Cancers arising in mucosal tissues account for a disproportionately large fraction of malignancies. Immunoglobulin G (IgG) and the neonatal Fc receptor for IgG (FcRn) have an important function in ...the mucosal immune system that we have now shown extends to the induction of CD8+ T cell-mediated antitumor immunity. We demonstrate that FcRn within dendritic cells (DCs) was critical for homeostatic activation of mucosal CD8+ T cells that drove protection against the development of colorectal cancers and lung metastases. FcRn-mediated tumor protection was driven by DCs activation of endogenous tumor-reactive CD8+ T cells via the cross-presentation of IgG complexed antigens (IgG IC), as well as the induction of cytotoxicity-promoting cytokine secretion, particularly interleukin-12, both of which were independently triggered by the FcRn–IgG IC interaction in murine and human DCs. FcRn thus has a primary role within mucosal tissues in activating local immune responses that are critical for priming efficient anti-tumor immunosurveillance.
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•FcRn in colonic DCs confers homeostatic CD8+ T cell activation and tumor protection•IgG immune complex crosslinking of FcRn in DCs promotes Th1/Tc1 cytokine secretion•FcRn protects serum IgG but promotes immunogenic catabolism of tissue IgG complexes•Increased FcRn+CD11c+ DCs in human colorectal tumors predicts improved survival
...the term "polyp" was proposed by some members of the committee to convey a more "neutral" biological perspective, with the hope that this term would be less confusing to our GI colleagues. ...the ...expert panel members voted on their preferred term and, as expected, the results were mixed. ...as a compromise, the term "SSA/P" was born. ...at the most recent 5th edition WHO planning committee meeting,1 the pathology participants were challenged with the task of correcting the mistakes of the past and, thus, were resigned to propose a new term for this "lesion" that would serve a number of the following goals: (1) consolidate the plethora of terms used in the past into 1 term that would be widely accepted both clinically and in research; and (2) create a term that, as best as possible, would be biologically and pathologically accurate.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Eosinophilic esophagitis (EOE) is a clinical pathologic syndrome characterized by influx of numerous eosinophils into the esophageal epithelium. It is important for clinicians to be aware of the ...spectrum, as well as the characteristic location and distribution, of morphologic changes in EOE to maximize the diagnostic yield in mucosal biopsy specimens. The major pathologic features of EOE include eosinophilic microabscesses, surface layering of eosinophils often associated with surface sloughing of necrotic squamous cells, and peak eosinophil counts usually greater than 15 per high power field (hpf) within the squamous epithelium. Minor features, which are frequent but less specific, include marked basal cell hyperplasia, lengthening of lamina propria papillae, intercellular edema, and lamina propria fibrosis with chronic inflammation. The number, distribution, and location of intraepithelial eosinophils in EOE vary greatly between previously published studies. Thus, utilization of a diagnostic cutoff point for intraepithelial eosinophils in EOE, particularly in the absence of other major features of EOE, is currently considered unwise. In fact, some patients may show combined features of both gastroesophageal reflux disease (GERD) and EOE, which complicates the histologic analysis of these patients. In contrast to GERD, EOE typically involves longer lengths of the esophagus, affects the proximal equally, or even more, than the distal esophagus, and the pathologic findings are often patchy in distribution. As a result, it is highly recommended that clinicians obtain biopsies from patients suspected of have EOE only after treatment with high-dose proton pump inhibitor therapy, and that biopsies be obtained from both the proximal and distal esophagus in both normal and abnormal appearing areas.
Esophageal adenocarcinoma (EA) incidence in many developed countries has increased dramatically over four decades, while survival remains poor. Persons with Barrett's esophagus (BE), who experience ...substantially elevated EA risk, are typically followed in surveillance involving periodic endoscopy with biopsies, although few progress to EA. No medical, surgical or lifestyle interventions have been proven to safely lower EA risk.
We investigated whether smoking, obesity or alcohol could predict progression to EA in a prospective cohort of 411 BE patients. Data were collected during personal interview. Adjusted hazard ratios (HR) were estimated using Cox regression.
39% had body mass index (BMI) over 30 and 64% had smoked cigarettes. Main analyses focused on those with at least 5 months of follow-up (33,635 person-months), in whom 45 developed EA. Risk increased by 3% per year of age (trend p-value 0.02), with approximate doubling of risk among males. EA risk increased with smoking pack-years (trend p-value 0.04) and duration (p-value 0.05). Compared to never-smokers, the HR for those in the highest pack-year tertile was 2.29 (95%CI 1.04-5.07). No association was found with alcohol or BMI, whereas a suggestion of increased risk was observed in those with higher waist-hip ratio, especially among males.
