GIST: Correlation of risk classifications and outcome.

In clinical practice, there are often discrepancies between the oncological prognosis of gastrointestinal stromal tumors (GIST) and the actual clinical course. This study aimed to check with our collective how reliably the current classifications (Miettinen, Fletcher) predict the prognosis of GIST and to evaluate whether an extension of the classifications by the parameter proliferation activity could make sense. This prospective study enrolled 58 patients who underwent surgery on GIST from 01/2006 to 12/2016. The postoperative course (curation, recurrence, progress) was correlated with the identified risk classification and the proliferative activity. Coincidences with other tumors were strikingly common in patients with GIST (43%). Based on the risk group assignment of GIST, no assessment of the probability of the occurrence of second neoplasia could be derived. Individual patients were under- or over-graduated concerning the assessment of biological behavior based on the standard risk classifications. The inclusion of proliferative activity did not allow for a more precise predictive power - neither to the risk of recurrence and metastasis nor to the development of a second neoplasia. The study showed that there is currently no parameter or logarithm that reliably predicts the biological behavior of GIST. Due to the frequency of coincidence of second neoplasia and (rare) distant metastases, for everyday clinical practice, appropriate staging diagnostic and regular follow-up care should also be used for benign GIST.

[Prophylactic Appendectomy: Yes or No?] / Begleitappendektomie: ja oder nein?

Background At more than 50%, appendicitis is the leading cause of acute intra-abdominal disease requiring surgery. In the course of various other operations, prophylactic appendectomy (PA) is frequently performed. Objectives This study examines to what extent PA is justified. Patients and Methods A prospective study was performed in all patients (n = 173) undergoing prophylactic appendectomy in Katharinen Hospital Unna between January 2010 and October 2013. The following variables were analysed: age, gender, type of primary surgery, emergency or elective surgery, complications, lethality, intraoperative and histopathological evaluation of the appendix. In addition, patients were contacted postoperatively with the request to complete a questionnaire. Results Prophylactic appendectomy was carried out without any specific complications. 117 patients (68%) participated in the survey. 15% of these patients had suffered symptoms that could be attributable to irritation of the appendix. With only one exception, all appendectomy specimens revealed pathological findings in the histopathological examination. PA allowed the early diagnosis of 4 adenomas, one neuroendocrine tumour and 6 metastases or manifestations of peritoneal carcinomatosis. Conclusion PA is ethically justifiable, as there are few complications. Moreover, it can help to avoid future appendicitis and allows early detection of malignancies.

Knockout of the c-Jun N-terminal Kinase 2 aggravates the development of mild chronic dextran sulfate sodium colitis independently of expression of intestinal cytokines TNFα, TGFB1, and IL-6.

INTRODUCTION: The c-Jun N-terminal kinases (JNKs) are involved in signal transduction of inflammatory bowel diseases. The aim of this study was to examine the function of JNKs by using a low-dose dextran sulfate sodium (DSS) model in JNK1 knockout mice (Mapk8-/-), JNK2 knockout mice (Mapk9-/-), and wild-type controls (WT1, WT2). METHODS: The animals were evaluated daily using a disease activity index. After 30 days, the intestine was evaluated histologically with a crypt damage score. CD4+ and CD8+ cells were quantified using immunofluorescence. Analysis of tumor necrosis factor-α (TNFα), interleukin-6 (IL-6), and transforming growth factor ß1 (TGFB1) expression was carried out using LightCycler(®) real-time polymerase chain reaction. RESULTS: Cyclic administration of low-dose DSS (1%) was not able to induce features of chronic colitis in Mapk8-/- WT2 mice. By contrast, DSS administration significantly increased the disease activity index in WT1 and Mapk9-/- mice. In Mapk9-/- mice, the crypt damage score and the number of CD4+ and CD8+ cells as features of chronic colitis/inflammation were also significantly elevated. Expression of TNFα, IL-6, and TGFB1 was not altered by the JNK knockout. CONCLUSION: Administering DSS at a defined low concentration that is unable to induce colitis in WT animals leads to clinically and histologically detectable chronic colitis in Mapk9-/- mice. The reason for this disease-inducing effect resulting from the loss of JNK2 remains to be elucidated. Expression of TNFα, IL-6, and TGFB1 does not appear to be involved; proapoptotic JNK2 may prolong the activity of proinflammatory immune cells, leading to perpetuation of the inflammation.

