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.

Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016

Tumor budding is a well-established independent prognostic factor in colorectal cancer but a standardized method for its assessment has been lacking. The primary aim of the International Tumor Budding Consensus Conference (ITBCC) was to reach agreement on an international, evidence-based standardized scoring system for tumor budding in colorectal cancer. The ITBCC included nine sessions with presentations, a pre-meeting survey and an e-book covering the key publications on tumor budding in colorectal cancer. The 'Grading of Recommendation Assessment, Development and Evaluation' method was used to determine the strength of recommendations and quality of evidence. The following 10 statements achieved consensus: tumor budding is defined as a single tumor cell or a cell cluster consisting of four tumor cells or less (22/22, 100%). Tumor budding is an independent predictor of lymph node metastases in pT1 colorectal cancer (23/23, 100%). Tumor budding is an independent predictor of survival in stage II colorectal cancer (23/23, 100%). Tumor budding should be taken into account along with other clinicopathological features in a multidisciplinary setting (23/23, 100%). Tumor budding is counted on H&E (19/22, 86%). Intratumoral budding exists in colorectal cancer and has been shown to be related to lymph node metastasis (22/22, 100%). Tumor budding is assessed in one hotspot (in a field measuring 0.785 mm2) at the invasive front (22/22, 100%). A three-tier system should be used along with the budding count in order to facilitate risk stratification in colorectal cancer (23/23, 100%). Tumor budding and tumor grade are not the same (23/23, 100%). Tumor budding should be included in guidelines/protocols for colorectal cancer reporting (23/23, 100%). Members of the ITBCC were able to reach strong consensus on a single international, evidence-based method for tumor budding assessment and reporting. It is proposed that this method be incorporated into colorectal cancer guidelines/protocols and staging systems.

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.

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.

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.

Systematic review: histological remission in inflammatory bowel disease. Is 'complete' remission the new treatment paradigm? An IOIBD initiative.

BACKGROUND AND AIMS: Advances in the medical management of inflammatory bowel disease (IBD) have altered treatment targets. Endoscopic mucosal healing is associated with better outcomes in IBD, though less is known about the significance of achieving histological remission. Our aim was to perform a systematic review to investigate whether histological or 'complete' remission constitutes a further therapeutic target in IBD. METHODS: A bibliographic search was performed on the 1st of October 2013 and subsequently on the 1st of March 2014 of online databases (OVID SP MEDLINE, OVID EMBASE, National Pubmed Central Medline, Cochrane Library, ISI, conference abstracts), using MeSH terms and key words: ("inflammatory bowel diseases" OR "crohn disease" OR "ulcerative colitis" OR "colitis") AND ("mucosal healing" OR "histological healing" OR "pathological healing" OR "histological scoring" OR "pathological scoring"). RESULTS: The search returned 2951 articles. 120 articles were cited in the final analysis. There is no validated definition of histological remission in IBD. There are 22 different histological scoring systems for IBD, none of which are fully validated. Microscopic inflammation persists in 16-100% of cases of endoscopically quiescent disease. There is evidence that histological remission may predict risk of complications in ulcerative colitis beyond endoscopic mucosal healing, though data are scarce in Crohn's disease. CONCLUSIONS: Histological remission in IBD represents a target distinct from endoscopic mucosal healing, not yet routinely sought in clinical trials or practice. There remains a need for a standardized and validated histological scoring system and to confirm the prognostic value of histological remission as a treatment target in IBD.

Whipple's disease in an Afro-Caribbean national / Enfermedad de whipple en un nacional afrocaribeño

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.

La enfermedad deWhipple es una rara enfermedad infecciosa multiorgánica causada por el Tropheryma whipplei. Es fatal sin tratamiento. Reportamos un hombre afro-jamaicano de 40 años que se presentó con una historia de seis meses de pérdida de peso y diarrea. Las investigaciones revelaron hipoalbuminemia y anemia ferropénica. La endoscopia gastrointestinal superior reveló lesiones blancas irregulares en el duodeno. La biopsia duodenal mostró la ampliación y engrosamiento de las vellosidades por un denso infiltrado de histiocitos espumosos dentro de la lámina propia, que se extienden hasta la submucosa adjunta. Las tinciones con ácido peryódico de Schiff fueron positivas. La microscopia electrónica fue confirmatoria y la prueba de la reacción en cadena de la polimerasa, identificó los organismos como T whipplei de forma concluyente El tratamiento antibiótico trajo como resultado la resolución de los síntomas. Si bien el diagnóstico de la enfermedad de Whipple es difícil, un aumento de la conciencia debe conducir a un aumento en los reportes de casos divulgados que reflejan un mejoramiento en la capacidad para hacer el diagnóstico.

