Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target.

OBJECTIVES: The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program was initiated by the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD). It examined potential treatment targets for inflammatory bowel disease (IBD) to be used for a "treat-to-target" clinical management strategy using an evidence-based expert consensus process. METHODS: A Steering Committee of 28 IBD specialists developed recommendations based on a systematic literature review and expert opinion. Consensus was gained if ≥75% of participants scored the recommendation as 7-10 on a 10-point rating scale (where 10=agree completely). RESULTS: The group agreed upon 12 recommendations for ulcerative colitis (UC) and Crohn's disease (CD). The agreed target for UC was clinical/patient-reported outcome (PRO) remission (defined as resolution of rectal bleeding and diarrhea/altered bowel habit) and endoscopic remission (defined as a Mayo endoscopic subscore of 0-1). Histological remission was considered as an adjunctive goal. Clinical/PRO remission was also agreed upon as a target for CD and defined as resolution of abdominal pain and diarrhea/altered bowel habit; and endoscopic remission, defined as resolution of ulceration at ileocolonoscopy, or resolution of findings of inflammation on cross-sectional imaging in patients who cannot be adequately assessed with ileocolonoscopy. Biomarker remission (normal C-reactive protein (CRP) and calprotectin) was considered as an adjunctive target. CONCLUSIONS: Evidence- and consensus-based recommendations for selecting the goals for treat-to-target strategies in patients with IBD are made available. Prospective studies are needed to determine how these targets will change disease course and patients' quality of life.

Whipple's Disease in an Afro-Caribbean National.

Whipple's disease is a rare multi-organ infectious disease caused by Tropheryma whipplei. It is fatal without treatment. We report on a 40-year old Afro-Jamaican man who presented with a six-month history of weight loss and diarrhoea. Investigations revealed iron deficiency anaemia and hypoalbuminaemia. Upper gastrointestinal endoscopy revealed white patchy lesions in the duodenum. The duodenal biopsy showed broadening and thickening of the villi by a dense infiltrate of foamy histiocytes within the lamina propria and focally extending into the attached submucosa. Periodic Acid-Schiff stains were positive. Electron microscopy was confirmatory and polymerase chain reaction testing conclusively identified the organisms as T whipplei. Antibiotic treatment resulted in resolution of symptoms. Although the diagnosis of Whipple's disease is difficult, increased awareness should lead to an increase in reported cases with the improvements in diagnostic capabilities.

It takes two: The relative contributions of parent versus child-led regulatory behaviours on toddler vaccination pain.

BACKGROUND: Past research has established the important role of parent soothing in early childhood pain management. However, limited research has assessed children's own emerging emotion regulation strategies to reduce their pain during vaccination. The purpose of the current study was to understand the relative contributions of child-led emotion-regulation behaviours over and above parent regulatory behaviours and pre-needle distress. METHODS: Toddler-caregiver dyads were videotaped at their 12- and/or 18-month vaccinations. Videos were coded for pain-related behavioural distress, child-led regulatory behaviours (disengagement of attention, parent-focused behaviours, and physical self-soothing), and parent regulatory/soothing behaviours (distraction, physical comfort, rocking, verbal reassurance). Pre-needle distress, followed by parent regulatory behaviours, followed by child regulatory behaviours were used as hierarchical predictors of pain regulation. Two sets of models were estimated at each age, by incorporating parent and child regulatory behaviours at 1 min and 2 min post-needle, separately. RESULTS: At both ages, child-led parent-focused behaviours predicted less regulation. At 18 months, parent soothing behaviours (e.g. distraction, verbal reassurance, rocking) played a stronger role in regulation, however; the only behaviour that increased regulation was rocking. CONCLUSIONS: Measuring both parent and child regulatory behaviours was important for fully understanding pain-related distress regulation. Toddlers' use of parent-focused regulatory behaviours (e.g. proximity seeking) suggests that they signal to their parent directly when they are struggling to regulate post-needle. The only parent behaviour that supported this regulation was rocking at 18 months, suggesting a greater need to understand the sensitivity of parent behaviours post-needle. SIGNIFICANCE: To our knowledge, this is the first study to examine both parent and child regulatory behaviours following vaccination at different stages in toddlerhood. This investigation allows a deeper understanding of the dyadic nature of early childhood vaccination, as well as the evolving role of the parent through toddlerhood. Importantly, findings suggest that toddlers do not simply wait for their parents to respond to their pain post-needle and provide clear signals to show their need of support in regulation.