Gene expression analysis of cell death induction by taurolidine in different malignant cell lines.

BACKGROUND: The anti-infective agent Taurolidine (TRD) has been shown to have cell death inducing properties, but the mechanism of its action is largely unknown. The aim of this study was to identify potential common target genes modulated at the transcriptional level following TRD treatment in tumour cell lines originating from different cancer types. METHODS: Five different malignant cell lines (HT29, Chang Liver, HT1080, AsPC-1 and BxPC-3) were incubated with TRD (100 µM, 250 µM and 1000 µM). Proliferation after 8 h and cell viability after 24 h were analyzed by BrdU assay and FACS analysis, respectively. Gene expression analyses were carried out using the Agilent-microarray platform to identify genes which displayed conjoint regulation following the addition of TRD in all cell lines. Candidate genes were subjected to Ingenuity Pathways Analysis and selected genes were validated by qRT-PCR and Western Blot. RESULTS: TRD 250 µM caused a significant inhibition of proliferation as well as apoptotic cell death in all cell lines. Among cell death associated genes with the strongest regulation in gene expression, we identified pro-apoptotic transcription factors (EGR1, ATF3) as well as genes involved in the ER stress response (PPP1R15A), in ubiquitination (TRAF6) and mitochondrial apoptotic pathways (PMAIP1). CONCLUSIONS: This is the first conjoint analysis of potential target genes of TRD which was performed simultaneously in different malignant cell lines. The results indicate that TRD might be involved in different signal transduction pathways leading to apoptosis.

Indications and early outcomes for total pancreatectomy at a high-volume pancreas center.

BACKGROUND: This study aimed to analyse the most common current indications for total pancreatectomy (TP) at a high-volume pancreas center. METHOD: Prospectively collected data on indications and short-term outcome of all TP's performed from January 2004 until June 2008 were analysed. RESULTS: The total pancreatectomies (TP) were 63, i.e., 6.7% of all pancreatic procedures (n = 948). Indications for TP were classified into 4 groups: tumors of advanced stage, n = 23 (36.5%), technical problems due to soft pancreatic tissue, n = 18 (28.6%), troubles due to perioperative surgical complications, n = 15 (23.8%), and therapy-resistant pain due to chronic pancreatitis, n = 7 (11.1%). Surgical complications occurred in 23 patients (36.5%). The mortality in elective TP was 6.25%. Median postoperative stay was 21 days. Mortality, morbidity and the other perioperative parameters differed substantially according to the indication for pancreatectomy. CONCLUSION: Total pancreatectomy is definitely indicated for a limited range of elective and emergency situations. Indications can be: size or localisation of pancreatic tumor, trouble, technical diffuculties and therapy-refractory pain in chronic pancreatitis. A TP due to perioperative complications (troubles) after pancreatic resections is doomed by extremely high morbidity and mortality and should be avoided.

Oral administration of the anti-proliferative substance taurolidine has no impact on dextran sulfate sodium induced colitis-associated carcinogenesis in mice.

BACKGROUND: New chemopreventive strategies for ulcerative colitis (UC)-associated dysplasia and cancer have to be evaluated. Taurolidine (TRD) has anti-inflammatory, anti-proliferative and anti-neoplastic properties with almost absent toxicity. The aim of the study was to determine whether TRD decreases dysplasia in the well-characterized Dextran Sulfate Sodium - Azoxymethane (DSS-AOM) animal model for UC-associated carcinogenesis. MATERIAL AND METHODS: The DSS-AOM model of carcinogenesis was induced in female inbred C57BL/6 mice. Half of the mice were treated with TRD, the other served as control. After 100 days macroscopic, histological and immunhistochemical (beta-Catenin, E-Cadherin, SOX9, Ki-67, Cyclin-D1) examination of the colon was performed. RESULTS: Incidence, multiplicity, grading and growth pattern of adenomas did not differ significantly between TRD and control group. In all animals, inflammatory changes were absent. Immunhistochemistry revealed increased expression of Ki-67, beta-catenin, SOX9 and Cyclin-D1 in adenomas compared to normal mucosa - without significant difference between TRD and control treatment. CONCLUSION: Oral administration of TRD has no impact on DSS-induced colitis-associated carcinogenesis. However, SOX9 and Cyclin-D1 representing key members of the Wnt pathway have not yet been described in the DSS-AOM model of carcinogenesis - underlining the importance of this oncogenic pathway in this setting.

