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AIMS - Well-differentiated small intestinal neuroendocrine tumours (SI-NETs) are often multifocal, and this has been suggested to impart worse disease-free survival. Practice guidelines have not been established for World Health Organisation (WHO) grading of multiple primary lesions.
METHODS AND RESULTS - We identified 68 patients with ileal/jejunal SI-NET for a combined total of 207 primary lesions. Each case was evaluated for patient age and sex; size of all tumours; presence of lymph node metastases, mesenteric tumour deposits or distant metastases; and disease-specific outcome. Ki67 staining was performed on all 207 primary lesions. The relationship between multifocality and clinicopathological factors was compared using Fisher's exact test. Outcome was tested using Cox proportional hazard regression. Forty-two patients had unifocal disease, and 26 had multifocal disease (median five lesions, range = 2-32). Most tumours were WHO grade 1 (201 of 207, 97%). Of the five patients with grades 2/3 tumours, three patients had unifocal disease, one patient had two subcentimetre grade 2 lesions (including the largest) and eight subcentimetre grade 1 lesions, and one patient had one 1.6-cm grade 3 lesion and one subcentimetre grade 1 lesion. There was a positive correlation between tumour size and Ki67 index (coefficient 0.28; 95% confidence interval 0.05-0.52, P = 0.017). There was no significant association between multifocality and nodal metastases, mesenteric tumour deposits, distant metastases or disease-specific survival.
CONCLUSIONS - In patients with multifocal SI-NET, unless a particular lesion has a high mitotic rate, only staining the largest lesion for Ki67 should serve to grade almost all cases accurately. Multifocality does not appear to significantly impact patient survival.
© 2018 John Wiley & Sons Ltd.
Mesenteric tumor deposits are an adverse prognostic factor for small intestinal well-differentiated neuroendocrine tumors. Per the American Joint Committee on Cancer (AJCC) Cancer Staging Manual (eighth edition), any mesenteric tumor deposit larger than 2 cm signifies pN2 disease. This criterion has not been critically evaluated as a prognostic factor for small intestinal neuroendocrine tumors, nor have multifocality or histologic features of mesenteric tumor deposits. We evaluated 70 small intestinal neuroendocrine tumors with mesenteric tumor deposits for lesional contour, sclerosis, inflammation, calcification, entrapped blood vessels, and perineural invasion. Ki67 proliferative indices of the largest mesenteric tumor deposit from each case were calculated, and number of tumor deposits and size of the largest deposit were recorded. Associations between these factors (along with patient age, primary tumor Ki67 index, and AJCC stage) and development of liver metastases and overall survival were assessed. Median mesenteric tumor deposit size was 1.5 cm (range: 0.2-7.0 cm); median deposit number was 1 (range: 1-13). Primary and tumor deposit Ki67 indices within a given patient were discordant in 40% of cases but showed similar hazard ratios for disease-specific survival. Size of tumor deposits had no significant effect on prognosis, whether analyzed on a continuous scale or dichotomized using the recommended 2 cm cutoff. In contrast, increasing number of deposits was associated with poor prognosis, with multiple deposits conferring an 8.19-fold risk of disease-specific death compared to a single deposit (P = 0.049). Morphologic features of deposits had no prognostic impact. Size of mesenteric tumor deposits does not affect prognosis in small intestinal neuroendocrine tumor patients; instead, deposit multifocality is associated with shorter disease-specific survival and should be incorporated into future staging criteria.
Pathologic examination of hepatic metastasectomies from patients with metastatic small intestinal or pancreatic neuroendocrine tumor frequently reveals micrometastases undetectable by radiologic or macroscopic gross examination. This finding raises the possibility that undetectable micrometastases remain in these patients after metastasectomy. Here we examined liver resections for micrometastases and assessed their impact on prognosis. Hepatic metastasectomies from 65 patients with neuroendocrine tumor of the small intestine (N = 43) or pancreas (N = 22) were reviewed for the presence of micrometastases, which were defined as microscopic tumor foci ≤1 mm in greatest dimension. Medical records were also reviewed for patient demographics, clinical history, and follow-up data. Micrometastasis was identified in 36 (55%) of 65 hepatic resection specimens. More hepatic micrometastases were seen in small intestinal cases than in pancreatic cases (29/43, 67%, versus 7/22, 32%; P < .01). They were typically present within portal tracts, sometimes with extension into the periportal region or sinusoidal spaces away from the portal tracts. Patients without hepatic micrometastases had fewer macrometastases or more R0 hepatic resections than those with micrometastases. The presence of hepatic micrometastases was associated with poor overall survival both before (hazard ratio [HR] 3.43; 95% CI 1.14-10.30; P = .03) and after accounting for confounding variables in stratified Cox regression (HR 4.82; 95% CI 1.0621.79; P = .04). In conclusion, hepatic micrometastases are common in patients with metastatic small intestinal or pancreatic neuroendocrine tumor and are independently associated with poor prognosis. These data suggest that surgical resection of hepatic metastases is likely not curative in these patients.
