Alkwin Wanders

Association between radiographic damage of the spine and spinal mobility for individual patients with ankylosing spondylitis: can assessment of spinal mobility be a proxy for radiographic evaluation?

Objective: To demonstrate the association between various measures of spinal mobility and radiographic damage of the spine in individual patients with ankylosing spondylitis, and to determine whether the assessment of spinal mobility can be a proxy for the assessment of radiographic damage. Methods: Radiographic damage was assessed by the mSASSS. Cumulative probability plots combined the radiographic damage score of an individual patient with the corresponding score for nine spinal mobility measures. Receiver operating characteristic analysis was performed to determine the cut off level of every spinal mobility measure that discriminates best between the presence and absence of radiographic damage. Three arbitrary cut off levels for radiographic damage were investigated. Likelihood ratios were calculated to explore further the diagnostic properties of the spinal mobility measures. Results: Cumulative probability plots showed an association between spinal mobility measures and radiographic damage for the individual patient. Irrespective of the chosen cut off level for radiographic progression, lateral spinal flexion and BASMI discriminated best between patients with and those without structural damage. Even the best discriminatory spinal mobility assessments misclassified a considerable proportion of patients (up to 20%). Intermalleolar distance performed worst (up to 30% misclassifications). Lateral spinal flexion best predicted the absence of radiographic damage, and a modified Schober test best predicted the presence of radiographic damage. Conclusion: This study unequivocally demonstrated a relationship between spinal mobility and radiographic damage. However, spinal mobility cannot be used as a proxy for radiographic evaluation in an individual patient.

Ischemia-Induced Transplant Arteriosclerosis in the Rat

The effect of cold graft ischemia time on the development of transplant arteriosclerosis was investigated. Aorta grafts from DA or PVG rats were stored in a cold perfusion solution for 1, 4, or 24 hours before being orthotopically transplanted to PVG recipients. After observation times ranging from 2 to 8 weeks, the grafts were examined for various cell populations. Regional changes in the intima and media layers were measured by using an image analysis system. The arteriosclerosis-like changes seen in syngeneic grafts with the longest ischemia time could be almost as prominent as those seen in the allogeneic transplants. The magnitude of the regional intima changes in the syngeneic group correlated well with the ischemia time and in the allogeneic group with the observation time. The cell composition found in the intima and media of the allogeneic vessels consisted of macrophages, T-lymphocytes, MHC class II-expressing cells, and smooth muscle cells, whereas the syngeneic grafts contained almost exclusively smooth muscle cells and macrophages. We therefore conclude that the damage due to prolonged cold ischemia time is sufficient to cause pronounced graft arteriosclerosis. The pathophysiological mechanism leading to ischemia-induced arteriosclerosis is different from the one seen in the allogeneic situation.

AdCD40L Immunogene Therapy for Bladder Carcinoma—The First Phase I/IIa Trial

Purpose: Immunotherapy with Bacillus Calmette-Guerin (BCG) instillation is recommended for high-risk, non–muscle invasive bladder cancer. Bacillus Calmette-Guerin is not effective in advanced tumors, and better alternatives are warranted. Immunostimulating gene therapy with adenoviral vectors expressing CD40 ligand (AdCD40L) has shown efficacy in tumor models. CD40 ligand stimulates systemic immunity and may be effective in local and invasive human disease. Experimental Design: Patients with invasive bladder cancer scheduled for cystectomy or patients with Ta tumors were enrolled in a phase I/IIa trial. Patients were treated with three cycles of intrabladder Clorpactin WCS-90 prewash, followed by AdCD40L instillation 1 week apart. Safety, gene transfer, immune effects, and antitumor responses were monitored. Results: All eight recruited patients were treated as scheduled, and therapy was well tolerated. The main adverse effect was transient local pain during prewash. Postoperatively, urinary tract infections and one case of late septicemia with elevated potassium were reported. No adverse events were ascribed to vector therapy. Gene transfer was detected in biopsies, and bladders were heavily infiltrated with T cells. The effector marker IFN-γ increased in biopsies, whereas levels of circulating T regulatory cells were reduced. Histologic evaluation indicated that AdCD40L therapy reduced the load of malignant cells. Conclusions: To our knowledge, this is the first report on immunogene therapy in bladder cancer and the first using AdCD40L in vivo. Local AdCD40L gene therapy was safe, boosted immune activation, and should be further evaluated as a single or an adjuvant therapy for urothelial malignancies. Clin Cancer Res; 16(12); 3279–87. ©2010 AACR.