Comparative analysis of cell death induction by Taurolidine in different malignant human cancer cell lines.

BACKGROUND: Taurolidine (TRD) represents an anti-infective substance with anti-neoplastic activity in many malignant cell lines. So far, the knowledge about the cell death inducing mechanisms and pathways activated by TRD is limited. The aim of this study was therefore, to perform a comparative analysis of cell death induction by TRD simultaneously in different malignant cell lines. MATERIALS AND METHODS: Five different malignant cell lines (HT29/Colon, Chang Liver/Liver, HT1080/fibrosarcoma, AsPC-1/pancreas and BxPC-3/pancreas) were incubated with increasing concentrations of TRD (100 microM, 250 microM and 1000 microM) for 6 h and 24 h. Cell viability, apoptosis and necrosis were analyzed by FACS analysis (Propidiumiodide/AnnexinV staining). Additionally, cells were co-incubated with the caspase Inhibitor z-VAD, the radical scavenger N-Acetylcystein (NAC) and the Gluthation depleting agent BSO to examine the contribution of caspase activation and reactive oxygen species in TRD induced cell death. RESULTS: All cell lines were susceptible to TRD induced cell death without resistance toward this anti-neoplastic agent. However, the dose response effects were varying largely between different cell lines. The effect of NAC and BSO co-treatment were highly different among cell lines--suggesting a cell line specific involvement of ROS in TRD induced cell death. Furthermore, impact of z-VAD mediated inhibition of caspases was differing strongly among the cell lines. CONCLUSION: This is the first study providing a simultaneous evaluation of the anti-neoplastic action of TRD across several malignant cell lines. The involvement of ROS and caspase activation was highly variable among the five cell lines, although all were susceptible to TRD induced cell death. Our results indicate, that TRD is likely to provide multifaceted cell death mechanisms leading to a cell line specific diversity.

Bacteribilia after preoperative bile duct stenting: a prospective study.

STUDY DESIGN: A prospective analysis of intraoperative bile duct cultures in patients undergoing surgery for both, malignant or benign periampullary diseases at the Department of Surgery, St Josef Hospital, Bochum, Germany, during a period of 18 months, between January 2004 and June 2005. GOALS: The goals of the presented study were to investigate the effects of preoperative bile duct stenting on intraoperative bile duct cultures and postoperative outcome in patients undergoing pancreatic surgery. BACKGROUND: In pancreatic surgery, bile duct stenting is often aimed at improving postoperative outcome. As implantation of xenograft material in the main bile duct facilitates bacterial contamination and cholangitis, a critical evaluation of stenting is mandatory. STUDY: In all patients with a hepaticojejunostomy (n=80), a bile duct culture was collected during the operation. All patients received antibiotic prophylaxis perioperatively and a retrograde flushing of bile ducts with warm saline after bile duct resection. Fifty-one percent (41/80) patients had biliary drainage before surgery, whereas 49% (39/80) were operated without preoperative draining procedures. RESULTS: After bile duct stenting, 98% of patients had a positive bile culture, whereas only 21% of infected bile was seen in patients without drainage (P<0.001). Despite infected bile, only 2% stented patients developed acute cholangitis postoperatively, versus 13% patients in the group without stent (P=0.231). After stenting, major complications occurred in 12%, versus 8% in patients without stent (P=0.817). CONCLUSIONS: Preoperative biliary drainage leads to an almost 100% bacterial contamination of bile ducts. With hospital-adjusted antibiotic prophylaxis and retrograde flushing of bile ducts, the postoperative rate of acute cholangitis and morbidity is not elevated. A critical evaluation of benefits from preoperative biliary drainage for each patient is necessary.

TRAIL and Taurolidine induce apoptosis and decrease proliferation in human fibrosarcoma.

