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Abstract Background A surgical resection is currently the preferred treatment for esophageal cancer if the tumor is considered to be resectable without evidence of distant metastases (cT1-3 N0-1 M0). A high percentage of irradical resections is reported in studies using neoadjuvant chemotherapy followed by surgery versus surgery alone and in trials in which patients are treated with surgery alone. Improvement of locoregional control by using neoadjuvant chemoradiotherapy might therefore improve the prognosis in these patients. We previously reported that after neoadjuvant chemoradiotherapy with weekly administrations of Carboplatin and Paclitaxel combined with concurrent radiotherapy nearly always a complete R0-resection could be performed. The concept that this neoadjuvant chemoradiotherapy regimen improves overall survival has, however, to be proven in a randomized phase III trial. Methods/design The CROSS trial is a multicenter, randomized phase III, clinical trial. The study compares neoadjuvant chemoradiotherapy followed by surgery with surgery alone in patients with potentially curable esophageal cancer, with inclusion of 175 patients per arm. The objectives of the CROSS trial are to compare median survival rates and quality of life (before, during and after treatment), pathological responses, progression free survival, the number of R0 resections, treatment toxicity and costs between patients treated with neoadjuvant chemoradiotherapy followed by surgery with surgery alone for surgically resectable esophageal adenocarcinoma or squamous cell carcinoma. Over a 5 week period concurrent chemoradiotherapy will be applied on an outpatient basis. Paclitaxel (50 mg/m2) and Carboplatin (Area-Under-Curve = 2) are administered by i.v. infusion on days 1, 8, 15, 22, and 29. External beam radiation with a total dose of 41.4 Gy is given in 23 fractions of 1.8 Gy, 5 fractions a week. After completion of the protocol, patients will be followed up every 3 months for the first year, every 6 months for the second year, and then at the end of each year until 5 years after treatment. Quality of life questionnaires will be filled out during the first year of follow-up. Discussion This study will contribute to the evidence on any benefits of neoadjuvant treatment in esophageal cancer patients using a promising chemoradiotherapy regimen. Trial registration ISRCTN80832026

Robert Sitarz,1–3 Małgorzata Skierucha,1,2 Jerzy Mielko,1 G Johan A Offerhaus,3 Ryszard Maciejewski,2 Wojciech P Polkowski1 1Department of Surgical Oncology, Medical University of Lublin, Lublin, Poland; 2Department of Human Anatomy, Medical University of Lublin, Lublin, Poland; 3Department of Pathology, University Medical Centre, Utrecht, The Netherlands Abstract: Gastric cancer is the second most common cause of cancer-related deaths in the world, the epidemiology of which has changed within last decades. A trend of steady decline in gastric cancer incidence rates is the effect of the increased standards of hygiene, conscious nutrition, and Helicobacter pylori eradication, which together constitute primary prevention. Avoidance of gastric cancer remains a priority. However, patients with higher risk should be screened for early detection and chemoprevention. Surgical resection enhanced by standardized lymphadenectomy remains the gold standard in gastric cancer therapy. This review briefly summarizes the most important aspects of gastric cancers, which include epidemiology, risk factors, classification, diagnosis, prevention, and treatment. The paper is mostly addressed to physicians who are interested in updating the state of art concerning gastric carcinoma from easily accessible and credible source. Keywords: gastric cancer, epidemiology, classification, risk factors, treatment

The ReBus cohort is a matched nested case-control cohort of patients with nondysplastic (ND) Barrett's esophagus (BE) at baseline who progressed (progressors) or did not progress (nonprogressors) to high-grade dysplasia (HGD) or cancer. This cohort is constructed using the most stringent inclusion criteria to optimize explorative studies on biomarkers predicting malignant progression in NDBE. These explorative studies may benefit from expanding the number of cases and by incorporating samples that allow assessment of the biomarker over space (spatial variability) and over time (temporal variability). To (i) update the ReBus cohort by identifying new progressors and (ii) identify progressors and nonprogressors within the updated ReBus cohort containing spatial and temporal information. The ReBus cohort was updated by identifying Barrett's patients referred for endoscopic work-up of neoplasia at 4 tertiary referral centers. Progressors and nonprogressors with a multilevel (spatial) endoscopy and additional prior (temporal) endoscopies were identified to evaluate biomarkers over space and over time. The original ReBus cohort consisted of 165 progressors and 723 nonprogressors. We identified 65 new progressors meeting the same strict selection criteria, resulting in a total number of 230 progressors and 723 matched nonprogressors in the updated ReBus cohort. Within the updated cohort, 61 progressors and 107 nonprogressors (mean age 61 ± 10 years) with a spatial endoscopy (median level 3 [2-4]) were identified. 33/61 progressors and 50/107 nonprogressors had a median of 3 (2-4) additional temporal endoscopies. Our updated ReBus cohort consists of 230 progressors and 723 matched nonprogressors using the most strict selection criteria. In a subgroup of 168 Barrett's patients (the SpaTemp cohort), multiple levels have been sampled at baseline and during follow-up providing a unique platform to study spatial and temporal distribution of biomarkers in BE., (© The Author(s) 2020. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Organoids are self-organizing 3D structures grown from stem cells that recapitulate essential aspects of organ structure and function. Here, we describe a method to establish long-term-expanding human airway organoids from broncho-alveolar resections or lavage material. The pseudostratified airway organoids consist of basal cells, functional multi-ciliated cells, mucus-producing secretory cells, and CC10-secreting club cells. Airway organoids derived from cystic fibrosis (CF) patients allow assessment of CFTR function in an organoid swelling assay. Organoids established from lung cancer resections and metastasis biopsies retain tumor histopathology as well as cancer gene mutations and are amenable to drug screening. Respiratory syncytial virus (RSV) infection recapitulates central disease features, dramatically increases organoid cell motility via the non-structural viral NS2 protein, and preferentially recruits neutrophils upon co-culturing. We conclude that human airway organoids represent versatile models for the in vitro study of hereditary, malignant, and infectious pulmonary disease., (© 2019 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)