EA risk significantly increased with increasing age and cigarette exposure. Abdominal obesity, but not BMI, was associated with a modest increased risk. Continued follow-up of this and other cohorts is needed to precisely define these relationships so as to inform risk stratification and preventive interventions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Barrett’s esophagus (BE) is the greatest risk factor for esophageal adenocarcinoma (EAC), but only a small proportion of patients with BE develop cancer. Biomarkers might be able to identify patients ...at highest risk of progression. We investigated genomic differences in surveillance biopsies collected from patients whose BE subsequently progressed compared to patients whose disease did not progress.
We performed a retrospective case–control study of 24 patients with BE that progressed to high-grade dysplasia (HGD, n = 14) or EAC (n = 10). The control group (n = 73, called non-progressors) comprised patients with BE and at least 5 years of total endoscopic biopsy surveillance without progression to HGD or EAC. From each patient, we selected a single tissue sample obtained more than 1 year before progression (cases) or more than 2 years before the end of follow-up (controls). Pathogenic mutations, gene copy numbers, and ploidy were compared between samples from progressors and non-progressors.
TP53 mutations were detected in 46% of samples from progressors and 5% of non-progressors. In this case–control sample set, TP53 mutations in BE tissues increased the adjusted risk of progression 13.8-fold (95% confidence interval, 3.2–61.0) (P < .001). We did not observe significant differences in ploidy or copy-number profile between groups. We identified 147 pathogenic mutations in 57 distinct genes—the average number of pathogenic mutations was higher in samples from progressors (n = 2.5) than non-progressors (n = 1.2) (P < .001). TP53 and other somatic mutations were recurrently detected in samples with limited copy-number changes (aneuploidy).
In genomic analyses of BE tissues from patients with or without later progression to HGD or EAC, we found significantly higher numbers of TP53 mutations in BE from patients with subsequent progression. These mutations were frequently detected before the onset of dysplasia or substantial changes in copy number.
Barrett's esophagus is thought to progress to esophageal adenocarcinoma (EAC) through a stepwise progression with loss of CDKN2A followed by TP53 inactivation and aneuploidy. Here we present ...whole-exome sequencing from 25 pairs of EAC and Barrett's esophagus and from 5 patients whose Barrett's esophagus and tumor were extensively sampled. Our analysis showed that oncogene amplification typically occurred as a late event and that TP53 mutations often occurred early in Barrett's esophagus progression, including in non-dysplastic epithelium. Reanalysis of additional EAC exome data showed that the majority (62.5%) of EACs emerged following genome doubling and that tumors with genomic doubling had different patterns of genomic alterations, with more frequent oncogenic amplification and less frequent inactivation of tumor suppressors, including CDKN2A. These data suggest that many EACs emerge not through the gradual accumulation of tumor-suppressor alterations but rather through a more direct path whereby a TP53-mutant cell undergoes genome doubling, followed by the acquisition of oncogenic amplifications.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Distinguishing ulcerative colitis (UC) from Crohn's disease (CD) is normally based on evaluation of a variety of clinical, radiologic, serologic and pathologic findings, the latter in biopsy and/or ...resection specimens. Unfortunately, some patients with IBD show overlapping pathologic features of UC and CD, which makes definite distinction between these two disorders difficult or even impossible. In most instances of uncertainty, the patient shows clinical and pathologic features of UC, but in addition, the patient's colon resection specimen reveals one or more CD-like features. In this setting, a diagnosis of indeterminate colitis (IC) is often rendered. IC is not a distinct disease entity, and, thus, it has no diagnostic criteria. The most common causes of uncertainty in IBD pathology that may lead to a diagnosis of IC in a colon resection specimen includes the presence of fulminant (severe and toxic) colitis, insufficient radiologic, endoscopic, or pathologic information (including analysis of prior biopsies) on the patient, failure to utilize major diagnostic criteria as hard evidence in favor of CD, failure to recognize unusual variants of UC and CD that may mimic each other, failure to recognize non-IBD mimics and other superimposed diseases that cause unusual pathologic features in a resection specimen, an attempt to distinguish UC from CD in mucosal biopsies of the colon and ileum, or an attempt to change the patients diagnosis (of UC or CD) based on pouch or diversion-related complications. Details of each of these causes of uncertainty are discussed, in detail, in this review article. A diagnosis of IC should never be made clinically or by pathologists based on evaluation of pre-resection colonic mucosal biopsies. Ultimately, the majority of indeterminate cases represent UC, and, thus, most of these patient can be treated safely with a colectomy combined with an ileal pouch anal anastomosis procedure.
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