Tumor regression grading after neoadjuvant treatment of esophageal and gastroesophageal junction adenocarcinoma: results of an international Delphi consensus survey.

Complete histopathologic tumor regression after neoadjuvant treatment is a well-known prognostic factor for survival among patients with adenocarcinomas of the esophagus and gastroesophageal junction. The aim of this international Delphi survey was to reach a consensus regarding the most useful tumor regression grading (TRG) system that could represent an international standard for histopathologic TRG grading of gastroesophageal carcinomas. Fifteen pathologists with special interest in esophageal and gastric pathology participated in the online survey. The initial questionnaire contained of 43 statements that addressed the following topics: (1) specimen processing, (2) gross examination, (3) cross sectioning, (4) staining, (5) Barrett's esophagus, (6) TRG systems, and (7) TRG in lymph node (LN). Participants rated the items using a 5-point Likert style scale and were encouraged to write comments for each statement. The expert panel recommended a 4-tiered TRG system for assessing the primary tumor: grade 1: No residual tumor (complete histopathologic tumor regression), grade 2: less than 10% residual tumor (near-complete regression), grade 3: 10%-50% residual tumor (partial regression), grade 4: greater than 50% residual tumor (minimal/no regression), combined with a 3-tiered system for grading therapeutic response in metastatic LNs: grade a: no residual tumor (complete histopathologic TRG), grade b: partial regression (tumor cells and regression), grade c: no regression (no sign of tumor response). This TRG grading system can be recommended as an international standard for histopathologic TRG grading in esophageal and gastroesophageal junction adenocarcinoma.

Assessing pain in infancy: the caregiver context.

BACKGROUND: Pain is largely accepted as being influenced by social context. Unlike most other developmental stages throughout the lifespan, infancy is marked by complete dependence on the caregiver. The present paper discusses the primary importance of understanding the caregiver context when assessing infant pain expression. OBJECTIVES: Based on a review of research from both the infant pain and infant mental health fields, three lines of evidence are presented. First, pain assessment is as subjective as the pain experience itself. Second, assessors must be cognizant of the relationship between infant pain expression, and caregiver sensitivity and emotional displays. Finally, larger systemic factors of the infant (such as caregiver relationship styles, caregiver psychological distress or caregiver acculturative stress) directly impact on infant expression. CONCLUSIONS: As a result of infants' inability to give a self-report of their pain experience, caregivers play a crucial role in assessing the pain and taking appropriate action to manage it. Caregiver behaviours and predispositions have been shown to have a significant impact on infant pain reactivity and, accordingly, should not be ignored when assessing the infant in pain.

Pathological features of colorectal carcinomas in MYH-associated polyposis.

AIMS: MYH is a DNA glycosylase in the base excision repair pathway. Germ-line biallelic mutations in the MYH gene are associated with the development of multiple colorectal adenomas and colorectal carcinoma (CRC). A slightly increased risk of CRC is suggested in monoallelic MYH mutation carriers. The aim was to characterize the histopathological features of carcinomas from biallelics and monoallelics. METHODS AND RESULTS: Clinicopathological features of 57 colorectal carcinomas from 50 patients identified in familial CRC registries were recorded. These included 16 cancers from 14 MYH biallelics; 25 cancers from 22 MYH monoallelics; and 16 cancers from 14 controls. Carcinomas in biallelics demonstrated tubular, papillary or cribriform patterns as the predominant histological subtype, and main histological groups differed according to mutation status (P = 0.0053). All biallelic cancers were low grade, with high-grade tumours more common in monoallelics and controls (P = 0.002). Synchronous polyps were observed in 75% of biallelics, 33% of monoallelics and 43% of controls (P = 0.035). Serrated carcinoma was the predominant type in 12% (3/25) of the monoallelics but in none of the biallelics or controls. MYH immunohistochemistry failed to distinguish between groups. CONCLUSIONS: Neither pathological features nor immunohistochemistry could predict the MYH mutation status of CRCs in this study.