Background & Aims: Familial adenomatous polyposis is an autosomal dominant disorder characterized by the development of hundreds of colorectal adenomas and eventually colorectal cancer. Oral administration of the spice curcumin has been followed by regression of polyps in patients with this disorder. We performed a double-blinded randomized trial to determine the safety and efficacy of curcumin in patients with familial adenomatous polyposis., Methods: This study included 44 patients with familial adenomatous polyposis (18-85 years old) who had not undergone colectomy or had undergone colectomy with ileorectal anastomosis or ileal anal pouches, had at least 5 intestinal adenomatous polyps, and had enrolled in Puerto Rico or the United States from September 2011 through November 2016. Patients were randomly assigned (1:1) to groups given 100% pure curcumin (1,500 mg orally, twice per day) or identical-appearing placebo capsules for 12 months. The number and size of lower gastrointestinal tract polyps were evaluated every 4 months for 1 year. The primary outcome was the number of polyps in the curcumin and placebo groups at 12 months or at the time of withdrawal from the study according to the intention-to-treat principle., Results: After 1 year of treatment, the average rate of compliance was 83% in the curcumin group and 91% in the placebo group. After 12 weeks, there was no significant difference in the mean number of polyps between the placebo group (18.6; 95% CI, 9.3-27.8) and the curcumin group (22.6; 95% CI, 12.1-33.1; P = .58). We found no significant difference in mean polyp size between the curcumin group (2.3 mm; 95% CI, 1.8-2.8) and the placebo group (2.1 mm; 95% CI, 1.5-2.7; P = .76). Adverse events were few, with no significant differences between groups., Conclusions: In a double-blinded randomized trial of patients with familial adenomatous polyposis, we found no difference in the mean number or size of lower intestinal tract adenomas between patients given curcumin 3,000 mg/day and those given placebo for 12 weeks. Clinicaltrials.gov ID NCT00641147., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Epstein-Barr virus (EBV)-positive gastric adenocarcinoma exhibits locally intense inflammation but systemic manifestations are uncertain. Our study examined whether circulating mediators of inflammation and immune response differ by tumor EBV status. From a Latvian series of 302 gastric cancer cases, we measured plasma levels of 92 immune-related proteins in the 28 patients with EBV-positive tumors and 34 patients with EBV-negative tumors. Eight markers were statistically significantly higher with tumor EBV positivity: chemokine C-C motif ligand (CCL) 20 (Odds Ratio (OR) = 3.6; p -trend = 0.001), chemokine C-X-C motif ligand 9 (OR = 3.6; p -trend = 0.003), programmed death-ligand 1 (PD-L1; OR = 3.4; p -trend = 0.004), interleukin (IL)-10 (OR = 2.4; p -trend = 0.019), CCL19 (OR = 2.3; p -trend = 0.019), CCL11 (OR = 2.2; p -trend = 0.026), IL-17A (OR = 2.0; p -trend = 0.038) and CCL8 (OR = 1.9; p -trend = 0.049). Systemic responses to EBV-positive gastric cancer are characterized by alterations in chemokines and PD-L1. Profiling of these molecules may enable non-invasive diagnosis of EBV status when tumor tissue is unavailable. Our findings provide theoretical justification for clinical evaluations of immune checkpoint therapy for EBV-positive gastric cancer.

Purpose: Pancreatic neuroendocrine tumors are a major manifestation of multiple endocrine neoplasia type 1 (MEN1). This tumor syndrome is caused by germline mutations in MEN1, encoding menin. Insight into pathogenesis of these tumors might lead to new biomarkers and therapeutic targets for these patients. Several lines of evidence point towards a role for p27 Kip1 and p18 Ink4c in MEN1-related tumor development in animal models for MEN1, but their contribution to human MEN1-related pancreatic neuroendocrine tumor development is not known., Methods: In this study, we characterized protein expression of p27 Kip1 and p18 Ink4c in human MEN1-related PanNETs by immunohistochemistry. From the nationwide DutchMEN1 Study Group database including > 90% of the Dutch MEN1 population, MEN1-patients, who underwent pancreatic surgery, were selected. A tissue micro-array was constructed with available paraffin tissue blocks, and PanNETs from 61 MEN1 patients were eligible for analysis., Results: Expression of p27 Kip1 was high in 57 (93%) PanNETs and 67% of the tumors showed low expression of p18 Ink4c (67.3%). No association was found between expression of either p27 Kip1 or p18 Ink4c and clinic-pathological characteristics., Conclusions: These findings indicate that loss of p18 Ink4c , but not p27 Kip1 , is a common event in the development of MEN1-related PanNETs. Restoration of p18 Ink4c function through CDK4/6 inhibitors could be a therapeutic option for MEN1-related PanNETs.

In Western countries the majority of gastric cancers (GC) are usually diagnosed in advanced stages reporting a 5-year survival rate of only 26%. The Laurén classification of GC was most widely used in clinical practice since it reflects GC morphology, epidemiology, tumor biology, clinical management and outcome. Despite the initial promise of individualizing antitumor treatment, the management of GC still remains relatively broad and general. Apart from clinical staging, molecular profiling enables targeting of the identified underlying alterations, rather than histology. In contrast to breast carcinoma, molecular classification of GC does not yet imply treatment modality. Molecular classifications of GC and their therapeutic implications are therefore extensively studied. The current proposed molecular divisions of GC come from three different parts of the world where different standard treatment modalities for advanced GC are recommended. Wider use of GC molecular subtyping may solve problems, such as susceptibility to novel systemic therapy regimens or selection of patients for aggressive surgery and targeted adjuvant/conversion therapy. In any case, the rapid entry of novel molecular targeted therapies into routine oncology practice clearly underscores the urgent need for clinicians to be aware of these new possibilities., Competing Interests: CONFLICTS OF INTEREST None.

