Isabel Pascual

A Phase I Clinical Trial of the Treatment of Crohn’s Fistula by Adipose Mesenchymal Stem Cell Transplantation

PURPOSEThe effective management of fistulas in patients with Crohn’s disease presents an extremely challenging problem. Mesenchymal adult stem cells extracted from certain tissues, such as adipose tissue, can differentiate into various cell types. Therefore, we have tried to use such cells to stimulate healing of Crohn’s fistulas.METHODSWe designed a prospective Phase I clinical trial, involving five patients with Crohn’s disease, to test the feasibility and safety of autologous stem cells transplantation in the treatment of fistulas. We also studied the expression of various cell markers and the growth rates of the lipoaspirate-derived cells that were used for transplantation.RESULTSOne patient was excluded because of bacterial contamination of cultured cells. We inoculated nine fistulas in four patients with autologous adipose tissue-derived stem cells at Passage 3 or earlier. Eight inoculated fistulas were followed weekly for at least eight weeks. In six fistulas, the external opening was covered with epithelium at the end of Week 8, and, thus, these fistulas were considered healed (75 percent). In the other two fistulas, there was only incomplete closure of the external opening, with a decrease in output flow (not healed; 25 percent). No adverse effects were observed in any patient at the end of the follow-up period (minimum follow-up,12 months; maximum follow-up, 30 months; follow-up average, 22 months).CONCLUSIONSTo our knowledge, this is the first report of a clinical trial of cell therapy using autologous stem cells obtained from a lipoaspirate. Our results indicate that our protocol is feasible and safe for the treatment of fistulas in Crohn’s disease. The number of patients included and the uncontrolled nature of Phase I clinical trials do not allow demonstration of the effectiveness of the treatment. However, the results of the present study encourage to perform further studies in Phase II.

Expanded Adipose-derived Stem Cells for the Treatment of Complex Perianal Fistula: a Phase Ii Clinical Trial

PURPOSE: The feasibility and safety of stem cell-based therapy with expanded adipose-derived stem cells (ASCs) has been investigated in a phase I clinical trial. The present study was designed as a phase II multicenter, randomized controlled trial to further investigate the effectiveness and safety of ASCs in the treatment of complex perianal fistulas. METHODS: Patients with complex perianal fistulas (cryptoglandular origin, n = 35; associated with Crohns disease, n = 14) were randomly assigned to intralesional treatment with fibrin glue or fibrin glue plus 20 million ASCs. Fistula healing and quality of life (SF-12 questionnaire) were evaluated at eight weeks and one year. If healing was not seen at eight weeks, a second dose of fibrin glue or fibrin glue plus 40 million ASCs was administered. RESULTS: Fistula healing was observed in 17 (71 percent) of 24 patients who received ASCs in addition to fibrin glue compared with 4 (16 percent) of 25 patients who received fibrin glue alone (relative risk for healing, 4.43; confidence interval, 1.74-11.27); P < 0.001). The proportion of patients with healing was similar in Crohns and non-Crohns subgroups. ASCs were also more effective than fibrin glue alone in patients with a suprasphincteric fistulous tract (P = 0.001). Quality of life scores were higher in patients who received ASCs than in those who received fibrin glue alone. At one year follow-up, the recurrence rate in patients treated with ASCs was 17.6 percent. Both treatments were well tolerated. CONCLUSION: Administration of expanded ASCs (20 to 60 million cells) in combination with fibrin glue is an effective and safe treatment for complex perianal fistula and appears to achieve higher rates of healing than fibrin glue alone.

Treatment of enterocutaneous fistula in Crohn’s Disease with adipose-derived stem cells: a comparison of protocols with and without cell expansion

BackgroundExpanded adipose-derived stem cells (ASC) have been shown to be effective in treating Crohn’s patients with enterocutaneous fistulas. It is possible that unexpanded cells corresponding to the stromal vascular fraction (SVF) may also be effective.Materials and methodsA subpopulation of patients from a previous proof-of-concept phase I study with enterocutaneous fistulas received autologous expanded ASCs. The same selection criteria for inclusion were applied to patients who underwent SVF implantation to treat enterocutaneous fistulas. After tract curettage, cell suspensions (either SVF cells from lipoaspirate or expanded ASCs) were injected into the tract walls, and the fistulous tract was sealed with fibrin adhesive (with or without cells).ResultsIn the series that received ASCs, four fistulas could be evaluated, and cure was achieved in three out of four cases. In the series that received SVF cells, four fistulas were evaluated, with cure achieved in one out of four cases.ConclusionsAlthough a comparison of case series cannot be considered firm evidence, a therapeutic protocol that uses expansion prior to implantation does seem to be more effective than one that uses SVF cells directly from a lipoaspirate sample.