Eosinophil granulocytes are activated during the remission phase of ulcerative colitis

Aim: The aim of this study was to establish a method of investigating intestinal eosinophil and neutrophil granulocytes by flow cytometry, and to compare the distribution and activity of these cells in different stages of ulcerative colitis (UC). Methods: Biopsy samples were taken from six locations of the entire colon and from the terminal ileum in 10 patients with active total UC, 10 patients with inactive total UC, eight patients with active distal UC, and 11 control subjects. Cell suspensions from biopsies and from peripheral blood were incubated with fluorophore conjugated monoclonal antibodies. The use of scatter plot-gating and specific antibodies was established in a flow cytometry assay. Results: Eosinophils were more numerous and more active in patients with active UC than in controls. Interestingly, during inactive UC, the number of activated eosinophils was even larger. Eosinophil activity was high in the rectum of patients with distal colitis but was also slightly elevated in the proximal colon. Neutrophils were increased in number and activity during active but not inactive UC. In patients with distal colitis, activated neutrophils were only found in the sigmoid colon and rectum. Conclusion: With this method, we confirm that neutrophils participate in the inflammatory process during active UC, and that they express a resting phenotype during remission. The finding of activated eosinophils in inflamed intestine strengthens the view of these cells as proinflammatory and tissue damaging. Nevertheless, our new finding of high eosinophil activation during inactive UC suggests that eosinophils play a role in repair of injured epithelium.

Clinical and subclinical intestinal inflammation assessed by the mucosal patch technique: studies of mucosal neutrophil and eosinophil activation in inflammatory bowel diseases and irritable bowel syndrome

Background and aims: There is a clear need for a rapid, simple, safe, and sensitive method of determining the type and intensity of inflammation in the gut mucosa in clinical practice. In this study, we have evaluated the potential of a new method, the mucosal patch technique, in patients with and without apparent gut inflammation, as assessed by conventional diagnostic procedures. Subjects and methods: The technique tested is based on the idea that inflammatory mediators released from the rectal mucosa can be absorbed by and then extracted from cellulose patches brought into contact with the mucosa by use of an instrument with an inflatable balloon. Measurements were performed in healthy controls (n = 16) and in patients with active (n = 19) and inactive ulcerative colitis (UC, n = 8), collagen colitis (CC, n = 12), coeliac disease (n = 13), and irritable bowel syndrome (IBS, n = 13). Results: Inflammatory mediators from neutrophils (myeloperoxidase (MPO)) and eosinophils (eosinophil cationic protein (ECP)) were increased on average 300- and 10-fold, respectively, in patients with active UC compared with healthy controls and were correlated with the endoscopic score. Patients with inactive UC, CC, coeliac disease, and IBS exhibited no endoscopic signs of inflammation. These patient groups had significantly lower levels of MPO and ECP than the active UC group but showed on average a four- to sevenfold increase in MPO compared with healthy controls. Conclusion: The mucosal patch technique was well tolerated by patients and easily applied by the investigator. Pronounced neutrophil and eosinophil involvement in UC was demonstrated. With the high sensitivity of the technique, low degree mucosal neutrophil activation could also be quantified in patients with CC and UC in clinical remission. The finding of increased neutrophil involvement in patients with IBS contributes to the pathophysiological ideas of this disease.

Prompt reversal of a severe complement activation by eculizumab in a patient undergoing intentional ABO-incompatible pancreas and kidney transplantation

Summary We describe the presumably first intentional ABO‐incompatible deceased‐donor kidney and pancreas transplantation with a severe antibody‐mediated rejection during a rebound of isoagglutinins. Rejection was successfully treated with eculizumab, which inhibits the terminal pathway of complement. Complement analysis (C3, C3d,g, and a modified assay of classical complement‐related hemolytic function) documented complement activation and confirmed that eculizumab completely blocked complement function. At 6 months, the patient had normal kidney and pancreas function, and histological evaluations revealed no evidence of sustained graft damage. This successful transplantation suggests that ABO barriers can safely be overcome without extensive preconditioning, when the complement inhibitor eculizumab is included.

The proximal gastric pouch invariably contains acid-producing parietal cells in Roux-en-Y gastric bypass

Background: Roux-en-Y gastric bypass (RYGBP) is well tolerated and effective in ameliorating diseases common to morbidly obese patients. A potential drawback, however, is the risk for stomal ulcers, probably due to acid and peptic digestion of the mucosa in the proximal Roux limb. Methods: In 23 RYGBP patients (mean BMI 45 kg/m2, age 39 years), the gastro-jejunostomy was performed by circular stapler and the gastric suture ring retrieved for histological examination. 13 consecutive patients received our standard totally transected 4 × 3 cm proximal gastric pouch. The anvil was passed transgastricly and reference biopsies were taken from the gastrotomy in the corpus of the stomach. In the last 10 patients, the pouch size was reduced to 2 × 3 cm by a modified surgical technique. Results: All suture rings from the standard pouches consisted of corpus-fundus mucosa with a large amount of parietal cells, histologically identical to the reference biopsies from the gastrotomy. Also, the 10 suture rings from the modified small pouches contained corpus-fundus mucosa. In 5 of these samples, cardiac mucosa was found, but only in a small segment (6 mm). In addition, 3 patients had esophageal epithelium in the suture ring. Conclusion: The proximal pouch invariably contains acid-producing parietal cells. In order to reduce acid production and, hence, the risk of stomal ulcers, the pouch has to be made as small as possible.