Management of Barrett's esophagus (BE) relies heavily on histopathological assessment of biopsies, associated with significant intra- and interobserver variability. Guidelines recommend biopsy review by an expert in case of dysplasia. Conventional review of biopsies, however, is impractical and does not allow for teleconferencing or annotations. An expert digital review platform might overcome these limitations. We compared diagnostic agreement of digital and conventional microscopy for diagnosing BE ± dysplasia. Sixty BE biopsy glass slides (non-dysplastic BE (NDBE); n = 25, low-grade dysplasia (LGD); n = 20; high-grade dysplasia (HGD); n = 15) were scanned at ×20 magnification. The slides were assessed four times by five expert BE pathologists, all practicing histopathologists (range: 5-30 years), in 2 alternating rounds of digital and conventional microscopy, each in randomized order and sequence of slides. Intraobserver and pairwise interobserver agreement were calculated, using custom weighted Cohen's kappa, adjusted for the maximum possible kappa scores. Split into three categories (NDBE, IND, LGD+HGD), the mean intraobserver agreement was 0.75 and 0.84 for digital and conventional assessment, respectively (p = 0.35). Mean pairwise interobserver agreement was 0.80 for digital and 0.85 for conventional microscopy (p = 0.17). In 47/60 (78%) of digital microscopy reviews a majority vote of ≥3 pathologists was reached before consensus meeting. After group discussion, a majority vote was achieved in all cases (60/60). Diagnostic agreement of digital microscopy is comparable to that of conventional microscopy. These outcomes justify the use of digital slides in a nationwide, web-based BE revision platform in the Netherlands. This will overcome the practical issues associated with conventional histologic review by multiple pathologists., (© The Authors 2017. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The prognostic value of WHO grade in pancreatic neuroendocrine tumors (PanNETs) in patients with Multiple Endocrine Neoplasia Type 1 (MEN1) is unknown., Methods: We performed a cohort study using the Dutch National MEN1 database, which includes >90% of the Dutch MEN1 population with data collected between 1990 and 2014. Formalin-fixed paraffin embedded tissue blocks from the largest resected PanNET per patient were collected. MIB1 staining was performed and KI67 labeling index (LI) was determined by manual eye-counting under a microscope and by digital image analysis. Mitotic count was evaluated from hematoxylin & eosin stains. Association between WHO grade and (time until) development of liver metastases was calculated., Results: Sixty-nine MEN1 patients who underwent pancreatic surgery were included. Ten patients (14%) developed liver metastases and all had PanNETs ≥3 cm. WHO G1, G2 and G3 PanNETs were seen in 83% (n = 57), 16% (n = 11) and 1% (n = 1) respectively. In non-functioning PanNETs >2 cm, liver metastases occurred in 80% of WHO G2 PanNETs (4/5) compared to 23% (5/22) in WHO G1 PanNETs (p = 0.03) when WHO grade was based on mitotic count only. This significant association was not seen for WHO grade based on Ki67 LI. After five years, liver metastases in non-functioning PanNETs were not seen in tumors ≤2 cm, in 10% of the large WHO G1 (according to mitotic count only) tumors and in 60% of large WHO G2 tumors (p-value 0.000)., Conclusion: High mitotic count is correlated with poor prognosis in MEN1 patients with large non-functioning PanNETs., (Copyright © 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

In the adenoma-carcinoma sequence, it is proposed that intestinal polyps evolve through a set of defined mutations toward metastatic colorectal cancer (CRC). Here, we dissect this adenoma-carcinoma sequence in vivo by using an orthotopic organoid transplantation model of human colon organoids engineered to harbor different CRC mutation combinations. We demonstrate that sequential accumulation of oncogenic mutations in Wnt, EGFR, P53, and TGF-β signaling pathways facilitates efficient tumor growth, migration, and metastatic colonization. We show that reconstitution of specific niche signals can restore metastatic growth potential of tumor cells lacking one of the oncogenic mutations. Our findings imply that the ability to metastasize-i.e., to colonize distant sites-is the direct consequence of the loss of dependency on specific niche signals.

Aims: Gastric pyloric gland adenomas (PGAs) are rare epithelial polyps that are found more commonly in autoimmune atrophic gastritis and familial adenomatous polyposis (FAP). Little is known about the morphology and genetics of PGAs in FAP. PGAs in FAP are studied morphologically and genetically. Findings in FAP-associated PGAs are compared to sporadic PGAs and related lesions such as oxyntic gland adenoma (OGA) to increase our understanding of these rare polyps., Methods and Results: Seven PGAs and 18 fundic gland polyps (FGPs) from FAP patients were collected. KRAS and GNAS mutations were determined in six PGAs and 18 FGPs. Immunohistochemistry was applied on five PGAs to provide further confirmation of the histological subtypes and genetic alterations. Morphology of all PGAs was studied and compared to literature on sporadic PGAs and related lesions. All successfully sequenced PGAs (six of six) carried GNAS mutations and half of the successfully sequenced PGAs carried a KRAS mutation (three of six). Nuclear β-catenin was seen only in one PGA with focal high-grade dysplasia. Morphologically, PGAs in FAP showed overlapping features with OGA., Conclusion: Familial adenomatous polyposis-associated PGAs have a similar genetic background as sporadic PGAs, i.e. KRAS and GNAS mutation. Based on morphological findings in FAP associated PGAs, it is hypothesized that PGAs and OGAs are closely related lesions., Competing Interests: Disclosure/Conflict of Interest: The authors have nothing to disclose., (© 2016 John Wiley & Sons Ltd.)

