Background and Aim
Barrett's esophagus is associated with increased risk of esophageal adenocarcinoma. The optimal management of low‐grade dysplasia arising in Barrett's esophagus remains ...controversial. We performed a retrospective study from a tertiary referral center for Barrett's esophagus neoplasia, to estimate time to progression to high‐grade dysplasia/esophageal adenocarcinoma in patients with confirmed low‐grade dysplasia compared with those with downstaged low‐grade dysplasia from index presentation and referral. We analyzed risk factors for progression.
Methods
We analyzed consecutive patients with low‐grade dysplasia in Barrett's esophagus referred to a single tertiary center (July 2006–October 2018). Biopsies were reviewed by at least two expert pathologists.
Results
One hundred and forty‐seven patients referred with suspected low‐grade dysplasia were included. Forty‐two of 133 (32%) of all external referrals had confirmed low‐grade dysplasia after expert histopathology review. Multivariable analysis showed nodularity at index endoscopy (P < 0.05), location of dysplasia (P = 0.05), and endoscopic therapy after referral (P = 0.09) were associated with progression risk. At 5 years, 59% of patients with confirmed low‐grade dysplasia had not progressed versus 74% of patients in the cohort downstaged to non‐dysplastic Barrett's esophagus.
Conclusion
Our data show variability in the diagnosis of low‐grade dysplasia. The cumulative incidence of progression and time to progression varied across subgroups. Confirmed low‐grade dysplasia had a shorter progression time compared with the downstaged group. Nodularity at index endoscopy and multifocal low‐grade dysplasia were significant risk factors for progression. It is important to differentiate these high‐risk subgroups so that decisions on surveillance/endotherapy can be personalized.
Our large retrospective study from a tertiary Barrett's center shows clear variability in the diagnosis of low‐grade dysplasia. Nodularity at index endoscopy and location of low‐grade dysplasia were associated with risk of progression in true low‐grade dysplasia patients. Endoscopic therapy and resources should potentially be more focused in this sub‐cohort of patients.
Summary
B‐cell maturation antigen (BCMA, also termed TNFRSF17) is an attractive therapeutic target due to its restricted expression on normal and malignant plasma cells (PC). GSK2857916 (or ...J6M0‐MMAF) is a BCMA‐specific antibody conjugated to the microtubule‐disrupting agent monomethyl auristatin F (MMAF) via a protease‐resistant linker. To evaluate the clinical potential of this agent, tumour cells from seventy multiple myeloma (MM) patients were assessed for BCMA expression by immunohistochemistry and flow cytometry. All patients tested expressed BCMA, at varying levels, and both surface and intracellular expression were observed. BCMA expression is maintained through relapse, extramedullary spread and in residual disease post therapy. BCMA levels may also be prognostically useful as higher levels of BCMA were associated with poorer outcomes, even taking into account genetic risk. We observed rapid internalization of surface BCMA and newly expressed protein by 1 h, suggesting a mechanism for J6M0‐MMAF activity even with low surface antigen. J6M0‐MMAF mediated cytotoxicity of MM cells varied with dose and antigen levels, with clonogenic progenitors killed at lower doses than mature cells. In comparison, J6M0‐MMAF killing of primary CD138+ myeloma cells occurred with slower kinetics. Our observations support BCMA to be a promising therapeutic target in MM for novel therapies such as J6M0‐MMAF.
Background & Aims It is a challenge to determine the dynamics of stem cells within human epithelial tissues such as colonic crypts. By tracking methylation patterns of nonexpressed genes, we have ...been able to determine how rapidly individual stem cells became dominant within a human colonic crypt. We also analyzed methylation patterns to study clonal expansion of entire crypts via crypt fission. Methods Colonic mucosa was obtained from 9 patients who received surgery for colorectal cancer. The methylation patterns of Cardiac-specific homeobox, Myoblast determination protein 1, and Biglycan were examined within clonal cell populations, comprising either part of, or multiple adjacent, normal human colonic crypts. Clonality was demonstrated by following cytochrome c oxidase-deficient (CCO− ) cells that shared an identical somatic point mutation in mitochondrial DNA. Results Methylation pattern diversity among CCO− clones that occupied only part of a crypt was proportional to clone size; this allowed us to determine rates of clonal expansion. Analysis indicated a slow rate of niche succession within the crypt. The 2 arms of bifurcating crypts had distinct methylation patterns, indicating that fission can disrupt epigenetic records of crypt ancestry. Adjacent clonal CCO− crypts usually had methylation patterns as dissimilar to one another as methylation patterns of 2 unrelated crypts. Mathematical models indicated that stem cell dynamics and epigenetic drift could account for observed dissimilarities in methylation patterns. Conclusions Methylation patterns can be analyzed to determine the rates of recent clonal expansion of stem cells, but determination of clonality over many decades is restricted by epigenetic drift. We developed a technique to follow changes in intestinal stem cell dynamics in human epithelial tissues that might be used to study premalignant disease.
