Published data on the natural history of low-grade dysplasia (LGD) in Barrett's esophagus (BE) are inconsistent and difficult to interpret. We investigated the natural history of LGD in a large ...community-based cohort of BE patients after reviewing the original histological diagnosis by an expert panel of pathologists.
Histopathology reports of all patients diagnosed with LGD between 2000 and 2006 in six non-university hospitals were reviewed by two expert pathologists. This panel diagnosis was subsequently compared with the histological outcome during prospective endoscopic follow-up.
A diagnosis of LGD was made in 147 patients. After pathology review, 85% of the patients were downstaged to non-dysplastic BE (NDBE) or to indefinite for dysplasia. In only 15% of the patients was the initial diagnosis LGD. Endoscopic follow-up was carried out in 83.6% of patients, with a mean follow-up of 51.1 months. For patients with a consensus diagnosis of LGD, the cumulative risk of progressing to high-grade dysplasia or carcinoma (HGD or Ca) was 85.0% in 109.1 months compared with 4.6% in 107.4 months for patients downstaged to NDBE (P<0.0001). The incidence rate of HGD or Ca was 13.4% per patient per year for patients in whom the diagnosis of LGD was confirmed. For patients downstaged to NDBE, the corresponding incidence rate was 0.49%.
LGD in BE is an overdiagnosed and yet underestimated entity in general practice. Patients diagnosed with LGD should undergo an expert pathology review to purify this group. In case the diagnosis of LGD is confirmed, patients should undergo strict endoscopic follow-up or should be considered for endoscopic ablation therapy.
The molecular mechanisms leading to epithelial metaplasias are poorly understood. Barrett's esophagus is a premalignant metaplastic change of the esophageal epithelium into columnar epithelium, ...occurring in patients suffering from gastroesophageal reflux disease. Mechanisms behind the development of the intestinal subtype, which is associated with the highest cancer risk, are unclear. In humans, it has been suggested that a nonspecialized columnar metaplasia precedes the development of intestinal metaplasia. Here, we propose that a complex made up of at least two factors needs to be activated simultaneously to drive the expression of intestinal type of genes. Using unique animal models and robust in vitro assays, we show that the nonspecialized columnar metaplasia is a precursor of intestinal metaplasia and that pSMAD/CDX2 interaction is essential for the switch toward an intestinal phenotype.
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•Overexpression of BMP4 in the esophageal epithelium of mice leads to columnar metaplasia•Induced reflux sequentially induces nonintestinal and intestinal metaplasia•Coexpression of BMP4 and CDX2 in epithelial cells induces specific intestinal genes•pSMAD and CDX2 form a complex required for the development of intestinal metaplasia
The molecular mechanisms leading to the preneoplastic intestinal type esophageal metaplasia seen in Barrett’s esophagus are unclear. Using unique animal models and robust in vitro assays, Mari et al. show that a nonspecialized columnar metaplasia is the precursor of intestinal metaplasia and that a collaboration between the transcriptional factors CDX-2 and pSMAD is essential for the transformation into the intestinal phenotype. This concept has far-reaching implications, given that the development of intestinal metaplasia predisposes for several highly malignant cancers.
Reported malignant progression rates for low-grade dysplasia (LGD) in Barrett's oesophagus (BO) vary widely. Expert histological review of LGD is advised, but limited data are available on its ...clinical value. This retrospective cohort study aimed to determine the value of an expert pathology panel organised in the Dutch Barrett's Advisory Committee (BAC) by investigating the incidence rates of high-grade dysplasia (HGD) and oesophageal adenocarcinoma (OAC) after expert histological review of LGD.
We included all BO cases referred to the BAC for histological review of LGD diagnosed between 2000 and 2011. The diagnosis of the expert panel was related to the histological outcome during endoscopic follow-up. Primary endpoint was development of HGD or OAC.
293 LGD patients (76% men; mean 63 years±11.9) were included. Following histological review, 73% was downstaged to non-dysplastic BO (NDBO) or indefinite for dysplasia (IND). In 27% the initial LGD diagnosis was confirmed. Endoscopic follow-up was performed in 264 patients (90%) with a median follow-up of 39 months (IQR 16-72). For confirmed LGD, the risk of HGD/OAC was 9.1% per patient-year. Patients downstaged to NDBO or IND had a malignant progression risk of 0.6% and 0.9% per patient-year, respectively.