A four-year review of fatal Aspergillosis.

Abstract To investigate the incidence, underlying diseases, and macropathological and microbiological features of invasive aspergillosis in a university hospital, the protocols of 1187 autopsies performed during the 4-year period 1993–1996 were reviewed. Invasive aspergillosis was diagnosed as the cause of death in 48 (4%) cases, four (8%) of which did not involve severe primary immunosuppression. In seven (15%) cases no pulmonary involvement was found; in six of these cases the portal of infection could not be established, whereas in one case invasive aspergillosis originated from Aspergillus peritonitis. Aspergillus grew in 42% of the samples obtained from the respiratory tracts of 32 patients with pulmonary aspergillosis and submitted within 10 days antemortem; at least one positive culture was obtained from 20 (63%) of these patients. It is concluded that the diagnosis of aspergillosis by means of culture has an appreciable sensitivity. Fatal invasive aspergillosis was rare among patients without severe immunosuppression, whereas invasive aspergillosis without pulmonary involvement was unexpectedly frequent.

Hsp90 is expressed and represents a therapeutic target in human oesophageal cancer using the inhibitor 17-allylamino-17-demethoxygeldanamycin.

Heat shock protein 90 (Hsp90) has been demonstrated to protect oncogenic variants of signalling molecules from degradation and may consequently serve as a therapeutic target for the treatment of oesophageal cancer for which adequate therapy is often lacking. We studied the expression of Hsp90 in tumour tissues of human oesophageal cancer and the impact of Hsp90 inhibition on oesophageal cancer cell lines using the drug 17-allylamino-17-demethoxygeldanamycin (17-AAG). Quantitative immunohistochemistry was performed on formalin-fixed paraffin-embedded tissues from patients with oesophageal cancer. In squamous cell carcinoma, a marked upregulation of Hsp90 could be noted in dysplastic epithelium and invasive cancer compared with normal epithelium. In adenocarcinoma, Hsp90 was expressed in neoplastic epithelium and also in normal non-neoplastic glands weakly. The inhibition of Hsp90 using 17-AAG led to a significant decrease in cell proliferation and viability in human oesophageal cancer cell lines. Using a clonogenic cell survival assay, Hsp90 inhibition significantly sensitised the cells for γ-photon irradiation. Heat shock protein 90 was found to be critical for proper signalling induced by both epidermal growth factor and insulin-like growth factor-1, in which the inhibition of signalling by 17-AAG correlated with the observed reduction in cell proliferation and viability. These results showed that Hsp90 was selectively expressed in oesophageal cancer tissue compared with the corresponding normal tissue, and the inhibition of Hsp90 resulted in decreased proliferation and viability as well as radiosensitisation of oesophageal cancer cells. Heat shock protein 90 represents a potential therapeutic target in the treatment of patients with oesophageal cancer, alone or in combination with radiotherapy.

High-risk human papilloma virus (HPV) and survival in patients with esophageal carcinoma: a pilot study

BackgroundHuman papilloma virus (HPV) in patients with esophageal carcinoma has previously been studied with an average detection rate of 15%, but the role of HPV in relation to survival is less clear. In cervical cancer, lung cancer and tonsil cancer HPV viral load is a predictive factor for survival and outcome of treatment. The primary aim was to study the spectrum of high-risk HPV types in esophageal tumors. Secondary, as a pilot study we investigated the association between HPV status and the survival rates.MethodsWe compared both the presence and the viral load of high-risk HPV types 16, 18, 31, 33, 39, 45, 52, 58, and 67 in relation to clinical data from patients with esophageal carcinoma. Survival data and tumor samples were retrieved from 100 patients receiving treatment at the Department of Oncology, Uppsala Hospital, Uppsala, Sweden. The tumor samples were investigated for HPV viral load using real-time PCR.ResultsHPV 16 was detected in 16% of the patients; no other HPV type was detected. HPV 16 infection had no significant effect on survival (p = 0.72). Also, HPV 16 did not improve survival after treatment (radiotherapy or chemotherapy).ConclusionOnly HPV 16 was detected among the patients. HPV 16 in esophageal carcinoma patients did not influence survival or improve therapy response. However, given the size of the study there is a need to examine a larger cohort in order to understand in more detail the effect of high risk HPV types in esophageal carcinoma.