Background & Aims: There is suboptimal inter-observer agreement, even among expert gastrointestinal pathologists, in the diagnosis of low-grade dysplasia (LGD) in patients with Barrett's esophagus (BE). We analyzed histopathologic criteria required for a diagnosis of LGD using the new subcategories of LGD with inflammatory and dysplastic features. We categorized each diagnosis based on the level of confidence and assessed inter-observer agreement among gastrointestinal pathologists from 5 tertiary centers in the United States and Europe., Methods: In the first phase of the study, 3 pathologists held a consensus conference at which they discussed the diagnostic criteria for LGD. In the second phase, 79 slides from patients with BE (23 samples of non-dysplastic BE, 22 samples of LGD, and 34 samples of high-grade dysplasia) were identified, randomly assigned to 7 pathologists (4 from the United States and 3 from Europe), and interpreted in a blinded fashion. κ Values were calculated for inter-observer agreement. We performed multinomial logistic regression analysis to assess the weighting of histologic features with the diagnosis., Results: The overall κ value for diagnosis was 0.43 (95% confidence interval [CI], 0.42-0.48). When categorized based on degree of dysplasia, the κ value was 0.22 (95% CI, 0.11-0.29) for non-dysplastic BE, 0.11 (95% CI, 0.004-0.15) for LGD, and 0.43 (95% CI, 0.36-0.46) for high-grade dysplasia. When all pathologists made a diagnosis with high confidence, the inter-observer agreement was substantial among the US pathologists (κ, 0.63; 95% CI, 0.61-0.66) and European pathologists (κ, 0.80; 95% CI, 0.74-0.97). The κ values for all diagnoses made by European pathologists were higher than those made by US pathologists., Conclusions: In an analysis of criteria used in histopathologic diagnosis of LGD, we did not observe improvement in level of agreement among experienced pathologists, even after accounting for inflammation. The level of inter-observer agreement increased with level of pathologist confidence. There was also a difference in reading of histopathology samples of BE tissues between US and European pathologists., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: When dysplastic lesions are encountered during surveillance colonoscopy of patients with inflammatory bowel disease (IBD), guidelines recommend collection of additional biopsies from the surrounding mucosa to ensure the lesion has been adequately circumscribed. We aimed to determine the rate of dysplasia in mucosa biopsies collected from tissues surrounding dysplastic lesions during IBD surveillance., Methods: In a retrospective study, we collected endoscopy and pathology reports from 1065 patients undergoing colonoscopic surveillance for IBD from 2000 through 2015 at 3 centers in the Netherlands. We analyzed reports from all patients with dysplastic lesions from whom biopsies of surrounding mucosa were collected. Among 194 patients with 1 or more visible dysplastic lesions, mucosal biopsies were collected from tissues adjacent to 140 dysplastic lesions from 71 patients (63% male; 48% with ulcerative colitis, 42% with Crohn's disease, and 10% with indeterminate colitis)., Results: The mean number of surrounding mucosa biopsies collected per lesion was 3.4 (range, 1-6). Dysplasia was detected in 7 biopsies surrounding 140 areas of dysplasia (5.0%) and 5 biopsies surrounding 136 areas of low-grade dysplasia (3.7%). Dysplasia in biopsies of surrounding mucosa could be observed during 5 of 87 white light endoscopies and during 2 of 53 chromoendoscopies. In patients with dysplasia in mucosa surrounding lesions of low-grade dysplasia, post-resection surveillance did not reveal high-grade dysplasia or colorectal cancer., Conclusions: Dysplasia is detected in only 5% of biopsies collected from mucosa surrounding dysplastic lesions. This observation indicates that endoscopists accurately delineate the borders of dysplastic lesions during surveillance of patients with IBD. The lack of clinical consequences from routinely collecting biopsies from areas surrounding dysplastic lesions casts doubt on the usefulness and cost-effectiveness of this practice., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: We aimed to determine pretreatment pathological tumor extent in the resection specimen after neoadjuvant chemoradiotherapy (nCRT) and to assess its prognostic value in patients with esophageal cancer., Methods: Patients with esophageal cancer, treated with nCRT plus surgery were included (2003-2011). Pretreatment pathological T-stage (prepT-stage) and N-stage (prepN-stage) were estimated based on the extent of regressional changes and residual tumor cells in the resection specimen. Interobserver agreement was determined between 3 pathologists. The prognostic performance of prepT-stage and prepN-stage was scored using the difference in Akaike information criterion (ΔAIC). PrepN-stage and posttreatment pathological N-stage (ypN-stage) were combined to determine the effect of nodal sterilization on prognosis., Results: Overall concordance for prepT-stage and prepN-stage was 0.69 and 0.84, respectively. Prognostic strength of prepT-stage was similar to clinical T-stage and worse compared with ypT-stage (ΔAIC 1.3 versus 2.0 and 8.9, respectively). In contrast, prognostic strength of prepN-stage was better than cN-stage and similar to ypN-stage (ΔAIC 17.9 versus 6.2 and 17.2, respectively). PrepN+ patients who become ypN0 after nCRT have a worse survival compared with prepN0 patients, with a five year overall survival of 51% versus 68%, P = 0.019, respectively., Conclusions: PrepT-stage and prepN-stage can be estimated reproducibly. Prognostic strength of prepT-stage is comparable with clinical T-stage, whereas prepN-stage is better than cN-stage. PrepN+ patients who become ypN0 after nCRT have a worse survival compared with prepN0 patients. Pretreatment pathological staging should be considered useful as a new staging parameter for esophageal cancer and could also be of interest for other tumor types.