CDH1/E-cadherin germline mutations in early-onset gastric cancer.

BACKGROUND: Gastric cancer remains a leading cause of cancer deaths worldwide. Genetic factors, including germline mutations in E-cadherin (CDH1, MIM#192090) in hereditary diffuse gastric cancer (HDGC, MIM#137215), are implicated in this disease. Family studies have reported CDH1 germline mutations in HDGC but the role of CDH1 germline mutations in the general population remains unclear. AIMS: To examine the frequency of CDH1 germline mutations in a population-based series of early-onset gastric cancer (EOGC <50 years old). METHODS: 211 cases of EOGC were identified in Central-East Ontario region from 1989 to 1993, with archival material and histological confirmation of non-intestinal type gastric cancer available for 81 subjects. Eligible cases were analysed for CDH1 germline mutations by single-strand conformation polymorphism, variants were sequenced, and tumours from cases with functional mutations were stained for E-cadherin (HECD-1) using immunohistochemistry. RESULTS: 1155 (89%) of 1296 polymerase chain reactions amplified successfully. One new germline deletion (nt41delT) was identified in a 30-year-old patient with isolated cell gastric cancer. The overall frequency of germline CDH1 mutations was 1.3% (1/81) for EOGC and 2.8% (1/36) for early-onset isolated cell gastric cancer. CONCLUSION: This is the first population-based study, in a low-incidence region, of genetic predisposition to gastric cancer. Combined with our previous report of germline hMLH1 mutations in two other subjects from this series, it is suggested that 2-3% of EOCG cases in North Americans may be owing to high-risk genetic mutations. These data should inform cancer geneticists on the utility of searching for specific genetic mutations in EOGC.

Perianal apocrine adenocarcinoma arising in a benign apocrine adenoma; first case report and review of the literature.

Benign apocrine lesions have been described in the anogenital region, although according to the World Health Organisation convincing examples of anal apocrine adenocarcinomas have not been published. This report describes the case of an invasive apocrine adenocarcinoma arising in a benign adenoma in the perianal region of a 45 year old woman. The origin and invasiveness are supported by histological and immunohistochemical studies.

Review article: the histological assessment of disease activity in ulcerative colitis.

BACKGROUND: In patients with ulcerative colitis (UC), mucosal healing has emerged as a major therapeutic goal, and is usually assessed endoscopically. Histological healing does not correlate very well with endoscopic mucosal healing in UC and persistent histological inflammation might be a better predictor of future clinical relapse than the endoscopic appearance alone. AIM: To define how histological assessment of disease activity should be best done in UC. METHODS: Electronic (PubMed/Embase) and manual search. RESULTS: At least 18 histological indices to assess disease activity in UC have been described, though none are fully validated. However, histological assessment is increasingly used as a secondary endpoint in clinical trials in UC. After reviewing and discussing existing histological scoring systems for UC activity, we describe features of histological response and define three grades of activity: (i) histological healing - complete resolution of abnormalities; (ii) quiescent disease, - lack of mucosal neutrophils but chronic inflammation may remain; (iii) active disease - presence of neutrophils plus possible epithelial damage. It is recommended that two biopsies are taken from each colonic segment which should include always biopsy of the rectum and the most affected segments. There is to date no agreed preferable scoring system but the Geboes Index is the best validated (kappa for interobserver variation 0.59-0.70). CONCLUSION: Histological assessment of disease activity in UC is increasingly used, but needs to be carefully defined.

Polyps and polypectomy surveillance--role of the histopathologist.

The traditional roles of the pathologist are those of diagnostician, and being able to communicate these diagnoses back to the clinician in a clear unambiguous form so that subsequent therapy can be planned. Important findings may require more direct communication, particularly when the implications involve a choice between therapeutic options. Some diagnoses have implications that require an educational role for the pathologist; these in turn may evolve into a research role, based on clinico-pathological correlation, active basic science research or simply supplying tissue for research. Clinicians must also be aware that the same biopsy can be interpreted in numerous ways, depending upon the clinical situation.

