[Show abstract][Hide abstract] ABSTRACT: In this retrospective analysis, 30 patients with acute GVHD (aGVHD) and 32 patients with chronic GVHD (cGVHD) treated with extracorporeal photopheresis (ECP) performed by the COBE Spectra System were evaluated. After 3 months of ECP treatment, a CR and PR were observed in 9 (30%) and 6 (20%) patients with aGVHD and in 2 (6%) and 12 (38%) patients with cGVHD. In 16 (53%) patients with aGVHD and 9 (28%) with cGVHD ECP treatment was already stopped after 3 months. One (3%) patient with aGVHD and 7 (22%) patients with cGVHD received new additional immunosuppressive therapy started during the first 3 months of ECP treatment and were classified as 'nonresponder' with regard to ECP. Of these patients a PR was achieved in one patient with aGVHD and in three patients with cGVHD. Steroids could be tapered by 50 in 83% of patients with aGVHD and in 29% of patients with cGVHD after 3 months of ECP treatment. Patients with aGVHD achieving a CR or PR showed a significant improved OS after allo-SCT (P=0.019). ECP is associated with significant response rates and successful reduction of steroids in patients with GVHD.Bone Marrow Transplantation advance online publication, 27 August 2012; doi:10.1038/bmt.2012.156.
Bone marrow transplantation 08/2012; 48(3). DOI:10.1038/bmt.2012.156 · 3.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The lower gastrointestinal tract (LGI) and liver are the GVHD target organs most associated with treatment failure and nonrelapse mortality. We recently identified regenerating islet-derived 3-α (REG3α) as a plasma biomarker of LGI GVHD. We compared REG3α with 2 previously reported GI and liver GVHD diagnostic biomarkers, hepatocyte growth factor (HGF) and cytokeratin fragment 18, in 954 hematopoietic cell transplantation patients. All 3 biomarkers were significantly elevated in LGI GVHD compared with non-GVHD diarrhea; REG3α discerned LGI GVHD from non-GVHD diarrhea better than HGF and cytokeratin fragment 18. Although all 3 biomarkers predicted nonresponse to therapy at day 28 in LGI GVHD patients, only REG3α and HGF concentrations predicted 1-year nonrelapse mortality (P = .01 and P = .02, respectively). Liver GVHD without GI involvement at GVHD onset and non-GVHD liver complications were uncommon; all 3 biomarkers were elevated in liver GVHD, but did not distinguish GVHD from other causes of hyperbilirubinemia.
[Show abstract][Hide abstract] ABSTRACT: Induction of indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme in tryptophan degradation along the kynurenine pathway, acts as a potent immunoregulatory loop. To address its role in human allogeneic stem cell transplantation, we measured major tryptophan metabolites, such as quinolinic acid and kynurenine, in serial urine specimens from 51 patients by liquid chromatography-tandem mass spectrometry. Samples were collected between admission and day 90 after transplantation, and metabolite levels were correlated with early clinical events and outcome. In selected patients, IDO gene expression was assessed by quantitative RT-PCR in intestinal biopsies. Surviving patients had significantly lower metabolite levels on days 28, 42, and 90, respectively, compared with patients dying of GVHD and associated complications (n = 10). Kynurenine levels were directly correlated with severity and clinical course of GVHD: Mean urinary quinolinic acid levels were 4.5 ± 0.3 μmol/mmol creatinine in the absence of acute GVHD, 8.0 ± 1.1 μmol/mmol creatinine for GVHD grade 1 or 2, and 13.5 ± 2.7 μmol/mmol creatinine for GVHD grade 3 or 4 (P < .001), respectively. GVHD-dependent induction of IDO was further suggested by increased expression of IDO mRNA in intestinal biopsies from patients with severe GVHD. Our data indicate reactive release of kynurenines in GVHD-associated inflammation.
