Diagnostic accuracy of contrast-enhanced diffusion-weighted MRI for liver metastases of pancreatic cancer: towards adequate staging and follow-up of pancreatic cancer - DIA-PANC study: study protocol for an international, multicenter, diagnostic trial.

BACKGROUND: At the time of surgery, approximately 10-20% of the patients with pancreatic cancer are considered unresectable because of unexpected liver metastasis, peritoneal carcinomatosis or locally advanced disease. This leads to futile surgical treatment with all the associated morbidity, mortality and costs. More than 50% of all liver metastases develop in the first six months postoperatively. These (subcentimeter) liver metastases are most likely already present at the time of diagnosis and have not been identified pre-operatively, due to the poor sensitivity of routine preoperative contrast-enhanced CT (CECT). METHODS: The DIA-PANC study is a prospective, international, multicenter, diagnostic cohort study investigating diffusion-weighted, contrast-enhanced MRI for the detection of liver metastases in patients with all stages of pancreatic cancer. Indeterminate or malignant liver lesions on MRI will be further investigated histopathologically. For patients with suspected liver lesions without histopathological proof, follow up imaging with paired CT and MRI at 3-, 6- and 12-months will serve as an alternative reference standard. DISCUSSION: The DIA-PANC trial is expected to report high-level evidence of the diagnostic accuracy of MRI for the detection of liver metastases, resulting in significant value for clinical decision making, guideline development and improved stratification for treatment strategies and future trials. Furthermore, DIA-PANC will contribute to our knowledge of liver metastases regarding incidence, imaging characteristics, their number and extent, and their change in time with or without treatment. It will enhance the worldwide implementation of MRI and consequently improve personalized treatment of patients with suspected pancreatic ductal adenocarcinoma. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03469726 . Registered on March 19th 2018 - Retrospectively registered.

Improving preoperative detection of synchronous liver metastases in pancreatic cancer with combined contrast-enhanced and diffusion-weighted MRI.

PURPOSE: To explore the value of gadolinium-enhanced MRI combined with diffusion-weighted MRI (Gd-enhanced MRI with DWI) in addition to contrast-enhanced CT (CECT) for detection of synchronous liver metastases for potentially resectable pancreatic cancer. METHODS: By means of a retrospective cohort study we included patients with potentially resectable pancreatic cancer on CECT, who underwent Gd-enhanced MRI with DWI between January 2012 and December 2016. A single observer evaluated MRI and CT and was blinded to imaging, pathology, and surgery reports. Liver lesions were scored in both modalities, using a 3-point scale: 1-benign, 2-indeterminate, 3- malignant (i.e., metastasis). The primary outcome parameters were the presence of liver metastases on Gd-enhanced MRI with DWI and the sensitivity of Gd-enhanced MRI with DWI for synchronous liver metastases. RESULTS: We included 66 patients (42 men, 24 women; median age 65 years, range 36-82 years). In 19 patients, liver metastases were present, which were confirmed by histopathology (n = 12), 18FDG-PET (n = 6), or surgical inspection (n = 1). Gd-enhanced MRI with DWI showed metastases in 16/19 patients (24%), which resulted in a sensitivity of 84% (95% CI 60-97%). Contrast-enhanced MRI showed 156 and DWI 397 metastases (p = 0.051), and 339 were particularly small (< 5 mm). CONCLUSIONS: In this study, Gd-enhanced MRI with DWI detected synchronous liver metastases in 24% of patients with potentially resectable pancreatic cancer on CECT with a sensitivity of 84%. Diffusion-weighted MRI showed a greater number of metastases than any other sequence, particularly small metastases (< 5 mm).

The in vitro mechanisms and in vivo efficacy of intravenous lidocaine on the neuroinflammatory response in acute and chronic pain.