While pathologists have always played a pivotal role in clinical trials ensuring accurate diagnosis and staging, pathology data from prognostic and predictive tests are increasingly being used to ...enrol, stratify and randomise patients to experimental treatments. The use of pathological parameters as primary and secondary outcome measures, either as standalone classifiers or in combination with clinical data, is also becoming more common. Moreover, reporting of estimates of residual disease, termed ‘pathological complete response’, have been incorporated into neoadjuvant clinical trials. Pathologists have the expertise to deliver this essential information and they also understand the requirements and limitations of laboratory testing. Quality assurance of pathology‐derived data builds confidence around trial‐specific findings and is necessarily focused on the reproducibility of pathological data, including ‘estimates of uncertainty of measurement’, emphasising the importance of pathologist education, training, calibration and demonstration of satisfactory inter‐observer agreement. There are also opportunities to validate objective image analysis tools alongside conventional histological assessments. The ever‐expanding portfolio of clinical trials will demand more pathologist engagement to deliver the reliable evidence‐base required for new treatments. We provide guidance for quality assurance of pathology scoring and reporting in clinical trials.
Molecular mechanisms responsible for hepatocellular carcinoma (HCC) remain largely unknown. Using genetically engineered mouse models, we show that hepatocyte-specific expression of unconventional ...prefoldin RPB5 interactor (URI) leads to a multistep process of HCC development, whereas its genetic reduction in hepatocytes protects against diethylnitrosamine (DEN)-induced HCC. URI inhibits aryl hydrocarbon (AhR)- and estrogen receptor (ER)-mediated transcription of enzymes implicated in L-tryptophan/kynurenine/nicotinamide adenine dinucleotide (NAD+) metabolism, thereby causing DNA damage at early stages of tumorigenesis. Restoring NAD+ pools with nicotinamide riboside (NR) prevents DNA damage and tumor formation. Consistently, URI expression in human HCC is associated with poor survival and correlates negatively with L-tryptophan catabolism pathway. Our results suggest that boosting NAD+ can be prophylactic or therapeutic in HCC.
•URI causes NAD+ depletion-dependent DNA damage leading to HCC development•Restoring NAD+ pools in vivo protects from DNA damage and HCC•URI inhibits AhR/ER transcriptional activity-mediated de novo NAD+ synthesis•URI-mediated de novo NAD+ synthesis inhibition may occur in human HCC
Tummala et al. show that overexpression of URI in mouse liver inhibits NAD+ metabolism, thereby causing DNA damage and tumorigenesis. Importantly, restoring NAD+ pools prevents DNA damage and tumor formation. URI expression in human HCC correlates negatively with L-tryptophan catabolism and patient survival.
Hereditary mixed polyposis syndrome (HMPS) is characterized by the development of mixed-morphology colorectal tumors and is caused by a 40-kb genetic duplication that results in aberrant epithelial ...expression of the gene encoding mesenchymal bone morphogenetic protein antagonist, GREM1. Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell fate that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem cell properties in Lgr5-negative progenitor cells that have exited the stem cell niche. These cells form ectopic crypts, proliferate, accumulate somatic mutations and can initiate intestinal neoplasia, indicating that the crypt base stem cell is not the sole cell of origin of colorectal cancer. Furthermore, we show that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic premalignant lesions with a hitherto unknown pathogenesis, and these lesions can be considered the sporadic equivalents of HMPS polyps.
Cancer cells can adapt and survive under low nutrient conditions, but underlying mechanisms remain poorly explored. We demonstrate here that glucose maintains a functional complex between the ...co-chaperone URI, PP1γ, and OGT, the enzyme catalyzing O-GlcNAcylation. Glucose deprivation induces the activation of PKA, which phosphorylates URI at Ser-371, resulting in PP1γ release and URI-mediated OGT inhibition. Low OGT activity reduces O-GlcNAcylation and promotes c-MYC degradation to maintain cell survival. In the presence of glucose, PP1γ-bound URI increases OGT and c-MYC levels. Accordingly, mice expressing non-phosphorylatable URI (S371A) in hepatocytes exhibit high OGT activity and c-MYC stabilization, accelerating liver tumorigenesis in agreement with c-MYC oncogenic functions. Our work uncovers that URI-regulated OGT confers c-MYC-dependent survival functions in response to glucose fluctuations.