[Show abstract][Hide abstract] ABSTRACT: There are no plasma biomarkers specific for GVHD of the gastrointestinal (GI) tract, the GVHD target organ most associated with nonrelapse mortality (NRM) following hematopoietic cell transplantation (HCT). Using an unbiased, large-scale, quantitative proteomic discovery approach to identify candidate biomarkers that were increased in plasma from HCT patients with GI GVHD, 74 proteins were increased at least 2-fold; 5 were of GI origin. We validated the lead candidate, REG3α, by ELISA in samples from 1014 HCT patients from 3 transplantation centers. Plasma REG3α concentrations were 3-fold higher in patients at GI GVHD onset than in all other patients and correlated most closely with lower GI GVHD. REG3α concentrations at GVHD onset predicted response to therapy at 4 weeks, 1-year NRM, and 1-year survival (P ≤ .001). In a multivariate analysis, advanced clinical stage, severe histologic damage, and high REG3α concentrations at GVHD diagnosis independently predicted 1-year NRM, which progressively increased with higher numbers of onset risk factors present: 25% for patients with 0 risk factors to 86% with 3 risk factors present (P < .001). REG3α is a plasma biomarker of GI GVHD that can be combined with clinical stage and histologic grade to improve risk stratification of patients.
[Show abstract][Hide abstract] ABSTRACT: The progression of acute pancreatitis to necrotizing pancreatitis which often results in high morbidity and mortality is difficult to predict. Here we report that serum concentrations of sCD137 are increased in patients with acute pancreatitis. Admission levels and 10-day median sCD137 levels positively correlate with markers of biliary pancreatitis and the 10-day sCD137 median is significantly higher in metabolic than in alcoholic pancreatitis. Serum concentrations of sCD137 at time of admission and the 10-day median of sCD137 correlate with the Ranson and APACHE II disease scores but not with the radiological Balthazar and Schroeder scores that reflect pancreatic and peripancreatic necrosis. Further, sCD137 levels correlate with the probability of complications and lethality. The association of sCD137, a product of activated T cells, with the severity of acute pancreatitis suggests that T cells contribute to the pathogenesis of acute pancreatitis.
[Show abstract][Hide abstract] ABSTRACT: Adipocytes of peripancreatic and intrapancreatic adipose tissue secret adipocytokines such as leptin, adiponectin, and resistin. For resistin, a role as an early predictor of peripancreatic necrosis and clinical severity in acute pancreatitis has been reported. It was the aim of this study to investigate whether the adipocytokine visfatin is able to serve as an early marker predicting peripancreatic necrosis and clinical severity.
A total of 50 patients (20 females and 30 males) with acute pancreatitis were included in this noninterventional, prospective, and monocentric cohort study on diagnostic accuracy. Clinical severity was classified by the Ranson score and APACHE-II (Acute Physiology and Chronic Health Evaluation II) score. Pancreatic and peripancreatic necrosis were quantified by the computed tomography-based Balthazar score, the Schroeder score, and the pancreatic necrosis score. Visfatin was measured at admission and daily for 10 days by enzyme-linked immunosorbent assay (ELISA).
Visfatin values were significantly and positively correlated with clinical severity (APACHE-II score and Ranson score) and with clinical end points such as death and need for interventions. Admission visfatin levels were significantly elevated in patients with higher pancreatic and extrapancreatic necrosis scores. It was shown by receiver operator characteristics that admission visfatin concentration provides a positive predictive value of 93.3% in predicting the extent of peripancreatic necrosis (area under the curve (AUC): 0.89, P<0.001, sensitivity: 93.3%, specificity: 81.8%, likelihood ratio: 5.1, post-test probability: 93%) by using a cutoff value of 1.8 ng/ml.
Admission visfatin concentration serves as an early predictive marker of peripancreatic necrosis and clinical severity in acute pancreatitis. Visfatin may have potential for clinical use as a new and diagnostic serum marker.
The American Journal of Gastroenterology 01/2011; 106(5):957-67. DOI:10.1038/ajg.2010.503 · 10.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: GvHD is a serious complication in patients after allo-SCT, presenting with unspecific symptoms such as abdominal pain or cramps and diarrhea. Early diagnosis of GvHD, after differentiation from other causes leading to the same symptoms, such as viral or bacterial enteritis, is highly important because the time needed for diagnosing GvHD is directly correlated to a worsening of the outcome. We examined 23 patients presenting with the abdominal symptoms mentioned above, of whom 20 had received an allo-SCT in their history and were thus potential candidates for enteric GvHD. The other three patients were included because they also presented with abdominal symptoms similar to those of GvHD, which could be ruled out due to their history. We wanted to evaluate CEUS in these patients as an additional subgroup to gain more data on the value of CEUS in early detection of enteral GvHD and in the differentiation of GvHD against other causes of abdominal discomfort. All patients underwent CEUS with particular attention to penetration of the intravenously applied microbubbles in the bowel lumen. In the patients having allo-SCT in their history we strove to achieve histological confirmation of GvHD of the GI-tract. The resulting examinations were documented digitally. Out of 17 patients with confirmed GvHD of the GI tract, 14 showed penetration of the intravenously applied microbubbles into the bowel lumen, leading to a sensitivity and specificity of 82% and 100% for transmural bubble penetration for GvHD of the GI-Tract, since the patients without GvHD of the GI tract showed no transmural bubble penetration. In patients with viral or bacterial infections of the GI tract, no transmural penetration of the microbubbles into the bowel lumen was observed. For microbubble penetration as a criterion for GvHD of the GI-Tract, this leads to a negative predictive value (NPV) of 67%, and a positive predicative value (PPV) of 100%.