INTRODUCTION: The neuroinflammatory response plays a key role in several pain syndromes. Intravenous (iv) lidocaine is beneficial in acute and chronic pain. This review delineates the current literature concerning in vitro mechanisms and in vivo efficacy of iv lidocaine on the neuroinflammatory response in acute and chronic pain. DATABASES AND DATA TREATMENT: We searched PUBMED and the Cochrane Library for in vitro and in vivo studies from July 1975 to August 2014. In vitro articles providing an explanation for the mechanisms of action of lidocaine on the neuroinflammatory response in pain were included. Animal or clinical studies were included concerning iv lidocaine for acute or chronic pain or during inflammation. RESULTS: Eighty-eight articles regarding iv lidocaine were included: 36 in vitro studies evaluating the effect on ion channels and receptors; 31 animal studies concerning acute and chronic pain and inflammatory models; 21 clinical studies concerning acute and chronic pain. Low-dose lidocaine inhibits in vitro voltage-gated sodium channels, the glycinergic system, some potassium channels and Gαq-coupled protein receptors. Higher lidocaine concentrations block potassium and calcium channels, and NMDA receptors. Animal studies demonstrate lidocaine to have analgesic effects in acute and neuropathic pain syndromes and anti-inflammatory effects early in the inflammatory response. Clinical studies demonstrate lidocaine to have advantage in abdominal surgery and in some neuropathic pain syndromes. CONCLUSIONS: Intravenous lidocaine has analgesic, anti-inflammatory and antihyperalgesic properties mediated by an inhibitory effect on ion channels and receptors. It attenuates the neuroinflammatory response in perioperative pain and chronic neuropathic pain.

Prognosis and value of adjuvant chemotherapy in stage III mucinous colorectal carcinoma.

BACKGROUND: Colorectal mucinous adenocarcinoma (MC) has been associated with impaired prognosis compared with nonmucinous adenocarcinoma (NMC). Response to palliative chemotherapy is poor in metastatic disease, but the benefit of adjuvant chemotherapeutic treatment has never been assessed in large patient groups. This study analyses overall survival and efficacy of adjuvant chemotherapy in terms of survival in patients following radical resection for MC. PATIENTS AND METHODS: This population-based study involved 27 251 unselected patients diagnosed with colorectal carcinoma between 1990 and 2010 and recorded in a prospective pathology-based registry. Kaplan-Meier analysis and log-rank testing were used to estimate survival. Cox proportional hazard model was used to calculate multivariate hazard ratios for death. RESULTS: MC was found in 12.3% (N = 3052) of colorectal tumors with a different distribution compared with NMC, with 24.4% located in the rectum and 54.3% in the proximal colon (versus 38.0% and 30.6%), P < 0.0001. NMC was more often classified as stage I disease than MC (20.5% versus 10.9%), P < 0.0001. After adjustments for covariates, MC was associated with a higher risk of death only when located in the rectum [hazard ratio 1.22; 95% confidence interval (CI) 1.11-1.34]. Multivariate regression analysis showed a similar survival after adjuvant chemotherapy for stage III MC and NMC patients. CONCLUSIONS: The poor prognosis for MC is only present in rectal cancer. In the adjuvant setting, there is no difference in the efficacy of chemotherapy between MC and NMC; therefore, current adjuvant treatment recommendations should not take histology into account.

[The clinical perspective of angiogenesis inhibitors]. / Het klinisch perspectief van angiogeneseremmers.

An important development in the treatment of cancer is the recognition that the tumour's microenvironment, notably its vasculature, may be an attractive target for therapy. In the eighties of the last century, the concept of angiogenesis (the formation of new blood vessels from existing vasculature) was developed. Angiogenesis is the driving force behind tumour growth and metastasis. Recent angiogenesis research has elucidated the role of growth factors (vascular endothelial growth factor (VEGF), epidermal growth factor), metalloproteinases and endogenous proteins such as angiostatin and endostatin. This new knowledge has led to the rapid development of several angiogenesis inhibiting strategies. Although these new strategies showed very promising results in preclinical animal studies, early clinical studies with individual angiogenesis inhibitors have shown no antitumour effect so far. However, in recent studies blocking VEGF in addition to conventional chemotherapy has led to an increase in disease-free survival time and in response rate to chemotherapy. Angiogenesis research has contributed to the knowledge of the biology of cancer, the design of modified clinical studies and the development of surrogate markers that can be used as pharmacodynamic end points in future studies.