BACKGROUND: Disseminated soft tissue sarcoma still represents a therapeutic dilemma because effective cytostatics are missing. Therefore we tested TRAIL and Tarolidine (TRD), two substances with apoptogenic properties on human fibrosarcoma (HT1080). METHODS: Viability, apoptosis and necrosis were visualized by TUNEL-Assay and quantitated by FACS analysis (Propidiumiodide/AnnexinV staining). Gene expression was analysed by RNA-Microarray and the results validated for selected genes by rtPCR. Protein level changes were documented by Western Blot analysis. NFKB activity was analysed by ELISA and proliferation assays (BrdU) were performed. RESULTS AND DISCUSSION: The single substances TRAIL and TRD induced apoptotic cell death and decreased proliferation in HT1080 cells significantly. Gene expression of several genes related to apoptotic pathways (TRAIL: ARHGDIA, NFKBIA, TNFAIP3; TRD: HSPA1A/B, NFKBIA, GADD45A, SGK, JUN, MAP3K14) was changed. The combination of TRD and TRAIL significantly increased apoptotic cell death compared to the single substances and lead to expression changes in a variety of genes (HSPA1A/B, NFKBIA, PPP1R15A, GADD45A, AXL, SGK, DUSP1, JUN, IRF1, MYC, BAG5, BIRC3). NFKB activity assay revealed an antipodal regulation of the several subunits of NFKB by TRD and TRD+TRAIL compared to TRAIL alone. CONCLUSION: TRD and TRAIL are effective to induce apoptosis and decrease proliferation in human fibrosarcoma. A variety of genes seems to be involved, pointing to the NFKB pathway as key regulator in TRD/TRAIL-mediated apoptosis.

Synergistic apoptotic effects of taurolidine and TRAIL on squamous carcinoma cells of the esophagus.

The treatment of choice for esophageal cancer is considered surgical resection, but a median survival of around 20 months after treatment is still discouraging. The value of adjuvant or neoadjuvant radiation or chemotherapy is limited and to date, benefits have only been described for certain tumor stages. Therefore, new therapeutic options are required. As alternative chemotherapeutics, we tested the antibiotic taurolidine (TRD) on KYSE 270 human esophageal carcinoma cells alone and in combination with rhTRAIL (TNF related apoptosis-inducing ligand). Viability, apoptosis and necrosis were visualized by TUNEL assay and quantitated by FACS analysis. Gene expression was analysed by RNA microarray. The most effective concentration of TRD as single substance (250 micromol/l) induced apoptosis to a maximum of 40% after 12-h dose dependently, leaving 4% viable cells after 48 h; by comparison, rhTRAIL did not have a significant effect. The combination of both substances doubled the effect of TRD alone. Gene expression profiling revealed that TRD downregulated endogenous TRAIL, TNFRSF1A, TRADD, TNFRSF1B, TNFRSF21, FADD, as well as MAP2K4, JAK2 and Bcl2, Bcl2l1, APAF1 and caspase-3. TNFRSF25, cytochrome-c, caspase-1, -8, -9, JUN, GADD45A and NFKBIA were upregulated. TRAIL reduced endogenous TRAIL, Bcl2l1 and caspase-1 expression. BIRC2, BIRC3, TNFAIP3, and NFKBIA were upregulated. The combined substances upregulated endogenous TRAIL, NFKBIA and JUN, whereas DFFA and TRAF3 were downregulated compared to TRD as single substance. We conclude that TRD overcomes TRAIL resistance in KYSE 270 cells. Synergistic effects are dependent on the same and on distinct apoptotic pathways which, jointly triggered, result in an amplified response. Several apoptotic pathways, including the TNF-receptor associated and the mitochondrial pathway, were differentially regulated by the substances on gene expression level. Additionally transcription factors seem to be influenced, NFKB in particular. Endogenous TRAIL expression is increased by the combination of substances, whereas it is reduced by each single substance. Taking into consideration that the non-toxic TRD was able to reduce rhTRAIL toxicity and dose, combined therapy with TRD and rhTRAIL may offer new options for treatment in esophageal cancer.

Tailored resective pancreatic surgery for pediatric patients with chronic pancreatitis.