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•URI/OGT/PP1γ forms a functional heterotrimeric complex in cancer cells•Glucose depletion phosphorylates URI at Ser-371, releasing PP1γ to inhibit OGT•OGT inhibition reduces c-MYC, promoting cancer cell survival upon metabolic stress•URI (S371A) increases O-GlcNAcylation, c-MYC levels, and hepatocarcinogenesis
Burén et al. show that glucose maintains a heterotrimeric URI/OGT/PP1γ complex and reveal a glucose-sensing mechanism in which URI acts as a rheostat regulating OGT, the enzyme catalyzing O-GlcNAcylation and thereby impacting c-MYC stability. Activated OGT and c-MYC stabilization accelerate hepatocarcinogenesis.
Abstract Objectives To develop and validate a qualitative scoring system for enteric Crohn's disease activity using MR enterography (MRE). Methods MRE was performed in 16 patients (mean age 33, 8 ...male) undergoing small bowel resection. Mural thickness, T2 signal, contrast enhancement, and perimural oedema were scored qualitatively (0–3) at 44 locations. Transmural histopathological scoring of acute inflammation (AIS) was performed at all locations (score 0–13). MRI parameters best predicting AIS were derived using multivariate analysis. The MRI activity index was applied to 26 Crohn's patients (mean age 32, range 13–69 years, 15 male) and correlated to terminal ileal biopsy scores of acute inflammation (“eAIS” score 1–6). Receiver operator characteristic curves were calculated. Results Mural thickness (coefficient 1.34 (95% CI 0.36, 2.32), p = 0.007) and T2 signal (coefficient 0.90 (95% CI −0.24, 2.04) p = 0.06) best predicted AIS (AIS = 1.79 + 1.34*mural thickness + 0.94*mural T2 score R-squared 0.52). There was a significant correlation between the MRI index and eAIS (Kendall's tau = 0.40, 95% CI 0.11–0.64, p = 0.02). The model achieved a sensitivity of 0.81 (95% CI 0.54–0.96), specificity of 0.70 (0.35–0.93) and AUC 0.77 for predicting acute inflammation (eAIS ≥2). Conclusions A simple qualitative MRI Crohn's disease activity score appears predictive against a histopathological standard of reference.
LGR5 is known to be a stem cell marker in the murine small intestine and colon, however the localization of LGR5 in human adenoma samples has not been examined in detail, and previous studies have ...been limited by the lack of specific antibodies. Here we used in situ hybridization to specifically examine LGR5 mRNA expression in a panel of human adenoma and carcinoma samples (n = 66). We found that a small number of cells express LGR5 at the base of normal colonic crypts. We then showed that conventional adenomas widely express high levels of LGR5, and there is no evidence of stereotypic cellular hierarchy. In contrast, serrated lesions display basal localization of LGR5, and the cellular hierarchy resembles that of a normal crypt. Moreover, ectopic crypts found in traditional serrated adenomas show basal LGR5 mRNA, indicating that they replicate the stem cell organization of normal crypts with the development of a cellular hierarchy. These data imply differences in the stem cell dynamics between the serrated and conventional pathways of colorectal carcinogenesis. Furthermore we noted high LGR5 expression in invading cells, with later development of a stem cell niche in adenocarcinomas of all stages.
IBD confers an increased lifetime risk of developing colorectal cancer (CRC), and colitis-associated CRC (CA-CRC) is molecularly distinct from sporadic CRC (S-CRC). Here we have dissected the ...evolutionary history of CA-CRC using multiregion sequencing.
Exome sequencing was performed on fresh-frozen multiple regions of carcinoma, adjacent non-cancerous mucosa and blood from 12 patients with CA-CRC (n=55 exomes), and key variants were validated with orthogonal methods. Genome-wide copy number profiling was performed using single nucleotide polymorphism arrays and low-pass whole genome sequencing on archival non-dysplastic mucosa (n=9), low-grade dysplasia (LGD; n=30), high-grade dysplasia (HGD; n=13), mixed LGD/HGD (n=7) and CA-CRC (n=19). Phylogenetic trees were reconstructed, and evolutionary analysis used to reveal the temporal sequence of events leading to CA-CRC.
10/12 tumours were microsatellite stable with a median mutation burden of 3.0 single nucleotide alterations (SNA) per Mb, ~20% higher than S-CRC (2.5 SNAs/Mb), and consistent with elevated ageing-associated mutational processes. Non-dysplastic mucosa had considerable mutation burden (median 47 SNAs), including mutations shared with the neighbouring CA-CRC, indicating a precancer mutational field. CA-CRCs were often near triploid (40%) or near tetraploid (20%) and phylogenetic analysis revealed that copy number alterations (CNAs) began to accrue in non-dysplastic bowel, but the LGD/HGD transition often involved a punctuated 'catastrophic' CNA increase.
Evolutionary genomic analysis revealed precancer clones bearing extensive SNAs and CNAs, with progression to cancer involving a dramatic accrual of CNAs at HGD. Detection of the cancerised field is an encouraging prospect for surveillance, but punctuated evolution may limit the window for early detection.
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