Early Initiation of Adalimumab Significantly Diminishes Postoperative Crohn's Disease Endoscopic Recurrence and Is Superior to 6-Mercaptopurine Therapy: An Open-Label, Randomized Controlled Study.

Postoperative recurrence (POR) is the rule in patients with Crohn's disease (CD), mitigated with prophylactic therapy. The evidence for therapeutic choice and timing of intervention is lacking. We aimed to compare the rates of POR in patients treated early with prophylactic 6-mercaptopurine (6-MP) or adalimumab. We conducted a prospective single-center randomized open-label clinical study in which patients in surgical remission following their first ileocecectomy were randomized to receive early treatment with 6-MP or adalimumab. Patients were followed up clinically every 3 months and underwent endoscopy at weeks 32 and 58 postoperatively. The primary endpoint was endoscopic recurrence (ePOR) at 1 year (week 58), defined as a Rutgeerts score ≥ i2. We enrolled 35 patients (25 males, mean age 35 ± 1.4 years, median disease duration 5 ± 6.1 years) following ileocecectomy. Of these, seven (20%) were current smokers and nine (26%) biologics-experienced. Patients allocated to adalimumab had significantly less ePOR than patients treated with 6MP at week 32 (21% vs. 69%, p = 0.004) and 58 (47% vs. 75%), (p = 0.03, HR = 0.39, 95% CI = 0.16-0.93). POR was associated with an increased diameter of the resected small bowel surgical specimen, lower baseline body mass index (BMI), increased week 18 fecal calprotectin, increased week 18 serum alanine aminotransferase and decreased week 18 hemoglobin level. Adalimumab was more effective than 6-MP in preventing ePOR. Increased operative small bowel diameter and lower postoperative BMI were associated with ePOR. At eighteen weeks, serum hemoglobin, ALT and fecal calprotectin levels were predictive of endoscopic disease recurrence. (ClinicalTrials.gov ID NCT01629628).

Immunohistochemistry staining for mismatch repair proteins: the endoscopic biopsy material provides useful and coherent results.

Immunohistochemistry (IHC) testing for mismatch repair proteins (MMRP) in patients with colorectal cancer can be performed on endoscopic biopsy material or the surgical resection material. Data are continuing to accumulate regarding the deleterious effect of neoadjuvant chemoradiation on MMRP expression. However, despite continuing rise in the use of endoscopic biopsies for IHC, most pathology departments still use mainly the surgical materials for IHC testing. In this study we compared the quality of stains among 96 colon cancer subjects with paired endoscopic and surgical material available for MLH1, MSH2, MSH6, and PMS2 stains (96 × 4, yielding 384 paired stains). Each slide received both a quantitative score (immunoreactivity [0-3] × percent positivity [0-4]) and a qualitative score (absent; weak and focal; strong). The quantitative scores of all MMRP were significantly higher among the endoscopic material (P<.001 for all). In 358 pairs (93.2%), both the endoscopic and operative material stained either strong (322, 83.9%) or absent (36, 9.4%). In 26 pairs (6.8%), the endoscopic material stained strong, whereas the operative material stained focal and weak. No endoscopic biopsy materials stained focal and weak. Our findings indicate that the biopsy material may provide more coherent results. Although these results may indicate that biopsy material provides coherent and useful results, it is yet to be determined if the demonstrated differences pose a real clinical problem in interpreting final results of IHC staining of such kind. Hence, we suggest that when available, the endoscopic material rather than the operative one should serve as the primary substrate for IHC staining.

How reliable is immunohistochemical staining for DNA mismatch repair proteins performed after neoadjuvant chemoradiation?