Purpose: Recent transcriptomic analyses have identified four distinct molecular subtypes of colorectal cancer with evident clinical relevance. However, the requirement for sufficient quantities of bulk tumor and difficulties in obtaining high-quality genome-wide transcriptome data from formalin-fixed paraffin-embedded tissue are obstacles toward widespread adoption of this taxonomy. Here, we develop an immunohistochemistry-based classifier to validate the prognostic and predictive value of molecular colorectal cancer subtyping in a multicenter study., Experimental Design: Tissue microarrays from 1,076 patients with colorectal cancer from four different cohorts were stained for five markers (CDX2, FRMD6, HTR2B, ZEB1, and KER) by immunohistochemistry and assessed for microsatellite instability. An automated classification system was trained on one cohort using quantitative image analysis or semiquantitative pathologist scoring of the cores as input and applied to three independent clinical cohorts., Results: This classifier demonstrated 87% concordance with the gold-standard transcriptome-based classification. Application to three validation datasets confirmed the poor prognosis of the mesenchymal-like molecular colorectal cancer subtype. In addition, retrospective analysis demonstrated the benefit of adding cetuximab to bevacizumab and chemotherapy in patients with RAS wild-type metastatic cancers of the canonical epithelial-like subtypes., Conclusions: This study shows that a practical and robust immunohistochemical assay can be employed to identify molecular colorectal cancer subtypes and uncover subtype-specific therapeutic benefit. Finally, the described tool is available online for rapid classification of colorectal cancer samples, both in the format of an automated image analysis pipeline to score tumor core staining, and as a classifier based on semiquantitative pathology scoring. Clin Cancer Res; 23(2); 387-98. ©2016 AACR., (©2016 American Association for Cancer Research.)

T1 colorectal cancer can be mimicked by pseudo-invasion in pedunculated polyps. British guidelines are currently one of the few which recommend diagnostic confirmation of T1 colorectal cancer by a second pathologist. The aim of this study was to provide insights into the accuracy of histological diagnosis of pedunculated T1 colorectal cancer in daily clinical practice. A sample of 128 cases diagnosed as pedunculated T1 colorectal cancer between 2000 and 2014 from 10 Dutch hospitals was selected for histological review. Firstly, two Dutch expert gastrointestinal pathologists reviewed all hematoxylin-eosin stained slides. In 20 cases the diagnosis T1 colorectal cancer was not confirmed (20/128; 16%). The discordant cases were subsequently discussed with a third Dutch gastrointestinal pathologist and a consensus diagnosis was agreed. The revised diagnoses were pseudo-invasion in 10 cases (10/128; 8%), high-grade dysplasia in 4 cases (4/128; 3%), and equivocal in 6 cases (6/128; 5%). To further validate the consensus diagnosis, the discordant cases were reviewed by an independent expert pathologist from the United Kingdom. A total of 39 cases were reviewed blindly including the 20 cases with a revised diagnosis and 19 control cases where the Dutch expert panel agreed with the original reporting pathologists diagnosis. In 19 of the 20 cases with a revised diagnosis the British pathologist agreed that T1 colorectal cancer could not be confirmed. Additionally, amongst the 19 control cases the British pathologist was unable to confirm T1 colorectal cancer in a further 4 cases and was equivocal in 3 cases. In conclusion, both generalist and expert pathologists experience diagnostic difficulty distinguishing pseudo-invasion and high-grade dysplasia from T1 colorectal cancer. In order to prevent overtreatment, review of the histology of pedunculated T1 colorectal cancers by a second pathologist should be considered with discussion of these cases at a multidisciplinary meeting.

Current mouse models for colorectal cancer often differ significantly from human colon cancer, being largely restricted to the small intestine. Here, we aim to develop a colon-specific inducible mouse model that can faithfully recapitulate human colon cancer initiation and progression. Carbonic anhydrase I (Car1) is a gene expressed uniquely in colonic epithelial cells. We generated a colon-specific inducible Car1 CreER knock-in (KI) mouse with broad Cre activity in epithelial cells of the proximal colon and cecum. Deletion of the tumor suppressor gene Apc using the Car1 CreER KI caused tumor formation in the cecum but did not yield adenomas in the proximal colon. Mutation of both Apc and Kras yielded microadenomas in both the cecum and the proximal colon, which progressed to macroadenomas with significant morbidity. Aggressive carcinomas with some invasion into lymph nodes developed upon combined induction of oncogenic mutations of Apc, Kras, p53, and Smad4 Importantly, no adenomas were observed in the small intestine. Additionally, we observed tumors from differentiated Car1-expressing cells with Apc/Kras mutations, suggesting that a top-down model of intestinal tumorigenesis can occur with multiple mutations. Our results establish the Car1 CreER KI as a valuable mouse model to study colon-specific tumorigenesis and metastasis as well as cancer-cell-of-origin questions., Competing Interests: The authors declare no conflict of interest.

Colorectal carcinogenesis is a process that follows a stepwise cascade that goes from the normal to an invisible pretumor stage ultimately leading to grossly visible tumor progression. During pretumor progression, an increasing accumulation of genetic alterations occurs, by definition without visible manifestations. It is generally thought that stem cells in the crypt base are responsible for this initiation of colorectal cancer progression because they are the origin of the differentiated epithelial cells that occupy the crypt. Furthermore, they are characterized by a long life span that enables them to acquire these cumulative mutations. Recent studies visualized the dynamics of stem cells both in vitro and in vivo. Translating this work into clinical applications will contribute to the evaluation of patients' predisposition for colorectal carcinogenesis and may help in the design of preventive measures for high-risk groups. In this review, we outline the progress made in the research into tracing stem cell dynamics. Further, we highlight the importance and potential clinical value of tracing stem cell dynamics in pretumor progression.