Copyright © 2018 Elsevier Inc. All rights reserved.
Cytosolic phosphoenolpyruvate carboxykinase (PEPCK) is a gluconeogenic enzyme that is highly expressed in the liver and kidney but is also expressed at lower levels in a variety of other tissues where it may play adjunct roles in fatty acid esterification, amino acid metabolism, and/or TCA cycle function. PEPCK is expressed in the enterocytes of the small intestine, but it is unclear whether it supports a gluconeogenic rate sufficient to affect glucose homeostasis. To examine potential roles of intestinal PEPCK, we generated an intestinal PEPCK knockout mouse. Deletion of intestinal PEPCK ablated ex vivo gluconeogenesis but did not significantly affect glycemia in chow, high-fat diet, or streptozotocin-treated mice. In contrast, postprandial triglyceride secretion from the intestine was attenuated in vivo, consistent with a role in fatty acid esterification. Intestinal amino acid profiles and C tracer appearance into these pools were significantly altered, indicating abnormal amino acid trafficking through the enterocyte. The data suggest that the predominant role of PEPCK in the small intestine of mice is not gluconeogenesis but rather to support nutrient processing, particularly with regard to lipids and amino acids. NEW & NOTEWORTHY The small intestine expresses gluconeogenic enzymes for unknown reasons. In addition to glucose synthesis, the nascent steps of this pathway can be used to support amino acid and lipid metabolisms. When phosphoenolpyruvate carboxykinase, an essential gluconeogenic enzyme, is knocked out of the small intestine of mice, glycemia is unaffected, but mice inefficiently absorb dietary lipid, have abnormal amino acid profiles, and inefficiently catabolize glutamine. Therefore, the initial steps of intestinal gluconeogenesis are used for processing dietary triglycerides and metabolizing amino acids but are not essential for maintaining blood glucose levels.
Modern single-cell technologies allow multiplexed sampling of cellular states within a tissue. However, computational tools that can infer developmental cell-state transitions reproducibly from such single-cell data are lacking. Here, we introduce p-Creode, an unsupervised algorithm that produces multi-branching graphs from single-cell data, compares graphs with differing topologies, and infers a statistically robust hierarchy of cell-state transitions that define developmental trajectories. We have applied p-Creode to mass cytometry, multiplex immunofluorescence, and single-cell RNA-seq data. As a test case, we validate cell-state-transition trajectories predicted by p-Creode for intestinal tuft cells, a rare, chemosensory cell type. We clarify that tuft cells are specified outside of the Atoh1-dependent secretory lineage in the small intestine. However, p-Creode also predicts, and we confirm, that tuft cells arise from an alternative, Atoh1-driven developmental program in the colon. These studies introduce p-Creode as a reliable method for analyzing large datasets that depict branching transition trajectories.
Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
RHOA, a founding member of the Rho GTPase family, is critical for actomyosin dynamics, polarity, and morphogenesis in response to developmental cues, mechanical stress, and inflammation. In murine small intestinal epithelium, inducible RHOA deletion causes a loss of epithelial polarity, with disrupted villi and crypt organization. In the intestinal crypts, RHOA deficiency results in reduced cell proliferation, increased apoptosis, and a loss of intestinal stem cells (ISCs) that mimic effects of radiation damage. Mechanistically, RHOA loss reduces YAP signaling of the Hippo pathway and affects YAP effector epiregulin (EREG) expression in the crypts. Expression of an active YAP (S112A) mutant rescues ISC marker expression, ISC regeneration, and ISC-associated Wnt signaling, but not defective epithelial polarity, in RhoA knockout mice, implicating YAP in RHOA-regulated ISC function. EREG treatment or active β-catenin Catnb mutant expression rescues the RhoA KO ISC phenotypes. Thus, RHOA controls YAP-EREG signaling to regulate intestinal homeostasis and ISC regeneration.
Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
BACKGROUND - Magnetic compression anastomosis (magnamosis) uses a pair of self-centering magnetic Harrison Rings to create an intestinal anastomosis without sutures or staples. We report the first-in-human case series using this unique device.
STUDY DESIGN - We conducted a prospective, single-center, first-in-human pilot trial to evaluate the feasibility and safety of creating an intestinal anastomosis using the Magnamosis device. Adult patients requiring any intestinal anastomosis to restore bowel continuity were eligible for inclusion. For each procedure, 1 Harrison Ring was placed in the lumen of each intestinal segment. The rings were brought together and mated, and left to form a side to side, functional end to end anastomosis. Device movement was monitored with serial x-rays until it was passed in the stool. Patients were monitored for adverse effects with routine clinic appointments, as well as questionnaires.