Dental and periodontal lesions in patients with gastro-oesophageal reflux disease

OBJECTIVE Dental erosion has been considered an extraesophageal manifestation of gastro-oesophageal reflux disease, but few reports have studied the relationship between this disease and other periodontal or dental lesions. The aim of this study was to investigate the prevalence of dental and periodontal lesions in patients with gastro-oesophageal reflux disease. PATIENTS AND METHODS A total of 253 subjects were prospectively studied between April 1998 and May 2000. Two study groups were established: 181 patients with gastro-oesophageal reflux disease and 72 healthy volunteers. Clinical assessment, including body mass index and consumption of tobacco and alcohol, was performed in all subjects, as well as a dental and periodontal examination performed by a dentist physician, blind as to the diagnosis of subjects. Parameters evaluated were: (a) presence and number of dental erosion, location and severity, according to the Eccles and Jenkins index [Prosthet Dent 1979;42:649-53], modified by Hattab [Int J Prosthes 2000;13:101-71; (b) assessment of dental condition by means of the CAO index; and (c) periodontal status analysed by the plaque index, the haemorrhage index, and gingival recessions. RESULTS Clinical parameters were similar in both groups (p > 0.05). Age was statistically associated with the CAO index, presence of dental erosion, and gingival recession (p < 0.001, Students t-test). Compared with the control group, the percentage of dental erosion was significantly higher in the gastro-oesophageal reflux disease group (12.5 vs. 47.5%, p < 0.001, chi2-test), as was the number and severity of dental erosions (p < 0.001, Students t-test). Location of dental erosion was significantly different between groups. Age was not statistically related to either the amount or severity of dental erosion. CAO and periodontal indices were similarly distributed between groups. CONCLUSIONS Dental erosion may even be considered as an extraesophageal manifestation of gastro-oesophageal reflux disease. The fact that the prevalence of caries and periodontal lesions is similar in patients with gastro-oesophageal reflux disease and in healthy volunteers suggests a lack of relationship with gastro-oesophageal reflux disease.

Recurrence of acute gallstone pancreatitis and relationship with cholecystectomy or endoscopic sphincterotomy.

OBJECTIVES:To determine the prevalence of recurrence of gallstone pancreatitis, its clinical features, and the presence of prognostic factors of recurrence.METHODS:From January 1, 2000 to August 31, 2003, 233 patients admitted with acute gallstone pancreatitis (AGP) were prospectively studied. Patients were divided into two groups: recurrent and nonrecurrent group. Clinical, analytical, radiological, prognostic parameters, and severity (Atlanta criteria) were assessed, along with the performance of cholecystectomy or endoscopic sphincterotomy (ES). Clinical features of recurrence were analyzed. Univariate (χ2, Students t-test) and multivariate tests were performed. Statistical significance was assumed if p < 0.05.RESULTS:Two hundred and eighty-six attacks were identified. Forty-two patients (18.2%) recurred, suffering 53 recurrent attacks, which took place within 30 days in 23.3%. Patients who did not undergo surgery after the first attack had 31-fold risk of recurrence (OR = 31.5%, CI = 95%[7.22–137.84], p < 0.001). In patients not operated, recurrence was more frequent if ES was not performed (37.04%vs 0%, p= 0.019). Among patients with surgical risk, none who recurred underwent ES, compared with 27.9% of those who did not recur. Patients in the nonrecurrent group underwent cholecystectomy within the first 30 days or ES more frequently (31.2%vs 7.3%, p= 0.001).CONCLUSIONS:Recurrence of gallstone pancreatitis is a frequent event. Delay of cholecystectomy implies an increased risk of recurrence. ES could be an acceptable option to prevent recurrence in patients who are not candidates for surgery or who do not desire to undergo cholecystectomy.

Elevated serum eotaxin levels in patients with inflammatory bowel disease

OBJECTIVE:Eotaxin is a recently characterized chemokine with potent and selective chemotactic activity for eosinophils. Previous studies indicating that eosinophils accumulate and become activated in inflammatory bowel disease (IBD) led us to hypothesize that eotaxin is potentially involved in the pathophysiology of IBD and, therefore, that eotaxin would be increased in the serum of patients with IBD. The objective of this study was to test those assumptions.METHODS:We investigated 72 patients with IBD, 35 with ulcerative colitis, and 37 with Crohns disease. A total of 27 patients had active and 45 inactive disease; 26 were receiving corticosteroids. Eotaxin serum levels were determined by solid phase sandwich ELISA. Lymphocytes, monocytes, and granulocyte subpopulations were determined in fresh blood samples with an automated autoanalyzer.RESULTS:Serum eotaxin levels were significantly higher in patients with Crohns disease and in those with ulcerative colitis than in the control subjects (p < 0.0001). Patients with inactive Crohns disease had significantly higher levels of eotaxin than patients with inactive ulcerative colitis (p < 0.05). We did not find significant differences for activity or inactivity of disease, nor for treatment with prednisone. A negative correlation (p < 0.05) was found between eotaxin serum level and eosinophil counts in peripheral blood in patients with Crohns disease.CONCLUSIONS:There is an increased expression of eotaxin in IBD patients, suggesting that eotaxin may be involved in the pathogenesis of IBD. This increase is more accentuated in Crohns disease and negatively correlates with the eosinophil number in peripheral blood. Our data support the increasing evidence that eosinophil are functionally involved in the pathophysiology of IBD.