Background & Aims: In some patients with Barrett's esophagus (BE) and a confirmed diagnosis of low-grade dysplasia (LGD), the LGD is not detected during follow-up examinations. We would like to avoid the unnecessary risks and costs of ablative treatment for these patients. Therefore, we investigated whether persistent LGD increases risk for high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) and what proportion of patients are no longer found to have dysplasia after an initial diagnosis of LGD., Methods: In a retrospective study, we collected information on 1579 patients with BE and LGD from 2005 through 2010 by using a nationwide registry of histopathology diagnoses in the Netherlands (PALGA). Confirmed LGD was defined as a diagnosis of LGD that was confirmed by any other pathologist. Persistent LGD was defined as LGD detected at the first and follow-up endoscopy. Data were collected on patients until treatment for HGD, detection of EAC, or the last endoscopy at which a biopsy was collected (through July 2014). We evaluated whether persistent LGD was a risk factor for malignant progression by using univariable and multivariable Cox regression analyses., Results: Of individuals with BE and LGD in the database, the diagnosis of LGD was confirmed for 161 patients (10% of total). In these patients, the incidence of HGD and/or EAC was 5.18/100 person-years (95% confidence interval [CI], 4.32-8.10/100 person-years) compared with 1.85/100 person-years (95% CI, 1.52-2.22/100 person-years) in patients for whom LGD was not confirmed at the first endoscopy. The incidence of EAC alone in patients with confirmed LGD was 2.51/100 person-years (95% CI, 1.46-3.99/100 person-years), compared with 1.01/per 100 person-years (95% CI, 0.41-2.10/100 person-years) in patients for whom LGD was not confirmed at the first endoscopy. Of patients in whom LGD was confirmed at the first endoscopic examination, 51% were not found to have dysplasia at the first follow-up endoscopy, and 30% had persistent LGD. In patients with persistent LGD, the incidence of HGD and/or EAC was 7.65/100 person-years (95% CI, 4.45-12.34) and of only EAC was 2.04/100 person-years (95% CI, 0.65-4.92); in patients without persistent LGD, the incidence of HGD and/or EAC was 2.32/100 person-years (95% CI, 1.08-4.40/100 person-years) and of only EAC was 1.45 (95% CI, 0.53-3.21/100 person-years). Persistent LGD was found to be an independent risk factor for the development of HGD and/or EAC, with hazard ratio of 3.5 (95% CI, 1.48-8.28)., Conclusions: In a large population-based cohort study of patients with BE and LGD, the risk of progression to HGD and/or EAC was higher in patients with confirmed LGD and highest in those with confirmed and persistent LGD., (Copyright © 2016. Published by Elsevier Inc.)

Background: Histologic characteristics have proven to be very useful for classifying different types of tumors of the pancreas. As a result, the major tumor types in the pancreas have long been classified based on their microscopic appearance., Main Body: Recent advances in whole exome sequencing, gene expression profiling, and knowledge of tumorigenic pathways have deepened our understanding of the underlying biology of pancreatic neoplasia. These advances have not only confirmed the traditional histologic classification system, but also opened new doors to early diagnosis and targeted treatment., Conclusion: This review discusses the histopathology, genetic and epigenetic alterations and potential treatment targets of the five major malignant pancreatic tumors - pancreatic ductal adenocarcinoma, pancreatic neuroendocrine tumor, solid-pseudopapillary neoplasm, acinar cell carcinoma and pancreatoblastoma.

Background: Bone morphogenetic protein 4 (BMP4) signaling is involved in the development of Barrett's esophagus (BE), a precursor of esophageal adenocarcinoma (EAC). In various cancers, BMP4 has been found to induce epithelial-mesenchymal transition (EMT) but its function in the development of EAC is currently unclear., Aim: To investigate the expression of BMP4 and several members of the BMP4 pathway in EAC. Additionally, to determine the effect of BMP4 signaling in a human Barrett's esophagus (BAR-T) and adenocarcinoma (OE33) cell line., Methods: Expression of BMP4, its downstream target ID2 and members of the BMP4 pathway were determined by Q-RT-PCR, immunohistochemistry and Western blot analysis using biopsy samples from EAC patients. BAR-T and OE33 cells were incubated with BMP4 or the BMP4 antagonist, Noggin, and cell viability and migration assays were performed. In addition, expression of factors associated with EMT (SNAIL2, CDH1, CDH2 and Vimentin) was evaluated by Q-RT-PCR and Western blot analysis., Results: Compared to squamous epithelium (SQ), BMP4 expression was significantly upregulated in EAC and BE. In addition, the expression of ID2 was significantly upregulated in EAC and BE compared to SQ. Western blot analysis confirmed our results, showing an upregulated expression of BMP4 and ID2 in both BE and EAC. In addition, more phosphorylation of SMAD1/5/8 was observed. BMP4 incubation inhibited cell viability, but induced cell migration in both BAR-T and OE33 cells. Upon BMP4 incubation, SNAIL2 expression was significantly upregulated in BAR-T and OE33 cells while CDH1 expression was significantly downregulated. These results were confirmed by Western blot analysis., Conclusion: Our results indicate active BMP4 signaling in BE and EAC and suggest that this results in an invasive phenotype by inducing an EMT-like response through upregulation of SNAIL2 and subsequent downregulation of CDH1.