RESULTS - Five patients have undergone small bowel anastomosis with the Magnamosis device. All 5 patients had severe systemic disease and underwent complex open urinary reconstruction procedures, with the device used to restore small bowel continuity after isolation of an ileal segment. All devices passed without obstruction or pain. No patients have had any complications related to their anastomosis, including anastomotic leaks, bleeding, or stricture at median follow-up of 13 months.
CONCLUSIONS - In this initial case series from the first-in-human trial of the Magnamosis device, the device was successfully placed and effectively formed a side to side, functional end to end small bowel anastomosis in all 5 patients. No patients have had any anastomotic complications at intermediate follow-up.
Copyright © 2017 American College of Surgeons. Published by Elsevier Inc. All rights reserved.
Although intestinal homeostasis is maintained by intestinal stem cells (ISCs), regeneration is impaired upon aging. Here, we first uncover changes in intestinal architecture, cell number, and cell composition upon aging. Second, we identify a decline in the regenerative capacity of ISCs upon aging because of a decline in canonical Wnt signaling in ISCs. Changes in expression of Wnts are found in stem cells themselves and in their niche, including Paneth cells and mesenchyme. Third, reactivating canonical Wnt signaling enhances the function of both murine and human ISCs and, thus, ameliorates aging-associated phenotypes of ISCs in an organoid assay. Our data demonstrate a role for impaired Wnt signaling in physiological aging of ISCs and further identify potential therapeutic avenues to improve ISC regenerative potential upon aging.
Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
Mesenteric tumor deposits (MTDs) are not included in the American Joint Committee on Cancer (AJCC) staging system for midgut small intestinal neuroendocrine tumors (NETs). We examined the prognostic significance of MTDs associated with midgut NETs. Hematoxylin and eosin slides from 132 resected jejunal/ileal NETs were reviewed for AJCC tumor stage, lymph node (LN) metastasis, MTDs, and hepatic metastases. MTDs were defined as discrete irregular mesenteric tumor nodules discontinuous from the primary tumor. Clinical or pathologic evidence of metastases and survival data were abstracted from electronic medical records. The cohort included 72 male and 60 female patients with a median age of 60 years. LN metastasis, MTDs, and liver metastasis were present in 80%, 68%, and 58% of patients, respectively. Female sex and presence of MTDs were independent predictors of liver metastasis. The odds ratio for hepatic metastasis in the presence of MTDs was 16.68 (95% confidence interval [CI], 4.66-59.73) and 0.81 (95% CI, 0.20-3.26) for LN metastasis. Age, MTDs, and hepatic metastasis were associated with disease-specific survival (DSS) in univariate analysis. Primary tumor histologic grade, pT3/T4 stage, and LN metastasis were not associated with DSS. Multivariate analysis of liver metastasis-free survival stratified by tumor grade showed that MTDs were associated with adverse outcomes. The hazard ratio for MTDs was 4.58 (95% CI, 1.89-11.11), compared with 0.98 (95% CI, 0.47-2.05) for LN metastasis. MTDs, but not LN metastasis, in midgut NETs are a strong predictor for hepatic metastasis and are associated with poor DSS.
p40, a Lactobacillus rhamnosus GG (LGG)-derived protein, transactivates epidermal growth factor receptor (EGFR) in intestinal epithelial cells, leading to amelioration of intestinal injury and inflammation. To elucidate mechanisms by which p40 regulates mucosal immunity to prevent inflammation, this study aimed to determine the effects and mechanisms of p40 on regulation of a proliferation-inducing ligand (APRIL) expression in intestinal epithelial cells for promoting immunoglobulin A (IgA) production. p40 upregulated April gene expression and protein production in mouse small intestine epithelial (MSIE) cells, which were inhibited by blocking EGFR expression and kinase activity. Enteroids from Egfr, but not Egfr-Vil-Cre mice with EGFR specifically deleted in intestinal epithelial cells, exhibited increased April gene expression by p40 treatment. p40-conditioned media from MSIE cells increased B-cell class switching to IgA cells and IgA production, which was suppressed by APRIL receptor-neutralizing antibodies. Treatment of B cells with p40 did not show any effects on IgA production. p40 treatment increased April gene expression and protein production in small intestinal epithelial cells, fecal IgA levels, IgAB220, IgACD19, and IgA plasma cells in lamina propria of Egfr, but not of Egfr-Vil-Cre, mice. Thus p40 upregulates EGFR-dependent APRIL production in intestinal epithelial cells, which may contribute to promoting IgA production.