Confirmed LGD in BO has a markedly increased risk of malignant progression. However, the vast majority of patients with community LGD will be downstaged after expert review and have a low progression risk. Therefore, all BO patients with LGD should undergo expert histological review of the diagnosis for adequate risk stratification.
Bile acid reflux is known to be associated with the development of Barrett's esophagus and esophageal adenocarcinoma (EAC), yet the role of specific bile acids and the mechanism behind the ...metaplastic changes is unclear. Here, we demonstrate that multi-layered glandular structures at the squamo-columnar junction in mice contain multiple cell lineages, which resemble the human esophageal submucosal gland ducts. Exposing mice to patient's refluxates induced expansion of multi-layered glandular structures and development of columnar metaplasia at the squamo-columnar junction. The glycine conjugated bile acids induced an intestinal type of metaplasia more typical for Barrett's esophagus. Through lineage tracing, we excluded the involvement of K5+, DCLK1+, and LGR5+ progenitor cells as the primary source in the development of the glandular metaplastic epithelium. We show that the mechanism behind development of metaplasia involves crypt fission and may be independent of stem cell proliferation. Our findings support the hypothesis that in humans, BE arises from non-squamous cells residing in submucosal gland ducts and that induction of intestinal type of metaplasia is most effectively induced by glycine-conjugated bile acids. These novel insights may lead to more effective strategies to prevent development of Barrett's esophagus and esophageal adenocarcinoma.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Esophageal adenocarcinoma (EAC) has a dismal prognosis, and survival benefits of recent multimodality treatments remain small. Cancer-associated fibroblasts (CAFs) are known to contribute to poor ...outcome by conferring therapy resistance to various cancer types, but this has not been explored in EAC. Importantly, a targeted strategy to circumvent CAF-induced resistance has yet to be identified. By using EAC patient-derived CAFs, organoid cultures, and xenograft models we identified IL-6 as the stromal driver of therapy resistance in EAC. IL-6 activated epithelial-to-mesenchymal transition in cancer cells, which was accompanied by enhanced treatment resistance, migratory capacity, and clonogenicity. Inhibition of IL-6 restored drug sensitivity in patient-derived organoid cultures and cell lines. Analysis of patient gene expression profiles identified ADAM12 as a noninflammation-related serum-borne marker for IL-6–producing CAFs, and serum levels of this marker predicted unfavorable responses to neoadjuvant chemoradiation in EAC patients. These results demonstrate a stromal contribution to therapy resistance in EAC. This signaling can be targeted to resensitize EAC to therapy, and its activity can be measured using serum-borne markers.
Background & Aims: Photodynamic therapy (PDT) for high-grade dysplasia (HGD) in Barrett’s esophagus is a Food and Drug Administration–approved alternative to esophagectomy. Critical information ...regarding overall survival of patients followed up long-term after these therapies is lacking. Our aim was to compare the long-term survival of patients treated with PDT with patients treated with esophagectomy. Methods: We reviewed records of patients with HGD seen at our institution between 1994 and 2004. PDT was performed 48 hours following the intravenous administration of a photosensitizer using light at 630 nm. Esophagectomy was performed by either transhiatal or transthoracic approaches by experienced surgeons. We excluded all patients with evidence of cancer on biopsy specimens. Vital status and death date information was queried using an institutionally approved Internet research and location service. Statistical analysis was performed using Kaplan–Meier curves and Cox proportional hazards ratios. Results: A total of 199 patients were identified. A total of 129 patients (65%) were treated with PDT and 70 (35%) with esophagectomy. Overall mortality in the PDT group was 9% (11/129) and in the surgery group was 8.5% (6/70) over a median follow-up period of 59 ± 2.7 months for the PDT group and 61 ± 5.8 months for the surgery group. Overall survival was similar between the 2 groups (Wilcoxon test = 0.0924; P = .76). Treatment modality was not a significant predictor of mortality on multivariate analysis. Conclusions: Overall mortality and long-term survival in patients with HGD treated with PDT appears to be comparable to that of patients treated with esophagectomy.