Inflammatory bowel disease is associated with increased mucosal levels of bactericidal/permeability-increasing protein.

BACKGROUND & AIMS: Clinical sepsis seldom accompanies inflammatory bowel disease. The aim of this study was to measure colonic mucosal levels of the neutrophil product bactericidal/permeability-increasing protein (BPI), which kills gram-negative bacteria in addition to inactivating endotoxin. METHODS: Enzyme-linked immunosorbent assay and immunohistochemistry for BPI were performed on homogenates and tissue secretions of biopsy specimens from patients with ulcerative colitis (n=11) and Crohn's disease (n=5) and from normal controls (n=5). RESULTS: Mucosal neutrophil content (144 +/- 23 vs. 35 +/- 9 neutrophils/mg protein; P<0.007) and BPI content (2.07 +/- 0.75 vs. 0.12 +/- 0.02 ng/mg protein; P<0.002) were greater in the colitis groups and correlated closely (r=0.68; P<0.001). This relationship held for both ulcerative colitis (P<0.002) and Crohn's disease (P<0.01) with a trend towards greater levels in Crohn's disease. There was a trend towards higher BPI levels with an increasing endoscopic inflammation score (grade I, 1.32 +/- 0.6 ng/mg protein; grade II, 2.82 +/- 1.4 ng/mg protein). Immunohistochemistry and the biopsy culture showed BPI to be both intracellular and extracellular, to be present in the crypt lumen, and to be released into incubating medium. CONCLUSIONS: Mucosal levels of BPI are increased in colitis. Such localization may ameliorate mucosal responses to gram-negative bacteria and their products.

Mechanisms underlying neutrophil adhesion to apical epithelial membranes.

Crypt abscesses allow prolonged apposition of activated neutrophils to the epithelial surface of the colon. Adhesion of neutrophils to both the vascular endothelium and basolateral epithelial membrane share common effector molecules but are distinct processes. This study aimed to define the mechanisms that effect adhesion, independent of transmigration, to the apical epithelium. HT29 (cl 19A) cells were grown to confluency and incubated with neutrophils under conditions of: (i) neutrophil stimulation with phorbol-myristate-acetate; (ii) monolayer stimulation with interferon gamma, tumour necrosis factor alpha (IFN gamma, TNF alpha); and (iii) recent epithelial cell trypsinisation. These experiments were carried out in the presence of neutralising antibodies to CD18, CD11b, LFA-1, E-selectin, P-selectin, intracellular adhesion molecule 1 (ICAM-1), and ICAM-2; a novel CD11b/CD18 antagonist, neutrophil inhibitory factor (rNIF); adenosine receptor agonists (5'N-ethycarboxamido adenosine/N6-cylopentyladenosine (NECA/CPA)) and a platelet activating factor (PAF) receptor antagonist lexipafant. Adhesion of stimulated neutrophils to resting monolayers was Mac-1, CD18 dependent and ICAM-1, ICAM-2, E-selectin, P-selectin, PAF independent. Cytokine activated monolayers exhibited higher binding of neutrophils which was inhibited by rNIF and aCD18. Recently trypsinised monolayers bound neutrophils in a CD11b/CD18 and CD18 independent manner. Adenosine agonists failed to influence neutrophil adhesion under any condition. This study shows neutrophil adhesion to apical epithelial membranes is similar to that at the epithelial basolateral membrane, though different to that seen at the vascular endothelium. These results highlight regional differences in neutrophil adhesion molecule usage.

Production and cellular source of interleukin-8 in ulcerative colitis.