Grading of dysplasia.

Lethal carcinomas are still found inadvertently in patients under surveillance; some may not be preceded by conventional dysplasia. However, there is a survival advantage for cancers detected endoscopically rather than symptomatically, and, therefore, by preventing them by colectomy when dysplasia first becomes apparent. It may, therefore, be unnecessary to grade dysplasia when found, for if unequivocally present, then immediate consideration of colectomy is appropriate. It is unreasonable to expect colonoscopists to rebiopsy what might be a minute patch of dysplasia that has no distinguishing features endoscopically. Aneuploidy deserves consideration as a potential marker of patients at particular risk of developing dysplasia, who might undergo more frequent colonoscopy and biopsies than those without the presence of aneuploidy. There is still considerable interobserver variability in the grading of dysplasia by pathologists; part of this may be because grading occurs around a mean, the width of the tails of this distribution curve determining interobserver variation.

Nonalcoholic liver disease. Overlooked causes of liver injury in patients with heavy alcohol consumption.

Alcoholic subjects with abnormal liver chemistry studies are often assumed to have alcoholic liver disease, even though the diagnosis is not established by liver biopsy. To determine the magnitude of nonalcoholic liver disease in patients with heavy alcohol consumption, the data on 145 consecutive patients judged to consume at least 80 g of alcohol daily for prolonged periods, and who underwent liver biopsy at the University of Chicago, were reviewed. Nonalcoholic liver disease was suspected clinically and confirmed by liver biopsy in 40 (28 per cent), whereas alcoholic liver disease was suspected in 105 but confirmed in only 83 (80 per cent). The remaining 22 patients had liver disorders, including cholangitis or pericholangitis, acute hepatitis or some form of chronic hepatitis, for which they required appropriate therapy. Neither clinical features, hepatitis B surface antigen (HBsAg), anti-HBsAg nor serum glutamic oxaloacetic transaminase to serum glutamic pyruvic transaminase (SGOT:SGPT) ratios distinguished these 22 patients from those with alcoholic liver disease. Thus, liver biopsy is necessary for the identification of nonalcoholic liver disease in patients suspected of harboring alcoholic liver disease, since other clinical features do not allow identification of these patients.

The biopsy diagnosis of gastroesophageal reflux disease, "carditis," and Barrett's esophagus, and sequelae of therapy.

Histologic changes indicative of gastroesophageal reflux disease (GERD) are found on both sides of the squamocolumnar junction (Z-line). In the gastric cardia, inflammation is found as part of GERD in the absence of Helicobacter pylori or other causes of gastritis (carditis). The squamous mucosa is the location most likely to show inflammatory changes, such as neutrophils or eosinophils, close to the Z-line, whereas traditional reactive changes in the squamous mucosa are found only in biopsies taken at least 3 cm above the Z-line. Endoscopic criteria for GERD have a morphologic counterpart in capillary congestion and hemorrhage into the papillae, which have largely been ignored by pathologists as secondary to biopsy trauma. A biopsy protocol that maximizes the chances of detecting changes of GERD is suggested. The traditional definition of Barrett's esophagus as requiring 3 cm of glandular mucosa extending into the esophagus is no longer tenable. However, even the concept of short-segment Barrett's esophagus, in which less than 3 cm of intestinalized mucosa is present, often as tongues, is being challenged because random biopsies immediately distal to the Z-line may also show intestinal metaplasia when Barrett's esophagus is unsuspected endoscopically. Moreover, it is difficult or impossible to determine whether these changes indicate the earliest lesion of Barrett's esophagus or intestinal metaplasia in native cardiac mucosa. It is suggested that Barrett's esophagus be redefined as intestinal metaplasia in the lower esophagus. It is presently unclear whether patients with such minimal Barrett's epithelium are at increased risk for adenocarcinoma or require surveillance. Successful therapy for GERD results in healing of disease in squamous mucosa and may result in regression of Barrett's epithelium. In the stomach it may be associated with temporary regression of H. pylori and associated inflammation, migration of H. pylori into the oxyntic mucosa, hypertrophy and hyperplasia of parietal cells, and a variant of fundic gland polyps. Some patients may be at risk for accelerated atrophic gastritis if inflammation is present before therapy.