Gastric polyps are found in 1% to 4% of patients undergoing gastroscopy. The vast majority are sporadic, but some gastric polyps indicate an underlying syndrome. Gastric polyps can manifest in each of the gastrointestinal polyposis syndromes, including the recently described gastric adenocarcinoma and proximal polyposis of the stomach syndrome. In addition, gastric polyps occur in Lynch syndrome and in a few rare conditions that are not primarily gastrointestinal. While some of these syndromes are clearly associated with an increased risk of gastric cancer, others are not. Interestingly, even in disorders with a well-established risk of gastric cancer, the neoplastic potential and the precursor status of these gastric polyps are not always clear. Although rare, recognition of syndromic gastric polyps is important for individual patient management. These conditions also serve as important models to study gastric homeostasis and gastric tumorigenesis., (© The Author(s) 2015.)

Background: Clinical staging of adenocarcinoma of the gastroesophageal junction (GEJ) determines the curative treatment regimen containing either neoadjuvant chemotherapy or chemoradiotherapy followed by either gastrectomy or esophagectomy. The value of current diagnostic tools is a matter of debate., Methods: A prospective database (2003-2013) was used to identify 266 consecutive patients with adenocarcinoma of the GEJ in order to evaluate the accuracy of endoscopic ultrasound (EUS) and computed tomography (CT) regarding tumor localization according to Siewert, nodal status and its consequences on treatment strategy., Results: Overall accuracy in determining tumor localization was 73% for endoscopy/EUS and 61% for CT (p = 0.018). With endoscopy/EUS, the accuracy was 97%, 66% and 75% respectively for type I, II and III. With CT this was respectively 69%, 57% and 80%. The overall accuracy for determining N-status (N0/N+) per patient was 75% for EUS and 71% for CT. Accuracy for determining a positive nodal station in patients without neoadjuvant therapy was 77% for EUS and 71% for CT (p = 0.001). Accuracy for detecting positive upper mediastinal nodes was 80-92%, whereas for peritumoral and abdominal nodes this was 50-80% in both EUS and CT. In 8/266 patients (3%) the type of surgery changed due to intraoperative findings. A radical resection was performed in 233 patients (88%)., Conclusions: Despite the suboptimal accuracy of determining tumor localization with EUS and CT, in only a small number of patients an intraoperative change of surgical treatment was needed. EUS is superior to CT in determining nodal status and tumor localization in GEJ tumors., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Currently, gastric cancer (GC) is one of the most frequently diagnosed neoplasms, with a global burden of 723000 deaths in 2012. It is the third leading cause of cancer-related death worldwide. There are numerous possible factors that stimulate the pro-carcinogenic activity of important genes. These factors include genetic susceptibility expressed in a single-nucleotide polymorphism, various acquired mutations (chromosomal instability, microsatellite instability, somatic gene mutations, epigenetic alterations) and environmental circumstances (e.g., Helicobcter pylori infection, EBV infection, diet, and smoking). Most of the aforementioned pathways overlap, and authors agree that a clear-cut pathway for GC may not exist. Thus, the categorization of carcinogenic events is complicated. Lately, it has been claimed that research on early-onset gastric carcinoma (EOGC) and hereditary GC may contribute towards unravelling some part of the mystery of the GC molecular pattern because young patients are less exposed to environmental carcinogens and because carcinogenesis in this setting may be more dependent on genetic factors. The comparison of various aspects that differ and coexist in EOGCs and conventional GCs might enable scientists to: distinguish which features in the pathway of gastric carcinogenesis are modifiable, discover specific GC markers and identify a specific target. This review provides a summary of the data published thus far concerning the molecular characteristics of GC and highlights the outstanding features of EOGC.

Gastric polyps occur in 1-4 % of patients undergoing gastroscopy. Although most are sporadic, some gastric polyps are part of an underlying hereditary syndrome. Gastric polyps can be seen in each of the well-known gastrointestinal polyposis syndromes, but also in Lynch syndrome and in several rare not primarily gastrointestinal syndromes. In addition, Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS) is a recently described heritable syndrome characterized by isolated gastric polyposis and risk of gastric cancer.Some of these syndromes are associated with an increased risk of gastric cancer, whereas others are not. However, the neoplastic potential and the precursor status of these gastric polyps are not always clear, even in syndromes with a well-established risk of gastric cancer. For instance, the neoplastic potential of Peutz-Jeghers polyps is debatable, despite the well-established risk of gastric cancer in this syndrome. Also fundic gland polyps and gastric foveolar-type adenomas in FAP carry a low risk of malignant transformation. In contrast, gastric juvenile polyps are precursor lesions of gastric cancer in juvenile polyposis syndrome through neoplastic progression of juvenile polyps in these patients.Although these hereditary syndromes with gastric polyps are rare, recognition is important for individual patient management. Furthermore, the initiation and progression of these lesions can be influenced by environmental factors such as Helicobacter Pylori infection. This makes these rare lesions an appropriate model for understanding the clonal evolution of early gastric cancer in the wider population.

Background: The advantage of laparoscopic gastrectomy compared to open gastrectomy has been established in Asian patient series with early gastric cancer. However, its feasibility in Western European patients with locally advanced gastric cancer is unknown., Methods: Between 2006 and 2014 70 consecutive patients with advanced gastric cancer underwent laparoscopic gastrectomy with D2 lymph node dissection. A Billroth II reconstruction was performed after distal gastrectomy. In case of total gastrectomy a jejunal J-pouch reconstruction was performed., Results: Total gastrectomy was performed in 56 patients and distal gastrectomy in 14 patients. Perioperative chemotherapy was administered in 45/70 (64%) patients. A radical resection was achieved in 63/70 (90%). The median number of dissected lymph nodes was 17 (2-62). The median intraoperative blood loss was 305 (30-2700) milliliters. The median postoperative hospital stay was 11 (5-91) days. The 30-day mortality was 4.3%., Conclusions: Laparoscopic gastrectomy can be performed in Western European patients with advanced gastric cancer and meets the oncologic standard with low intraoperative blood loss and short hospital stay., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