Is prophylactic cholecystectomy useful in obese patients undergoing gastric bypass

Background: Obesity constitutes a clear risk factor for cholelithiasis, especially if it is associated with a rapid weight loss, as is the case of patients following bariatric surgery. Prophylactic cholecystectomy is indicated in biliopancreatic diversions due to the high incidence of postoperative cholelithiasis. However, there is no agreement on gastric bypass. This study was conducted to establish the incidence of cholecystopathy demonstrated by histology and to assess the indication for prophylactic cholecystectomy in a systematic way on patients undergoing gastric bypass. Methods: The evaluation is based on 100 consecutive morbidly obese patients undergoing open gastric bypass surgery with concomitant prophylactic cholecystectomy. Variables studied were: age, gender, body mass index, preoperative ultrasound and the anatomopathologic analysis of the gallbladder that was removed. Results: Of the 100 patients who took part in the trial, 11 had had a previous cholecystectomy. Among the 89 patients remaining, preoperative ultrasound diagnosis of cholelithiasis was 16.8%, and the actual postoperative incidence was 24.7%. Other histologic alterations were: cholesterolosis 46.1%, chronic unspecified cholecystitis 22.5%, and granulomatous cholecystitis 1.1%. The total incidence of cholecystopathy was 93.3%. The morbi-mortality related to cholecystectomy was 0%. Conclusions: Based on these results and given the absence of morbidity, we believe that prophylactic cholecystectomy is suitable during open gastric bypass.

A risk score system for identification of patients with upper-GI bleeding suitable for outpatient management

BACKGROUND The aim of this study was to develop a risk score system for identification of patients with upper-GI hemorrhage who are suitable for outpatient management. METHODS From a prospective cohort of 983 consecutive patients with upper-GI hemorrhage not associated with portal hypertension, 581 cases that did not meet pre-established criteria for admission were selected, and a logistic regression analysis was performed to identify factors associated with two adverse outcomes: recurrent bleeding and/or the need for emergency surgery. The risk score system was developed by using the beta coefficients of the logistic model, and its performance was evaluated. The results of this model were combined with pre-established criteria for admission to build a simplified scoring system for identification of patients who can be managed safely on an outpatient basis. RESULTS Chronic alcoholism, active malignancy, prior upper digestive tract surgery, wasting syndrome, hemodynamic compromise, duodenal ulcer as the cause of upper-GI hemorrhage, and hemorrhage of unknown cause were independently associated with a greater risk of unfavorable outcomes in the group that did not meet pre-established criteria for admission. The logistic model showed a high capacity for discrimination (C statistic: 0.87) and good calibration (p value for Hosmer-Lemeshow goodness-of-fit test, 0.62), with a sensitivity of 100% and specificity of 64%. The simplified score had a sensitivity of 100% and specificity of 29% for adverse outcomes, and sensitivity of 78% and specificity of 38% for mortality. CONCLUSIONS The score system developed in this study may be helpful in deciding between hospitalization and outpatient management for patients with upper-GI hemorrhage, but it remains to be validated in patient groups other than those used for its development.

Adipose-derived mesenchymal stem cells in biosutures do not improve healing of experimental colonic anastomoses.

The feasibility of producing ‘biosutures’ coated with adipose‐derived mesenchymal stem cells (ASCs) was assessed and their effect on colonic anastomoses evaluated.

Usefulness of alanine and aspartate aminotransferases in the diagnosis of microlithiasis in idiopathic acute pancreatitis

SummaryBackground. It has been shown that biochemical laboratory values only are useful parameters in distinguishing gallstone from nongallstone acute pancreatitis. We assessed the diagnostic usefulness of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) for identification of occult microlithiasis in idiopathic acute pancreatitis.Methods. Ninety-one patients with idiopathic acute pancreatitis who underwent microscopic examination of stimulated duodenal bile sediments were retrospectively studied. According to earliness of ALT and AST assay after the onset of abdominal pain, patients were divided into two groups: group A, within the first 24 h (n=56) and group B, between 24 and 72 h (n=35).Results: ALT and AST values expressed as number of elevations of the upper limits of normal were higher in group A patients with positive biliary drainage than in group B. Median (range) ALT and AST values were 2.5 (0.1–18.1) vs 0.4 (0.1–8.6) and 3 (0.3–17.4) vs 0.5 (0.3—11.9), respectively. In the univariate analysis and receiver operating characteristic (ROC) curves, ALT within the first 24 h showed a sensitivity of 73%, specificity of 86%, and positive predictive value of 92% for a cutoff of 1.2 elevations of the upper limit of normal. These values were slightly higher, although without statistically significant differences, than those of AST (73, 80, and 89%, respectively).Conclusion. Serum increases of aminotransferases, especially alanine aminotransferase (ALT), were suggestive of microlithiasis in idiopathic acute pancreatitis, particularly when assessed early after the onset of abdominal pain.