Tumour regression after radiotherapy for rectal cancer - Results from the randomised Stockholm III trial.

BACKGROUND AND PURPOSE: Neoadjuvant radiotherapy (RT) in rectal cancer induces tumour regression with a possible complete response (pCR). The optimal fractionation and timing to surgery is not established. The Stockholm III trial randomly assigned 840 patients to 5 × 5 Gy surgery within one week (SRT), 5 × 5 Gy with surgery after 4-8 weeks, and 2 Gy × 25 with surgery after 4-8 weeks (LRT-delay). The aim of this substudy was to assess tumour regression and correlation to survival. MATERIAL AND METHODS: All available microscopy slides were assessed by one pathologist, blinded to treatment, regarding tumour regression, graded according to the Dworak system (TRG), TNM-stage and other standard histopathology characteristics. Patients' data were collected from the Swedish ColoRectal Cancer Registry. Outcomes were TRG, pCR-rates, overall survival (OS) and time to recurrence (TTR). RESULTS: 318, 285 and 94 patients were included in the SRT, SRT-delay and LRT-delay groups. Median follow up was 5.7 years. There were significantly lower tumour stages after SRT-delay. pCR was seen in 1 (0.3%), 29 (10.4%) and 2 (2.2%) patients in SRT, SRT-delay and LRT-delay, respectively. The pCR and Dworak grade 4 were associated with superior survival. pCR vs no-pCR Hazard Ratio (95% Confidence Interval) OS: 0.51 (0.26-0.99) p = 0.046, TTR: 0.27 (0.09-0.86) p = 0.027. CONCLUSION: SRT-delay induces pCR in about 10% of the patients and is in this aspect superior to 25 × 2 Gy. A complete tumour response, TRG 4 using the Dworak system, or a pCR, is associated with superior OS and TTR.

Value of Fecal Calprotectin as a Biomarker for Juvenile Polyps in Children Investigated With Colonoscopy.

OBJECTIVES: The clinical presentation of colonic juvenile polyps with abdominal discomfort and occult rectal bleedings make them difficult to recognize. The aim of this study was to report the clinical features of colonic juvenile polyps in children referred to colonoscopy and evaluate fecal calprotectin (FCP) as a screening biomarker for their diagnosis. METHODS: The study included a total of 266 children (range 3.1-19.0 years, median age 15.8 years) investigated with ileocolonoscopy; of whom, 239 (89%) were investigated for inflammatory bowel disease (IBD). FCPs were analyzed as a marker of colonic inflammation, and levels < 50 mg/kg was considered to be negative. RESULTS: Juvenile polyps were detected in 12 (4.5%) children; the remaining 67 (25.2%) had Crohn disease, 57 (21.4%) ulcerative colitis, 5 (1.9%) unclassified IBD, 4 (1.5%) allergic colitis, bleeding source was localized in 6 (2.3%), and 115 (43.2%) had unspecific or normal findings. FCP was available in 203 (76.3%) children before colonoscopy; levels of FCP were higher in children with juvenile polyps (range 28-2287 mg/kg, median 844 mg/kg) compared with those with normal colonoscopies (range < 20-2443 mg/kg, median 130 mg/kg, P < 0.0001), but not compared with those with active IBD (range < 20-7780 mg/kg, median 962 mg/kg, P = 0.6299). FCPs were available in 9 of 12 children after polypectomy, of whom all had their FCP levels significantly reduced (range 0-281 mg/kg, median 49 mg/kg, P <  .0001). CONCLUSIONS: Colonic juvenile polyps are frequently found in pediatric patients presenting with hematochezia and elevated FCP levels. Colonic juvenile polyps are difficult to differentiate from pediatric IBD without a colonoscopy.

The immunophenotypic relationship between the submucosal gland unit, columnar metaplasia and squamous islands in the columnar-lined oesophagus.