: Evidence has accumulated that interleukin-1ß (IL-1ß) plays an pivotal role in mediating the inflammatory changes in ulcerative colitis (UC) and that interleukin-8 (IL-8) is responsible for some of the neutrophil-activating actions of IL-1ß in vivo. We determined the IL-8 content and its cellular source in mucosal specimens of patients with UC, and analyzed whole gut lavage fluid on the presence of IL-8. In addition, we monitored these patients for a follow-up period of 1 year to see if IL-8 levels are indicative for colon at risk. Patients with active disease were enrolled; disease activity, endoscopical scores, and histopathological grading were assessed. Transcription and translation of IL-8 were demonstrated by in situ hybridisation and immunohistochemistry. Biopsy specimens from 30 UC patients and five controls were homogenized, and IL-8 content was determined. Lavage fluid from 10 UC patients and six controls was processed and analyzed for the presence of IL-8. Clinical events were monitored for a period of 1 year. IL-8 production was detected in both enterocytes and mucosal inflammatory cells. The mean IL-8 content in control biopsy specimens was 98.0 pg/mg (±10 pg/mg). The IL-8 content was 176.7 pg/mg (±21 pg/mg) in specimens obtained from noninflamed colon regions of UC patients, and 204 pg/mg (±27 pg/mg) in specimens taken from inflamed colonic areas (p = 0.023 and p = 0.013, respectively). The mean IL-8 levels in lavage fluid from UC patients was 36.4 pg/ml (±22.5 pg/ml) versus 3.1 pg/ml (±0.8 pg/ml) in control patients (p < 0.05). Lavage IL-8 levels correlated with endoscopical score (r = 0.81; p = 0.009). During a follow-up period of 1 year, patients with high IL-8 levels in their noninvolved colon mucosa experienced more flare-ups than patients with low levels of normal mucosal IL-8. This study demonstrates that IL-8 is expressed in the normal large bowel mucosa. High levels are present in both macroscopically inflamed and noninflamed mucosa in UC. Both enterocytes and inflammatory cells contribute to the IL-8 production. Analysis of gut perfusate can be used to study IL-8 in UC, and IL-8 production in normally appearing mucosa in patients with ulcerative colitis may be indicative of colon at risk for inflammation.

Anti-CD4 Therapy Decreases Epithelial Expression of HLA-DR Molecules in Patients with Crohn's Disease.

: Mucosal cells from patients with Crohn's disease regularly express HLA-class II antigens, which are thought to be induced by cytokines, in particular interferon gamma, that are secreted by activated T-cells. Abberant MHC-class II expression by epithelial cells may play a role in diseases characterized by T-cell activation. Activated CD4-positive T-cells are present in the lamina propria of patients with Crohn's disease. In this study we report the results of an open label, single center anti-CD4 ~ trial in patients with steroid refractory Crohn's disease. A rapid and near complete loss of HLA-DR expression by mucosal cells was observed in 10 out of 12 patients, following infusion of the chimeric anti-CD4 antibody M-T412. These results suggest that CD4-positive T-cells are necessary for epithelial class II expression in patients with Crohn's disease.

Interleukin 1 beta is expressed predominantly by enterocytes in experimental colitis.

The cytokine interleukin 1 beta is an important mediator of inflammatory processes capable of inducing eicosanoid production, T-cell activation, and increased vascular permeability. In this study, in situ hybridization techniques were used to delineate the kinetics and cellular source of induced interleukin 1 beta in acute experimental colitis. The induction of interleukin 1 beta messenger RNA was an early phenomenon and occurred predominantly in undifferentiated cells located in the basal part of the mucosal crypts but not in differentiated enterocytes. The undifferentiated enterocytes retained the messenger RNA during differentiation and migration to more apical parts of the crypts. These results suggest that induction of interleukin 1 beta messenger RNA in enterocytes is causally related to the subsequent inflammatory changes seen in acute experimental colitis.