BACKGROUND: Surgical treatment for chronic pancreatitis (CP) in children comprises predominantly nonresective draining procedures. The purpose of this study was to identify indications, techniques, and results of organ-preserving resective pancreatic procedures for pediatric CP at our institution. PATIENTS AND METHODS: A retrospective chart review was performed of all children undergoing pancreatic surgery for CP over a period of 4 years. RESULTS: Overall, 6 pediatric patients (3 male, 3 female, ages 7-18 years) underwent a duodenum-preserving pancreatic head resection (3), a middle segmental pancreatic resection (2), or a distal pancreatectomy (1) for CP of different etiologies (idiopathic 2, posttraumatic 2, pancreas divisum 1, situs inversus 1). No mortality or major surgical complication occurred. Mean operative time was 294 min (207-412 min) and intraoperative blood loss was 541 mL (100-1300 mL). Postoperative hospital stay was 13 days (10-18 days). No endocrine or exocrine insufficiency occurred during follow up of 46 months (25-50 m), and pain control was improved in 5 of 6 patients. CONCLUSIONS: Tailored organ-preserving resective pancreatic surgery can be performed with low morbidity and mortality in pediatric patients with CP and not responding to conservative treatment.

Oral administration of taurolidine ameliorates chronic DSS colitis in mice.

Taurolidine (TRD) has antimicrobial and anti-inflammatory properties. However, the anti-inflammatory effects of TRD in inflammatory bowel diseases (IBD) have not been investigated. Here, we have analyzed the toxicity of TRD after oral long-term application in mice and examined the impact of oral TRD in a dextran sulfate sodium (DSS) model of experimental colitis. Female C57/BL6 mice received TRD in various concentrations (0.1% to 0.4%) for 60 days. Toxicity was evaluated by use of a disease activity index (DAI) and histological examination of major metabolic organs. Furthermore, the impact of 0.2% TRD on a chronic DSS colitis was examined by daily DAI, histological crypt damage score (CDS), bacterial translocation into mesenteric lymph nodes (MLN), and colonic expression of tumor necrosis factor (TNF) alpha, transforming growth factor (TGF) beta, interleukin (IL)-1beta, IL-6, cytochrome oxidase (COX)-2, and monocyte chemotactic protein (MCP)-1 by real-time polymerase chain reaction (PCR). Oral TRD administration for 60 days was well tolerated by the animals and did not show any toxic effects in terms of DAI and histological changes. TRD treatment of DSS colitis led to increased survival of 100%, compared to 33% in the untreated colitis group (p < or = .005). Clinical amelioration was mirrored by significantly reduced DAI and CDS in the TRD treated colitis. Colonic cytokine expression and bacterial translocation into MLN showed no differences between both groups. We thus report for the first time that oral application of TRD results in amelioration of an experimental IBD model. We hypothesize direct intraluminal antimicrobial effects of TRD as well as anti-inflammatory effects during the acute phase of DSS colitis.

Pancreatic redo procedures: to do or not to do -- this is the question.

BACKGROUND: Pancreatic redo procedures belong to the most difficult abdominal operations because of altered anatomy, significant adhesions, and the potential of recurrent disease. We report on our experience with 15 redo procedures among a series of 350 consecutive pancreatic operations. PATIENT AND METHODS: From January 1, 2004 to May 31, 2006 a total of 350 patients underwent pancreatic surgery in our department. There were 15 patients identified who had pancreatic redo surgery for benign (14) or malignant (1) disease. Perioperative parameters and outcome of 15 patients undergoing redo surgery after pancreatic resections were evaluated. RESULTS: Operative procedures included revision and redo of the pancreaticojejunostomy after resection of the pancreatic margin (6), completion pancreatectomy (3), conversion from duodenum-preserving pancreatic head resection to pylorus-preserving pancreaticoduodenectomy (3), classic pancreaticoduodenectomy after nonresective pancreatic surgery (1), redo of left-sided pancreatectomy (1), and classic pancreaticoduodenectomy after left-sided pancreatectomy (1). Histology revealed chronic pancreatitis in 14 and a mucinous adenocarcinoma of the pancreas in 1 patient. Median operative time was 335 min (235-615 min) and median intraoperative blood loss was 600 ml (300-2,800 ml). Median postoperative ICU stay was 20 h (4-113 h) and median postoperative hospital stay was 15 days (7-30 days). There was no perioperative mortality and morbidity was 33%. CONCLUSION: Pancreatic redo surgery can be performed with low morbidity and mortality. Redo surgery has a defined spectrum of indications, but to achieve good results surgery may be performed at high-volume centers.

Nosocomial pneumonia: third-group chinolone versus clindamycin/ceftriaxone in modulation of the acute phase reaction and outcome and cost efficacy.