[Show abstract][Hide abstract] ABSTRACT: Peripancreatic necrosis determines clinical severity in acute pancreatitis. Early markers predicting peripancreatic necrosis and clinical severity are lacking. Because adipocytes of peripancreatic adipose tissue secret highly active adipocytokines, the aim of the study was to investigate whether adipocytokines are able to serve as early markers predicting peripancreatic necrosis and clinical severity.
A total of 50 patients (20 women, 30 men) with acute pancreatitis were included in this noninterventional, prospective, and monocentric cohort study on diagnostic accuracy. Clinical severity was classified by the Ranson score and the APACHE (Acute Physiology And Chronic Health Evaluation) II score. Pancreatic and peripancreatic necrosis were quantified by using the computed tomography-based Balthazar score, the Schroeder score, and the pancreatic necrosis score. Adiponectin, leptin, and resistin were measured at admission and daily for at least 10 days by enzyme-linked immunosorbent assay.
In contrast to admission C-reactive protein values, admission resistin values were significantly correlated with clinical severity and even with clinical end points such as death and need for interventions. Admission resistin levels were significantly elevated in patients with higher pancreatic and extrapancreatic necrosis scores. It was shown by receiver-operator characteristics that admission resistin concentration provides a positive predictive value of 89% in predicting the extent of peripancreatic necrosis (area under the curve, 0.8; P=0.002; sensitivity, 80%; specificity, 70%) by using a cutoff value of 11.9 ng/ml.
Admission resistin concentration serves as an early predictive marker of peripancreatic necrosis and clinical severity in acute pancreatitis. Resistin may have potential for clinical use as a new and diagnostic serum marker.
The American Journal of Gastroenterology 11/2010; 105(11):2474-84. DOI:10.1038/ajg.2010.278 · 10.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Graft-versus-Host Disease (GvHD) is the most serious complication of allogeneic stem cell transplantation (SCT) and results from an activation of donor lymphocytes by recipient antigen-presenting cells (APCs). For a long time, it has been postulated that the intestinal microflora and endotoxin exert a crucial step in this APC activation, as there is early and severe gastrointestinal damage induced by pretransplant conditioning. With the detailed description of pathogen-associated molecular patterns and pathogen recognition receptors single nucleotide polymorphisms of TLRs and especially NOD2 have been identified as potential risk factors of GvHD and transplant related complications thus further supporting the crucial role of innate immunity in SCT, related complications. Gastrointestinal decontamination and neutralization of endotoxin have been used to interfere with this early axis of activation with some success but more specific approaches of modulation of innate immunity are needed for further improvement of clinical outcome.
[Show abstract][Hide abstract] ABSTRACT: GVHD is a common complication in patients after allo-SCT. Early detection is important because early therapy may improve the outcome. We evaluated contrast-enhanced ultrasound (CEUS) in patients with GVHD to assess typical imaging features. CEUS was performed in nine patients with histologically proven GVHD. As a control four healthy volunteers and six patients with Crohn's disease (CD) were examined. We employed a high-resolution multi-frequency transducer (6-9 MHz) with contrast harmonic imaging. After the injection of 2.4 mL SonoVue (Bracco, Milan, Italy) intravenously data were acquired and stored digitally. Regions of interest were manually placed over the surrounding mesenteric fat, bowel wall and bowel lumen. Maximum signal increase of each compartment was calculated. Patients with CD and GVHD showed significant contrast uptake in the bowel wall. In contrast to CD patients and healthy volunteers, patients with GVHD showed transmural penetration of microbubbles into the bowel lumen. We assume that the damaged gut mucosal barrier in GVHD enables the microbubbles to penetrate through the bowel wall into the bowel lumen. The penetration of microbubbles into the bowel lumen may serve as a novel diagnostic feature for GVHD if confirmed in controlled clinical trials.