The normal esophagus.

The diagnosis of diseases affecting the esophagus frequently depends on a knowledge of the normal anatomy and histology of the esophagus. This paper describes and relates normal esophageal gross and histological features to pathological conditions affecting the esophagus. Special attention is given to the problems of diagnosis encountered when confronted with mucosal biopsy specimens from the gastroesophageal junction.

Musculo-fibrous anomaly in Barrett's mucosa with dysplasia.

We investigated the histological alterations occurring in the muscularis mucosae, the lamina propria mucosae, and the submucosa in areas adjacent to invasive adenocarcinoma in 32 resected esophagi with Barrett's mucosa. In 26 of the 32 specimens, we observed a thickening of the muscularis mucosae, with overgrowth of the muscle fibers into the lamina propria mucosae. In other areas, collagen-rich fibrotic tissue replaced the muscularis mucosae, the lamina propria mucosae, and even the submucosa. In 31 of the 32 specimens, we noted cystic dilatations of the esophageal glands. Normal esophageal glands and cystically dilated glands with dysplastic lining were often surrounded, compressed, and deformed by the fibrotic tissue. The compression of the glandular outlets by the collagen-rich tissue or by proliferating dysplastic cells appeared to be the two main factors in the histogenesis of these cysts. This may result in difficulty in differentiating, in biopsy specimens, between normal and dysplastic esophageal glands "trapped" in the collagen-rich fibrotic tissue and true invasive adenocarcinoma in the Barrett's mucosa.

Histology of the stomach and duodenum in Crohn's disease.

Crohn's disease (CD) not uncommonly affects the stomach and duodenum, but its histologic appearance is not well described beyond the identification of granulomas. We retrospectively identified 209 upper gastrointestinal biopsy samples from 80 sets of biopsies from 49 patients with CD. Age- and sex-matched control biopsies were selected from recent cases of Helicobacter pylori gastritis (73 biopsy samples from 34 patients), from patients with a known history of nonsteroidal antiinflammatory drug use (18 biopsy samples from 12 patients), and from three patients with ulcerative colitis. Architectural and inflammatory changes were evaluated and compared. Over three fourths of the patients with CD had abnormal biopsy results. Fifty-six percent of patients with CD had acute inflammation, but only 10% of the patients were infected with H pylori. Focal acute inflammation was a characteristic of H pylori-negative CD (stomach, 31%; duodenum, 40%), which was much less common in the non-CD group (stomach, 2%; duodenum, 8%). Surface intraepithelial neutrophils of the duodenum were more common in H pylori-negative patients with CD (25%) than in those who did not have CD (4%), and deep acute inflammation of the duodenum was more likely in H pylori-negative patients with CD (19% vs. 0%). Granulomas were found in only 9% of the CD group. Focal acute inflammation of the gastroduodenum, especially in a background of noninflamed mucosa, is strong evidence for CD in the appropriate clinical context, but the stomach and duodenum must be properly sampled and carefully examined for any evidence of H pylori.

Bone core biopsies. Plastic or paraffin?

Plastic embedding of bone core biopsy specimens has been promoted as providing superior morphology, primarily because semi-thin sections can thereby be cut at 1-2 mu. The major disadvantages of plastic embedding are that it increases the technical load, is more expensive, and potentially has its own intrinsic problems, including difficulties in performing special stains and immunoperoxidase studies. In order to investigate the possibility that semi-thin paraffin sections may provide similar morphological results without the intrinsic disadvantages of plastic sections, we examined 45 bone core biopsy specimens that were sufficiently large to process one half in plastic and the other half in paraffin following decalcification. Both were cut at 1-2 mu. Although many plastic sections appear esthetically more pleasing, semi-thin paraffin sections of very high quality can also be obtained routinely. Additional advantages of paraffin sections were the ability to perform peroxidase studies, lower cost, less technologist time, and avoidance of problems occasionally arising with plastic, such as difficulties with impregnation or problems with polymerization. Peroxidase studies were particularly useful in patients with possible myeloma that was not overt on hematoxylin-and-eosin section and in confirming the presence or source of metastatic carcinoma. We therefore recommend the use of semi-thin (1-2 mu) paraffin sections for routine examination of bone core biopsy specimens.