International experts met to discuss recent advances and to revise the 2004 recommendations for assessing and reporting precursor lesions to invasive carcinomas of the pancreas, including pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm, and other lesions. Consensus recommendations include the following: (1) To improve concordance and to align with practical consequences, a 2-tiered system (low vs. high grade) is proposed for all precursor lesions, with the provision that the current PanIN-2 and neoplasms with intermediate-grade dysplasia now be categorized as low grade. Thus, "high-grade dysplasia" is to be reserved for only the uppermost end of the spectrum ("carcinoma in situ"-type lesions). (2) Current data indicate that PanIN of any grade at a margin of a resected pancreas with invasive carcinoma does not have prognostic implications; the clinical significance of dysplasia at a margin in a resected pancreas with IPMN lacking invasive carcinoma remains to be determined. (3) Intraductal lesions 0.5 to 1 cm can be either large PanINs or small IPMNs. The term "incipient IPMN" should be reserved for lesions in this size with intestinal or oncocytic papillae or GNAS mutations. (4) Measurement of the distance between an IPMN and invasive carcinoma and sampling of intervening tissue are recommended to assess concomitant versus associated status. Conceptually, concomitant invasive carcinoma (in contrast with the "associated" group) ought to be genetically distinct from an IPMN elsewhere in the gland. (5) "Intraductal spread of invasive carcinoma" (aka, "colonization") is recommended to describe lesions of invasive carcinoma invading back into and extending along the ductal system, which may morphologically mimic high-grade PanIN or even IPMN. (6) "Simple mucinous cyst" is recommended to describe cysts >1 cm having gastric-type flat mucinous lining at most minimal atypia without ovarian-type stroma to distinguish them from IPMN. (7) Human lesions resembling the acinar to ductal metaplasia and atypical flat lesions of genetically engineered mouse models exist and may reflect an alternate pathway of carcinogenesis; however, their biological significance requires further study. These revised recommendations are expected to improve our management and understanding of precursor lesions in the pancreas.

Background: For patients with an identified germline E-cadherin-1 (CDH1) mutation, prophylactic gastrectomy is the treatment of choice to eliminate the high risk of developing diffuse gastric cancer. Laparoscopic total gastrectomy with jejunal pouch reconstruction is a novel approach that may be especially suitable in these patients., Methods: Patients with a germline CDH1 mutation who underwent prophylactic laparoscopic total gastrectomy with jejunal pouch were included in our prospective database., Results: A total of 11 patients with a median age of 40 (22-61) years were included. The average operative time was 4:26 ± 0:49 h and the average blood loss was 219 ± 155 ml. Median length of hospital stay was 10 (7-27) days. In two patients, an esophagojejunal anastomotic leakage occurred (grade 4). The leakages were seen in patient numbers 2 and 3, which may be a result of a learning curve. The latter eight patients did not develop anastomotic leakage. Pulmonary complications occurred in one patient with atelectasis and in one patient with pneumonia (grade 2). The 60-day mortality rate was 0 %. Multiple foci of intramucosal diffuse gastric signet ring cell carcinoma were found in the resection specimen of 9/11 (82 %) patients. All 11/11 (100 %) resections were microscopically radical., Conclusions: Prophylactic laparoscopic total gastrectomy with jejunal pouch reconstruction in patients with a CDH1 germline mutation is feasible and safe. In 82 % of patients, foci of intramucosal diffuse gastric signet ring cell carcinoma in the resection specimen were found.

Colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer death in men and women in the United States. About 30% of patients with CRC report a family history of CRC. However, only 5% of CRCs arise in the setting of a well-established mendelian inherited disorder. In addition, serrated polyposis is a clinically defined syndrome with multiple serrated polyps in the colorectum and an increased CRC risk for which the genetics are unknown. This article focuses on genetic and clinical aspects of Lynch syndrome, familial adenomatous polyposis, and MUTYH-associated polyposis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Identifying druggable targets in the Wnt-signaling pathway can optimize colorectal cancer treatment. Recent studies have identified a member of the RNA helicase family DDX3 (DDX3X) as a multilevel activator of Wnt signaling in cells without activating mutations in the Wnt-signaling pathway. In this study, we evaluated whether DDX3 plays a role in the constitutively active Wnt pathway that drives colorectal cancer. We determined DDX3 expression levels in 303 colorectal cancers by immunohistochemistry. 39% of tumors overexpressed DDX3. High cytoplasmic DDX3 expression correlated with nuclear β-catenin expression, a marker of activated Wnt signaling. Functionally, we validated this finding in vitro and found that inhibition of DDX3 with siRNA resulted in reduced TCF4-reporter activity and lowered the mRNA expression levels of downstream TCF4-regulated genes. In addition, DDX3 knockdown in colorectal cancer cell lines reduced proliferation and caused a G1 arrest, supporting a potential oncogenic role of DDX3 in colorectal cancer. RK-33 is a small molecule inhibitor designed to bind to the ATP-binding site of DDX3. Treatment of colorectal cancer cell lines and patient-derived 3D cultures with RK-33 inhibited growth and promoted cell death with IC50 values ranging from 2.5 to 8 μM. The highest RK-33 sensitivity was observed in tumors with wild-type APC-status and a mutation in CTNNB1. Based on these results, we conclude that DDX3 has an oncogenic role in colorectal cancer. Inhibition of DDX3 with the small molecule inhibitor RK-33 causes inhibition of Wnt signaling and may therefore be a promising future treatment strategy for a subset of colorectal cancers.