Bone marrow transplantation 10/2010; 46(7):1006-11. DOI:10.1038/bmt.2010.232 · 3.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nucleotide-binding oligomerization domain 2/caspase recruitment domain 15 (NOD2/CARD15) polymorphisms have been identified as risk factors of both Crohn's disease and graft-versus-host disease (GVHD) following allogeneic stem cell transplantation. However, the role of these receptors of innate immunity in the pathophysiology of gastrointestinal GVHD is still poorly defined. Immunohistological features of intestinal GVHD were analysed in gastrointestinal biopsies from 58 patients obtained at the time of first onset of intestinal symptoms. The observed changes were correlated with concomitant risk factors and the presence of polymorphisms within the pathogen recognition receptor gene NOD2/CARD15. Intestinal GVHD was associated with a stage-dependent decrease in CD4 T cell infiltrates and an increase in CD8 T cells in the lamina propria; CD8 infiltrates correlated with extent of apoptosis and consecutive epithelial proliferation. The presence of NOD2/CARD15 variants in the recipient was associated with a significant loss of CD4 T cells: in a semiquantitative analysis, the median CD4 score for patients with wild-type NOD2/CARD15 was 1.1 (range 3), but only 0.4 (range 2) for patients with variants (P = 0.002). This observation was independent from severity of GVHD in multivariate analyses and could not be explained by the loss of forkhead box P3(+) T cells. Our results suggest a loss of protective CD4 T cells in intestinal GVHD which is enhanced further by the presence of NOD2/CARD15 variants. Our study might help to identify more selective therapeutic strategies in the future.
[Show abstract][Hide abstract] ABSTRACT: Both indirect and direct effects contribute to changes in the clinical presentation of graft-versus-host disease (GvHD) after reduced-intensity conditioning (RIC) compared with standard intensity regimens. A delay in acute GvHD after RIC may be explained by reduced conditioning-related inflammation and by altered allostimulatory capacities of recipient antigen-presenting cells (APC). A higher frequency of chronic GvHD results from the almost exclusive use of peripheral blood stem cells, the absence of tolerance induction by current regimens for prophylactic immunosuppression and modified kinetics in the replacement of recipient APC. Established acute and chronic GvHD requires standard treatment irrespective of the type of conditioning. To improve long-term outcome in GvHD, pre-emptive strategies or more selective approaches aimed at immunomodulation rather than immunosuppression are needed.
Current opinion in oncology 06/2009; 21 Suppl 1(Suppl 1):S39-41. DOI:10.1097/01.cco.0000357475.66035.d2 · 4.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Severe acute pancreatitis is characterized by lipase-induced peripancreatic fat cell necrosis. Because adipocytes secret several highly active molecules, the aim of the present study was to investigate the hypothesis that adipocytokines could serve as potential markers predicting peripancreatic necrosis and severity in acute pancreatitis.
A total of 23 patients (11 females, 12 males) with acute pancreatitis were included and a computed tomography (CT) examination was available in 20 patients. Balthazar score, Schröder score, pancreatic necrosis score, Ranson score and APACHE II score were calculated, correlated with biochemical parameters and analyzed using receiver-operator characteristics (ROC) analysis. Adipocytokine serum levels were measured daily by enzyme-linked immunosorbent assay (ELISA) over 10 days after admission.
Resistin and leptin were significantly elevated in patients with severe pancreatitis and were correlated with a radiological scoring system for extrapancreatic necrosis. Whereas resistin correlated positively with clinical scoring systems, time until discharge and the need for interventions, leptin was correlated positively with C-reactive protein (CRP) levels. Resistin levels measured on the day of admittance had a positive predictive value of 93.3% (cut-off: >6.95 ng/mL) in predicting a Schröder score >3.
Resistin, and to a lesser extent leptin, but not adiponectin levels are novel potential markers for extrapancreatic necrosis and severity of acute pancreatitis and should therefore be tested in larger cohorts of patients.
Journal of Gastroenterology and Hepatology 04/2007; 22(3):326-34. DOI:10.1111/j.1440-1746.2006.04364.x · 3.50 Impact Factor