OBJECTIVE:This study compared outcomes of patients with esophageal cancer and clinically complete response (cCR) after neoadjuvant chemoradiotherapy (nCRT) undergoing active surveillance or immediate ...surgery.
BACKGROUND:Since nearly one-third of patients with esophageal cancer show pathologically complete response after nCRT according to CROSS regimen, the oncological benefit of immediate surgery in cCR is topic of debate.
METHODS:Patients with cCR based on endoscopic biopsies and endoscopic ultrasonography with fine-needle aspiration initially declining or accepting immediate surgery after nCRT were identified between 2011 and 2018. Primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), rate and timing of distant dissemination, and postoperative outcomes.
RESULTS:Some 98 patients with cCR were identified31 in the active surveillance- and 67 in the immediate surgery group with median follow-up of survivors of 27.7 and 34.8 months, respectively. Propensity score matching resulted in 2 comparable groups (n = 29 in both groups). Patients undergoing active surveillance or immediate surgery had a 3-year OS of 77% and 55% (HR 0.41; 95% CI 0.14–1.20, P = 0.104), respectively. The 3-year PFS was 60% and 54% (HR 1.08; 95% CI 0.44–2.67, P = 0.871), respectively. Patients undergoing active surveillance or immediate surgery had a comparable distant dissemination rate (both groups 28%), radical resection rate (both groups 100%), and severity of postoperative complications (Clavien–Dindo grade≥343% vs 45%, respectively).
CONCLUSION:In this retrospective study, OS and PFS in patients with cCR undergoing active surveillance or immediate surgery were not significantly different. Active surveillance with postponed surgery for recurrent disease was not associated with a higher distant dissemination rate or more severe adverse postoperative outcomes.
Immune checkpoint inhibition may affect growth or progression of highly aggressive cancers, such as esophageal adenocarcinoma (EAC). We investigated the regulation of expression of major ...histocompatibility complex, class 1 (MHC-I) proteins (encoded by HLA-A, HLA-B, and HLA-C) and the immune response to EACs in patient samples.
We performed quantitative polymerase chain reaction array analyses of OE33 cells and OE19 cells, which express different levels of the ATP binding cassette subfamily B member 1 (TAP1) and TAP2, required for antigen presentation by MHC-I, to identify microRNAs (miRNAs) that regulate their expression. We performed luciferase assays to validate interactions between miRNAs and potential targets. We overexpressed candidate miRNAs in OE33, FLO-1, and OACP4 C cell lines and performed quantitative polymerase chain reaction, immunoblot, and flow cytometry analyses to identify changes in messenger RNA (mRNA) and protein expression; we studied the effects of cytotoxic T cells. We performed miRNA in situ hybridization, RNA-sequencing, and immunohistochemical analyses of tumor tissues from 51 untreated patients with EAC in the Netherlands. Clinical and survival data were collected for patients, and EAC subtypes were determined.
We found OE19 cells to have increased levels of 7 miRNAs. Of these, we found binding sites for miRNA 125a (MIR125a)-5p in the 3′ untranslated region of the TAP2 mRNA and binding sites for MIR148a-3p in 3′ untranslated regions of HLA-A, HLA-B, and HLA-C mRNAs. Overexpression of these miRNAs reduced expression of TAP2 in OE33, FLO-1, and OACP4 C cells, and reduced cell-surface levels of MHC-I. OE33 cells that expressed the viral peptide BZLF1 were killed by cytotoxic T cells, whereas OE33 that overexpressed MIR125a-5p or MIR 148a along with BZLF1 were not. In EAC and nontumor tissues, levels of MIR125a-5p correlated inversely with levels of TAP2 protein. High expression of TAP1 by EAC correlated with significantly shorter overall survival times of patients. EACs that expressed high levels of TAP1 and genes involved in antigen presentation also expressed high levels of genes that regulate the adaptive immune response, PD-L1, PD-L2, and IDO1; these EACs had a poor response to neoadjuvant chemoradiotherapy and associated with shorter overall survival times of patients.