The effect of a third-group chinolone and clindamycin/ceftriaxone regarding outcome of patients with nosocomial pneumonia (NP) and modulation of the acute phase reaction as measured by immunologic parameters were studied in a prospective randomized trial on a surgical intensive care unit (ICU), as well as a comparison of therapy costs. Determination in 18 patients of serum tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, procalcitonin, and endotoxin levels and assessment of clinical outcome of NP were followed by the calculation of therapy costs. Decline in all immunologic parameters between the first and last measurement of each patient was slightly greater for clindamycin patients but statistically significant only for TNF-alpha. One-day therapy costs were 63.5 Euro (chinolone) versus 86.9 Euro (clindamycin/ceftriaxone). There was no difference in the outcome of NP treated with either a third-group chinolone or clindamycin/ceftriaxone.

Pre-emptive antibiotic treatment vs 'standard' treatment in patients with elevated serum procalcitonin levels after elective colorectal surgery: a prospective randomised pilot study.

BACKGROUND: Procalcitonin (PCT) is regarded as a specific indicator of bacterial infection. Infectious complications in patients after colorectal surgery are a common cause of morbidity and mortality. The aim of this study was to investigate (a) whether PCT could serve as a negative predictive marker for postoperative complications and (b) whether, in patients with elevated PCT levels, a pre-emptive treatment with the third-generation cephalosporin ceftriaxone is superior to an antibiotic treatment starting later on the appearance of clinical signs and symptoms of infection. PATIENTS AND METHODS: By screening 250 patients with colorectal surgery, we identified 20 patients with PCT serum levels more than 1.5 ng/ml on at least 2 of the first 3 postoperative days. The remaining 230 patients were followed-up for the occurrence of infectious complications. The 20 patients with elevated PCT were included in a prospective randomised pilot study comparing pre-emptive antibiotic treatment with ceftriaxone vs standard treatment. RESULTS: The negative predictive value of PCT for systemic infectious complications was 98.3%. In patients receiving pre-emptive antibiotic treatment (ceftriaxone), both the incidence and the severity of postoperative systemic infections were significantly lower compared to those in a control group (Pearson's chi(2) test; p=0.001 and p=0.007, respectively). Major differences were also observed with respect to duration of antibiotic treatment and length of hospital stay. CONCLUSIONS: PCT is an early marker for systemic infectious complications after colorectal surgery with a high negative predictive value. A significant reduction in the rate of postoperative infections in patients with elevated PCT serum concentrations was achieved by means of pre-emptive antibiotic treatment.

Effect of the LT-alpha (+250 G/A) polymorphism on markers of inflammation and clinical outcome in critically ill patients.

BACKGROUND: Tumor necrosis factor alpha as a central mediator of the inflammation cascade is correlated to sepsis outcome. Tumor necrosis factor beta (LT-alpha) binds the same cell receptor and polymorphisms in both genes have been described. To evaluate the importance of the LT-alpha (+250 G/A) polymorphism for the clinical outcome of patients developing postsurgical sepsis, 85 patients were consecutively included into this study. METHODS: Blood samples were obtained for analysis of the biallelic LT-alpha (+250 G/A) polymorphism and for determination of serum levels of sTNF-R1, TNF-alpha, IL-6, IL-8, IL-10, procalcitonin, and neopterin. Cytokine levels were measured repeatedly until the patients' discharge from the ICU. RESULTS: The allele frequency was 0.28 for TNFB1 and 0.72 for TNFB2. The genotype distribution was TNFB1 homozygotes 4/79 (5.1%), TNFB1/TNFB2 heterozygotes 37/79 (46.8%), and TNFB2 homozygotes 38/79 (48.1%). Fifty-four out of 80 (67.5%) fulfilled the criteria for severe sepsis; 36/80 (45.0%) developed septic shock. Multiple organ failure occurred in 60/80 patients (75.0%), and the overall mortality was 26/80 (32.5%). Concerning the LT-alpha-genotypes, there was no difference in the frequency of severe sepsis or shock or in the development of multi-organ failure or death between the three subgroups. The peak plasma TNF-alpha levels were similar for all genotype subgroups. CONCLUSIONS: There was no correlation between the biallelic LT-alpha (+250 G/A) polymorphism and the outcome of critically ill patients. Genotyping this locus does not seem to be useful in predicting sepsis outcome.