AIMS: To characterize the immunophenotypic relationship between the squamous and the glandular compartments in the oesophagus of patients with columnar-lined oesophagus (CLO). METHODS AND RESULTS: Eight tissue blocks from three oesophageal resection specimens from patients who underwent oesophagectomy for adenocarcinoma of the oesophagus were selected for immunohistochemical analysis. The markers of intestinal differentiation [CK20, CDX2 and MUC2] were all expressed in the expected pattern, solely in the glandular compartment of the resection specimens. CK4, CK17 and lysozyme were expressed in both the glandular and the squamous compartments. In addition, CK17 expression was found on both the squamous and glandular margins of the squamocolumnar transformation zones and in the submucosal gland (SMG) intraglandular and excretory ducts. CONCLUSIONS: There is an immunophenotypic relationship between the squamous and the glandular compartments of the CLO, with expression of lysozyme, CK4 and CK17 in both squamous and columnar cells. These overlapping immunophenotypes indicate similar differentiation paths, and link the SMG unit with the columnar metaplasia and the neosquamous islands in CLO. Our findings support the theory of a cellular origin of CLO and neosquamous islands from the SMG unit.

Hyperplasia of the submucosal glands of the columnar-lined oesophagus.

AIM: To evaluate the presence of multi-layered epithelium (ME) and to compare the distribution, size and morphology of the oesophageal submucosal glands (SMG) beneath reflux exposed metaplastic columnar mucosa with those of normal squamous epithelium in patients with columnar-lined oesophagus (CLO). METHODS AND RESULTS: In eight oesophageal resection specimens, the SMG of the metaplastic segments were significantly larger than those in the squamous segments of patients with CLO (0.81 versus 0.56 mm(2) , P = <0.001). There was an accumulation of SMG close to the neosquamocolumnar junction (NSCJ), as indicated by a higher median frequency of SMG (0.080 SMG/mm) compared with that of the squamous (0.013 SMG/mm) and metaplastic segments (0.031 SMG/mm) (P = 0.022). The frequency of ME was significantly higher in the metaplastic compared with the normal squamous segments (1/158 mm and 1/341 mm, respectively, P = 0.028) and ME was found almost exclusively (96%) in direct connection with the excretory ducts of SMG. CONCLUSIONS: Hyperplasia of SMG in the metaplastic segment, accumulation of SMG near the NSCJ, the presence of ME in connection with the excretory ducts of SMG and metaplasia are all reflux-induced morphological changes, possibly induced by stimulation of progenitors in the excretory ducts of the SMG.

Submucosal glands in the columnar-lined oesophagus: evidence of an association with metaplasia and neosquamous epithelium.

AIM: A multipotential stem cell, possibly located in the submucosal gland ducts, has been suggested as the origin of metaplastic mucosa in the oesophagus. The topographic distribution of these glands and their excretory ducts (SMG) within the columnar lined oesophagus (CLO) is largely unknown. The aim of this study was to examine the distribution of SMG in relation to the type of overlying epithelium in patients with CLO. METHODS AND RESULTS: Seven oesophageal resection specimens were examined histologically in toto. The median frequency of SMG was similar in the metaplastic segments (0.12 SMG/mm) and the normal squamous segments (0.10 SMG/mm). Within the metaplastic segments, the median frequency of SMG beneath the squamous islands was significantly higher than that observed under the columnar lined parts (0.22 versus 0.08 SMG/mm, P = 0.046), There was a strong accumulation of SMG at the squamo-columnar transition zones (0.53 SMG/mm), which was significantly greater than that found in the columnar and squamous parts (P = 0.001 and 0.002, respectively). CONCLUSIONS: The relative accumulation of SMG beneath squamous islands and the squamo-columnar junctions within the metaplastic segment supports the hypothesis that both metaplastic columnar mucosa and neosquamous epithelium originate from a progenitor in the SMG.

Low expression of CysLT1R and high expression of CysLT2R mediate good prognosis in colorectal cancer.

Colorectal cancer is the third most common cancer type in the Western world. In search of new treatment possibilities, the inflammation mediators, know as cysteinyl leukotrienes (CysLTs), have been shown to regulate intestinal epithelial cell survival and proliferation via the CysLT(1)R, and cell differentiation via the CysLT(2)R. These results prompted us to investigate the significance of CysLT(1)R and CysLT(2)R expression in colorectal cancer tissue for patient survival. The CysLT(1)R, CysLT(2)R, beta-catenin and Bcl-xL protein expression levels were evaluated by immunohistochemistry in a tissue microarray of 329 colorectal patients. We found that high nuclear expression of CysLT(1)R is associated with a poor prognosis, whereas high nuclear expression of CysLT(2)R is associated with a good prognosis. We also observed that patients with colorectal tumours characterised by high CysLT(1)R but low CysLT(2)R nuclear expression had the lowest survival expectancy, whereas patients with colorectal tumours characterised by low CysLT(1)R but high CysLT(2)R nuclear expression had the best survival expectancy. Interestingly, beta-catenin as a single prognostic marker did not exhibit any prognostic value. However, in patients with tumours characterised by a high CysLT(1)R nuclear expression, an elevated beta-catenin nuclear expression had a significantly prognostic value. In conclusion these data indicate that nuclear expressions of CysLTRs are potential prognostic indicators of colorectal cancer.