In studies of EAC cell lines and tumor tissues, we found increased levels of MIR125a-5p and MIR148a-3p to reduce levels of TAP2 and MHC-I, required for antigen presentation. High expression of MHC-I molecules by EAC correlated with markers of an adaptive immune response and significantly shorter overall survival times of patients.
Alterations in microRNA (miRNA) expression have been reported in different cancers. We assessed the expression of 754 oncology-related miRNAs in esophageal adenocarcinoma (EAC) samples and evaluated ...their correlations with clinical parameters. We found that miR-221 and 483-3p were consistently upregulated in EAC patients vs. controls (Wilcoxon signed-rank test: miR-221
< 0.0001; miR-483-3p
< 0.0001). Kaplan-Meier analysis showed worse cancer-related survival among all EAC patients expressing high miR-221 or miR-483-3p levels (log-rank
= 0.0025 and
= 0.0235, respectively). Higher miR-221 or miR-483-3p levels also correlated with advanced tumor stages (Mann-Whitney
= 0.0195 and
= 0.0085, respectively), and overexpression of miR-221 was associated with worse survival in low-risk EAC patients. Moreover, a significantly worse outcome was associated with the combined overexpression of miR-221 and miR-483-3p (log-rank
= 0.0410). To identify target genes affected by miRNA overexpression, we transfected the corresponding mimic RNA (miRVANA) for either miR-221 or miR-483-3p in a well-characterized esophageal adenocarcinoma cell line (OE19) and performed RNA-seq analysis. In the miRNA-overexpressing cells, we discovered a convergent dysregulation of genes linked to apoptosis, ATP synthesis, angiogenesis, and cancer progression, including a long non-coding RNA associated with oncogenesis, i.e., MALAT1. In conclusion, dysregulated miRNA expression, especially overexpression of miR-221 and 483-3p, was found in EAC samples. These alterations were connected with a lower cancer-specific patient survival, suggesting that these miRNAs could be useful for patient stratification and prognosis.
Approximately 15% to 43% of esophageal adenocarcinomas (EACs) are human epidermal growth factor receptor 2 (HER2) positive. Because dual-agent HER2 blockade demonstrated a survival benefit in breast ...cancer, we conducted a phase II feasibility study of trastuzumab and pertuzumab added to neoadjuvant chemoradiotherapy (nCRT) in patients with EAC.
Patients with resectable HER2-positive EAC received standard nCRT with carboplatin and paclitaxel and 41.4 Gy of radiotherapy, with 4 mg/kg of trastuzumab on day 1, 2 mg/kg per week during weeks 2 to 6, and 6 mg/kg per week during weeks 7, 10, and 13 and 840 mg of pertuzumab every 3 weeks. The primary end point was feasibility, defined as ≥ 80% completion of treatment with both trastuzumab and pertuzumab. An exploratory comparison of survival with a propensity score-matched cohort receiving standard nCRT was performed, as were exploratory pharmacokinetic and biomarker analyses.
Of the 40 enrolled patients (78% men; median age, 63 years), 33 (83%) completed treatment with trastuzumab and pertuzumab. No unexpected safety events were observed. R0 resection was achieved in all patients undergoing surgery, with pathologic complete response in 13 patients (34%). Three-year progression-free and overall survival (OS) were 57% and 71%, respectively (median follow-up, 32.1 months). Compared with the propensity score-matched cohort, a significantly longer OS was observed with HER2 blockade (hazard ratio, 0.58; 95% CI, 0.34 to 0.97). Results of pharmacokinetic analysis and activity on
Ffluorodeoxyglucose positron emission tomography scans did not correlate with survival or pathologic response. Patients with HER2 3+ overexpression or growth factor receptor-bound protein 7 (Grb7) -positive tumors at baseline demonstrated significantly better survival (
= .007) or treatment response (
= .016), respectively.
Addition of trastuzumab and pertuzumab to nCRT in patients with HER2-positive EAC is feasible and demonstrates potentially promising activity compared with historical controls. HER2 3+ overexpression and Grb7 positivity are potentially predictive for survival and treatment response, respectively.
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