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.

Benign hidradenoma: magnetic resonance and ultrasound features of two cases.

Tumors of sweat gland origin are rare in the hand but should be considered in the differential diagnosis when certain imaging features are present. We present a case of nodular hidradenoma of the hand, with previously unreported magnetic resonance imaging features, and a further case in the thigh, both with ultrasound and histopathological correlation. The imaging literature of this tumor is reviewed, and its significance is discussed with respect to the current understanding of its malignant potential.

Interstitial cells of Cajal in health and disease. Part I: normal ICC structure and function with associated motility disorders.

Ramon y Cajal (1852-1934) is considered to be one of the founders of the field of neuroscience. In 1911, he described interstitial neurons in the gut, noting that they were primitive accessory components that perhaps modify smooth muscle contraction, themselves subject to regulation from principle neurons. The accuracy of his description of their appearance and activities has led to these cells now being called the interstitial cells of Cajal (ICC). Thuneberg and Faussone-Pellegrini were instrumental in bringing these cells to the attention of gastroenterologists and pathologists in the early 1980s. Subsequently, the development of antibodies to c-kit has allowed routine identification of the ICC in pathology specimens. c-Kit is a transmembrane protein kinase which has as ligand stem cell factor and is involved in cell development in a variety of cell lineages. In the gut musculature, ICC and mast cells are the only cells that have prominent c-kit expression. The ICC are now known to play an important role in gut motility and absent or disordered ICC networks have been identified in a variety of motility disorders.

Interstitial cells of Cajal in health and disease. Part II: ICC and gastrointestinal stromal tumours.

Mesenchymal tumours in the gastrointestinal tract have long been problematic in terms of diagnosis, prognosis and therapy, but recent advances in immunohistochemistry and related therapies have allowed more specific diagnosis. In particular, the recognition that both the interstitial cells of Cajal (ICC) and many gastrointestinal stromal tumours (GISTs) are positive for c-kit and CD34 and have other features similar to those of ICC has led to the use of imatinib, a novel small molecule therapy that blocks the CD117/c-kit tyrosine kinase receptor, which shows remarkable efficacy in treatment of malignant and metastatic GISTs as well as other malignancies.

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.

Indeterminate colitis.

Indeterminate colitis (IC) originally referred to those 10-15% of cases of inflammatory bowel disease (IBD) in which there was difficulty distinguishing between ulcerative colitis (UC) and Crohn's disease (CD) in the colectomy specimen. However, IC is increasingly used when a definitive diagnosis of UC or CD cannot be made at colonoscopy, in colonic biopsies or at colectomy. The diagnostic difficulties may explain the variably reported prevalence of IC. Clinically, most patients with IC evolve to a definite diagnosis of UC or CD on follow up. The role of ancillary tests in the distinction of UC from CD is reviewed. The low sensitivity of serological markers limits their usefulness. Other tests include upper endoscopy and magnetic resonance imaging. The definition of IC may not be a purely histological one derived from resected specimens, but rather a clinicopathological one. This review offers some personal observations and viewpoints, and proposes an approach to some of the relatively more esoteric combinations of findings.

Detection of species-specific helicobacter ribosomal DNA in intestinal biopsy samples from a population-based cohort of patients with ulcerative colitis.

The inflammatory bowel diseases are considered an abnormal host immune response to an environmental stimulus. Evidence suggests a role for intestinal bacteria in initiating and/or providing an ongoing stimulus for inflammation in inflammatory bowel disease. Helicobacter pylori is the major cause of active chronic gastritis and peptic ulcers in humans and has been linked to gastric carcinoma and lymphoma. Studies in various animal models, particularly mice, have identified enterohepatic Helicobacter species that are capable of causing hepatitis and enterocolitis. We hypothesize that Helicobacter species may have a role in maintaining inflammation in humans with inflammatory bowel disease. In order to investigate this, biopsy specimens were obtained from patients with and without inflammatory bowel disease. DNA was extracted from the tissues and subjected to PCR with primers designed to detect the ribosomal DNA of members of the Helicobacter species. DNA from six biopsy samples from 60 inflammatory bowel disease patients tested positive. This included 5 of 33 ulcerative colitis patients that were positive compared to 0 of 29 age-matched controls (P < 0.04). Sequencing of the bands produced by PCR amplification revealed >or=99% homology with H. pylori. These results indicate that a member of the Helicobacter species may be involved in some cases of ulcerative colitis.