Screening detects a high proportion of celiac disease in young HLA-genotyped children.

BACKGROUND AND AIMS: Celiac disease is associated with tissue transglutaminase autoantibodies (tTGAb) and the human leukocyte antigen (HLA)-risk alleles DQB1*02 and DQB1*0302. The aim was to estimate the proportion of undiagnosed celiac disease in children with HLA risk at 3 years of age. PATIENTS AND METHODS: From a population-based HLA-DQ screening study of newborns born between June 2001 and August 2004 in the southern part of Sweden, 6206 children with HLA-risk alleles were identified and asked to participate at a mean 3.3 +/- 0.4 years of age. As controls, 7654 children with HLA-nonrisk alleles were asked to participate. In all, 1620 (26.1%) children with HLA risk and 1815 (23.7%) controls were screened for tTGAb using radioligand-binding assays. Celiac disease was established by intestinal biopsy in children with a confirmed positive tTGAb test. RESULTS: Twenty-three children reported already having clinically diagnosed celiac disease and did not participate further. In children with HLA-risk genotypes, 73 of 1620 (4.5%, 95% CI 3.5%-5.5%) were tTGAb-positive compared with none of 1815 from the controls (P < 0.0001). Seventy-one children underwent biopsy (1 refused biopsy and 1 biopsy failed), of whom 56 of 1618 (3.5%, 95% CI 2.6%-4.4%) had damaged intestinal mucosa classified as celiac disease. The ratio between clinically and screening detected celiac disease in this study was 1:2.4 (23:56). CONCLUSIONS: The proportion of clinically undetected celiac disease may be particularly high among 3-year-old children with HLA-DQB1*02 and DQB1*0302 in Sweden, where these 2 HLA-risk alleles frequently occur.

Autoantibodies against soluble and immobilized human recombinant tissue transglutaminase in children with celiac disease.

OBJECTIVES: The conformation of tissue transglutaminase might influence the performance of immunoassays to detect autoantibodies from patients with celiac disease. The present study investigated how the exposure of tissue transglutaminase kept in a liquid phase and fixed to a solid support affected the binding of immunoglobulin (Ig)A and IgG autoantibodies in children with untreated and treated celiac disease. METHODS: Included were 73 untreated celiac disease children, 50 controls and 80 children with treated celiac disease. IgA and IgG antitissue transglutaminase were measured with solid phase enzyme-linked immunoassay (ELISA) and liquid phase radioligand binding assays. For IgG antitissue transglutaminase detection with radioligand binding assays antihuman IgG and protein A were used. IgA endomysial autoantibodies were measured by indirect immunofluorescence. RESULTS: Both ELISA and radioligand binding assays detected IgA antitissue transglutaminase in 65 of 73 untreated celiac disease children and in 2 of 50 controls. One additional control child was detected with radioligand binding assays. Endomysial autoantibodies were present in 62 of 73 celiac disease children and in 2 of 50 controls. IgG antitissue transglutaminase was detected with both ELISA and radioligand binding assays in 40 of 73 untreated celiac disease children and in 2 of 50 controls. Radioligand binding assays using protein A detected 20 of 73 additional untreated celiac disease children and one control child with increased IgG antitissue transglutaminase. In treated celiac disease children, 21 of 80 were IgA antitissue transglutaminase positive with radioligand binding assays, 3 of 80 with ELISA, whereas none had endomysial autoantibodies. CONCLUSIONS: No qualitative differences between radioligand binding assays and ELISA in IgA or IgG antitissue transglutaminase binding from untreated celiac disease children was demonstrated. However, discrepancies in the binding of IgA antitissue transglutaminase from a subgroup of treated celiac disease children indicated that alterations of tissue transglutaminase might occur on fixation of the antigen. Protein A used for radioligand binding assays seemed not to assess IgG autoantibodies exclusively. IgA antitissue transglutaminase detection in screening of childhood celiac disease can be performed either by ELISA or radioligand binding assays because the two assays are interchangeable.