Loss of CD117 (c-kit)- and CD34-positive ICC and associated CD34-positive fibroblasts defines a subpopulation of chronic intestinal pseudo-obstruction.

Chronic idiopathic intestinal pseudo-obstruction is a syndrome in which symptoms of intestinal obstruction are present in the absence of mechanical obstruction. Lack of normal pacemaker activity, usually generated by the interstitial cells of Cajal (ICC), could account for the apparent obstruction. ICC are normally located around and between the myenteric plexus ganglia and within muscle and also in the deep muscular plexus of the small bowel and the submuscular plexus of the large intestine, just within the circular muscle. ICC can be demonstrated immunohistochemically with CD117 (c-kit) as well as with CD34, although this is less specific. CD34 also stains a population of fibroblasts that are intimately associated with ICC. To determine whether there is a relative deficiency of ICC and CD34-positive fibroblasts in patients with chronic idiopathic intestinal pseudo-obstruction, tissue from 30 patients of large intestine and eight patients with small intestine pseudo-obstruction was obtained. Controls (large intestinal specimens from 12 patients, small intestinal specimens from six patients) were chosen from resections for Crohn's disease and colorectal neoplasia, both with and without dilatation. Examination of pseudo-obstruction cases identified 10 patients (nine large intestinal and one small intestinal) in which both CD117 and CD34 were absent or severely reduced in all three of the examined areas. In contrast, the control cases, including those with preobstructive dilatation, showed relatively constant ICC staining. These results suggest that there is a proportion of pseudo-obstruction cases in which the ICC are markedly reduced. These results also demonstrate that, in these cases, loss of the kit immunoreactivity is correlated with the loss of CD34 staining: this indicates that both the ICC and the CD34-positive fibroblasts associated with the ICC are absent. These findings will allow surgical pathologists to identify this subpopulation of patients with CIIP using tissue obtained by laparoscopic biopsy of the muscularis propria or surgical resection.

Interstitial cells of Cajal as precursors of gastrointestinal stromal tumors.

Interstitial cells of Cajal (ICC) are implicated in the regulation of gut peristalsis and are immunostained by antibodies against Kit (CD117), a tyrosine kinase receptor. Most gastrointestinal mesenchymal tumors (GIMTs) are of uncertain histogenesis, although many are CD34-positive. CD34 was found to colocalize with vimentin (Vim) and the Kit-positive networks of cells within and around neural plexi, indicating that ICC can be Vim- and CD34-positive. ICCs appear to be the only Kit+CD34+Vim+ cell in the gut. Formalin-fixed, paraffin-embedded tissues from 43 GIMTs were immunostained for Kit, CD34, Vim, PGP 9.5 (PGP, a neural marker), muscle-specific actin (MSA), and other markers including desmin (Des). Eight tumors were myoid (MSA+Des+Vim-Kit-CD34-), and one was a schwannoma (PGP+S100+Vim+Kit-CD34-), but 34 tumors were of uncertain histogenesis (gastrointestinal stromal tumors, GIST), exhibiting neither a complete myoid nor a schwannian immunophenotype. All 34 were Vim+, and 33/34 were either Kit (n = 30) or CD34 (n = 23) immunoreactive. Of these 34 GIST, 24 were negative for all myoid and neural markers, 6 were PGP+S100-, and 4 were MSA+Des-. The Kit+CD34+Vim+ immunophenotype of GIST suggests that they originate from, or have differentiated into, ICC-like cells; the term ICC tumor (ICCT) is suggested. Kit is a more sensitive marker than CD34 for ICCT, but both are required in tumor identification. All clinically malignant GISTs were pathologically malignant (size, mitoses) but also showed loss of either CD34 or Kit. "Blind" examination of electron micrographs in 10 tumors showed them to be heterogeneous. Some had features seen in normal ICC, but cells could not be positively identified as being adult ICC. GIMT may therefore be classifiable into those with pure myoid, schwannian (or neural) differentiation, but the majority are of ICC origin or show ICC differentiation immunophenotypically (ICCT).