoma, plasma cell granuloma and medullary carcinoma. Clinical correlation and immunohistochemistry are crucial in avoiding pitfalls.
    No preview · Article · Nov 2014
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    ABSTRACT: Objective: To investigate the safety of minimal immunosuppression (IS) in liver transplantation (LT). Background: The lack of long-term follow-up studies, including pathologic data, has led to a protean handling of IS in LT. Methods: Between February 2000 and September 2004, 156 adults were enrolled in a prospective, randomized, double-blind, placebo-controlled minimization trial comparing tacrolimus placebo (TAC-PLAC) and TAC short-term steroid (TAC-STER) IS. All patients had a minimum clinical, biochemical, and histological follow-up of 5 years. Results: Five-year actual patient and graft survival rates in TAC-PLAC and TAC-STER groups were 78.1% and 82.1% (P = 0.89) and 74.2% and 76.9% (P = 0.90), respectively. Five-year biopsies were available in 112 (89.6%) of 125 survivors. Twelve patients refused a biopsy because of their excellent evolution; tissue material was insufficient in 1 patient; 11 had normal liver tests; and 2 patients had developed alcoholic and secondary biliary cirrhosis. Histology was normal in 44 (39.3%) patients; 35 (31.3%) had disease recurrence. The remaining biopsies showed nonspecific chronic hepatitis (14.3%), mild inflammatory infiltrates (10.7%), and steatosis (3.5%). All findings were equally distributed between both groups. In each group, 3 patients (4.8%) presented with acute cellular rejection after the first year and only 1 (0.9%) TAC-PLAC patient developed chronic rejection after IS withdrawal because of pneumonitis. Arterial hypertension, diabetes mellitus, renal insufficiency, hypercholesterolemia, gout, and obesity were equally low in both groups. Conclusions: Excellent long-term results can be obtained under minimal IS and absence of steroids. TAC-based monotherapy is feasible in most adult liver recipients until 5 years of follow-up.
    Full-text · Article · Nov 2014 · Annals of Surgery
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    ABSTRACT: Objective The transcription factor SOX9 was recently shown to stimulate ductal gene expression in pancreatic acinar-to-ductal metaplasia and to accelerate development of premalignant lesions preceding pancreatic ductal adenocarcinoma (PDAC). Here, we investigate how SOX9 operates in pancreatic tumourigenesis. Design We analysed genomic and transcriptomic data from surgically resected PDAC and extended the expression analysis to xenografts from PDAC samples and to PDAC cell lines. SOX9 expression was manipulated in human cell lines and mouse models developing PDAC. Results We found genetic aberrations in the SOX9 gene in about 15% of patient tumours. Most PDAC samples strongly express SOX9 protein, and SOX9 levels are higher in classical PDAC. This tumour subtype is associated with better patient outcome, and cell lines of this subtype respond to therapy targeting epidermal growth factor receptor (EGFR/ERBB1) signalling, a pathway essential for pancreatic tumourigenesis. In human PDAC, high expression of SOX9 correlates with expression of genes belonging to the ERBB pathway. In particular, ERBB2 expression in PDAC cell lines is stimulated by SOX9. Inactivating Sox9 expression in mice confirmed its role in PDAC initiation; it demonstrated that Sox9 stimulates expression of several members of the ERBB pathway and is required for ERBB signalling activity. Conclusions By integrating data from patient samples and mouse models, we found that SOX9 regulates the ERBB pathway throughout pancreatic tumourigenesis. Our work opens perspectives for therapy targeting tumourigenic mechanisms.
    Full-text · Article · Oct 2014 · Gut
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    ABSTRACT: Our goal was to optimize the radiosensitizing potential of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, when given concomitantly with preoperative radiotherapy in KRAS wild-type locally advanced rectal cancer (LARC). Based on pre-clinical studies conducted by our group, we designed a phase II trial in which panitumumab (6 mg/kg/q2 weeks) was combined with preoperative radiotherapy (45 Gy in 25 fractions) to treat cT3-4/N + KRAS wild-type LARC. The primary endpoint was complete pathologic response (pCR) (H0 = 5 %, H1 = 17 %, α = 0.05, β = 0.2). From 19 enrolled patients, 17 (89 %) were evaluable for pathology assessment. Although no pCR was observed, seven patients (41 %) had grade 3 Dworak pathological tumor regression. The regimen was safe and was associated with 95 % of sphincter-preservation rate. No NRAS, BRAF, or PI3KCA mutation was found in this study, but one patient (5 %) showed loss of PTEN expression. The quantification of plasma EGFR ligands during treatment showed significant upregulation of plasma TGF-α and EGF following panitumumab administration (p < 0.05). At surgery, patients with important pathological regression (grade 3 Dworak) had higher plasma TGF-α (p = 0.03) but lower plasma EGF (p = 0.003) compared to those with grade 0-2 Dworak. Our study suggests that concomitant panitumumab and preoperative radiotherapy in KRAS wild-type LARC is feasible and results in some tumor regression. However, pCR rate remained modest. Given that the primary endpoint of our study was not reached, we remain unable to recommend the use of panitumumab as a radiosensitizer in KRAS wild-type LARC outside a research setting.
    Full-text · Article · Oct 2014 · Targeted Oncology
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    Christine Sempoux · Charles Balabaud · Paulette Bioulac-Sage

    Preview · Article · Oct 2014

  • No preview · Article · Oct 2014 · Cancer Research

Publication Stats

5k Citations
1,176.52 Total Impact Points

Institutions

  • 2010-2015
    • The Catholic University of America
      Washington, Washington, D.C., United States
    • Clinique Saint-Luc, Bouge
      Namen, Walloon Region, Belgium
  • 1995-2015
    • Catholic University of Louvain
      • • Institute of Experimental and Clinical Research (IREC)
      • • Laboratory of Hepatogastroenterology
      • • Colorectal Surgery Unit
      • • Department of Surgery - CHIR
      • • Department of Radiology and Medical Imaging - RAIM
      • • School of Medicine
      Лувен-ла-Нев, Wallonia, Belgium
  • 2014
    • Pathologie Institut Enge
      Zürich, Zurich, Switzerland
  • 1994-2014
    • Cliniques Universitaires Saint-Luc
      • • Division of Pathology
      • • Department of Clinical Biology and Pathology
      Bruxelles, Brussels Capital Region, Belgium
  • 1997-2010
    • University Hospital Brussels
      Bruxelles, Brussels Capital, Belgium