Immunohistochemistry (IHC) testing for mismatch repair proteins (MMRP) is currently being used primarily in colorectal cancer resection specimens. We aimed to compare the results of IHC staining performed on biopsy specimens obtained at endoscopy with that performed on surgical specimens after neoadjuvant therapy. Thirty-two rectal cancer subjects had paired preneoadjuvant and postneoadjuvant tissue available for IHC staining (MLH1, MSH2, MSH6, and PMS2), whereas 39 rectosigmoid cancer patients who did not receive neoadjuvant treatment served as controls. Each slide received a qualitative (absent, focal, and strong) and quantitative score (immunoreactivity [0-3] × percent positivity [0-4]). The quantitative scores of MMRP from the operative material were significantly lower in the neoadjuvant group than in the control (P < .05 for all).The scores of all MMRP from endoscopic biopsies were not significantly different between the neoadjuvant and the control groups. Disagreement between the endoscopic biopsy and the operative material was evident in 23 of 128 stains (18.5%) in the neoadjuvant group and in 12 of 156 stains (7.7%) in the control group (P = .009). In the neoadjuvant group, a disagreement pattern of "endoscopic strong operative focal" was observed in 28.1% for PMS2, 12.5% for MSH6, 12.5% for MLH1, and 6.3% for MSH2, and in the control group, this same disagreement pattern was found in 12.8% for PMS2, 7.7% for MSH6, 7.7% for MLH1, and 0% for MSH2. Based on our findings, we suggest that for rectal cancer, the endoscopic material rather than the operative material should serve as the primary material for IHC staining.

Matrix metalloproteinases 2 and 9 are markers of inflammation but not of the degree of fibrosis in chronic hepatitis C.

BACKGROUND: The degree of liver fibrosis and inflammation is important in patients with chronic hepatitis C (CHC) in terms of therapy as well as prognosis. To obviate the need of liver biopsy, serum markers such as procollagen I, III and hyaluronic acid have been proposed but were found to be inaccurate. Controversy still exists regarding the role of matrix metalloproteinases (MMPs) as valid markers of liver fibrosis. AIM: To assess liver and serum MMP-2 and -9 as markers of fibrosis and inflammation in patients with CHC. METHODS: Thirty-five CHC patients and 8 non-hepatitis C patients with normal liver enzymes underwent liver biopsy. Activities of inflammation and fibrosis stage were determined by the Desmet score on a scale of 0-4. Serum and liver tissue MMP-2 and -9 activities were measured by zymography using substrate impregnated gels. RESULTS: Patient and control groups were similar in terms of age (50.8 +/- 15.1 vs. 50.6 +/- 15.2) and male/female ratio (18/17 vs. 4/4). In serum, MMP-9 activity was increased in patients compared to controls (308 +/- 110 vs. 163.5 +/- 35 , p < 0.05). In liver tissue, MMP-9 was also higher in patients than in controls (21 +/- 4.5 vs. 17.1 +/- 5.1, p < 0.05), whereas MMP-2 did not differ between patients and controls. Serum MMP-9 values correlated with liver histologic inflammatory grade (290.4 +/- 83 in grade 2 vs. 562.1 +/- 128 in grade 3, p < 0.05) but not with fibrosis stage. The highest rising in serum MMP-9 levels was observed between grade 2 to grade 3 and was superior to the rising in serum transaminase levels, indicating its advantage in assessing the progression of disease activity. No correlation between liver MMP activities and liver fibrosis or inflammation was observed. CONCLUSION: Serum MMPs, in particular MMP-9, can serve as markers of disease activity rather than fibrosis stage in chronic HCV patients.

Chronic hepatitis C in Israeli children.

Natural history, epidemiology, and histopathological features of chronic hepatis C (CHC) are well established in adults. Data on histopathological findings of CHC in children are still limited and controversial. We aimed to evaluate the histopathological features of CHC in children in Israel. We reviewed, retrospectively, 20 liver specimens from 20 children with CHC for inflammation and fibrosis, hepatocyte necrosis, fatty changes, cholestasis, bile duct damage, sinusoidal lymphocytosis, and glycogen storage. The most common histological feature was portal inflammation (95%) and lobular inflammation (70%). Sinusoidal lymphocytosis was present in 85% and glycogen storage vacuoles in 40%. Most of the children (80%) had no fibrosis, 15% had mild fibrosis and 5% moderate fibrosis. Advanced fibrosis or cirrhosis was not found. No correlation was found between the age at biopsy and any of the histological parameters. Our study shows that children with CHC have a different phenotype of liver disease with slowly progressive natural history irrespective of duration of the disease.