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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.
Blood vessel epicardial substance (BVES) is a tight-junction associated protein that was originally discovered from a cDNA screen of the developing heart. Research over the last decade has shown that not only is BVES is expressed in cardiac and skeletal tissue, but BVES is also is expressed throughout the gastrointestinal epithelium. Mice lacking BVES sustain worse intestinal injury and inflammation. Furthermore, BVES is suppressed in gastrointestinal cancers, and mouse modeling has shown that loss of BVES promotes tumor formation. Recent work from multiple laboratories has revealed that BVES can regulate several molecular pathways, including cAMP, WNT, and promoting the degradation of the oncogene, c-Myc. This review will summarize our current understanding of how BVES regulates the intestinal epithelium and discuss how BVES functions at the molecular level to preserve epithelial phenotypes and suppress tumorigenesis.
BACKGROUND & AIMS - Previous studies reported an association of the bacteria Helicobacter pylori, the primary cause of gastric cancer, and risk of colorectal cancer (CRC). However, these findings have been inconsistent, appear to vary with population characteristics, and may be specific for virulence factor VacA. To more thoroughly evaluate the potential association of H pylori antibodies with CRC risk, we assembled a large consortium of cohorts representing diverse populations in the United States.
METHODS - We used H pylori multiplex serologic assays to analyze serum samples from 4063 incident cases of CRC, collected before diagnosis, and 4063 matched individuals without CRC (controls) from 10 prospective cohorts for antibody responses to 13 H pylori proteins, including virulence factors VacA and CagA. The association of seropositivity to H pylori proteins, as well as protein-specific antibody level, with odds of CRC was determined by conditional logistic regression.
RESULTS - Overall, 40% of controls and 41% of cases were H pylori-seropositive (odds ratio [OR], 1.09; 95% CI, 0.99-1.20). H pylori VacA-specific seropositivity was associated with an 11% increased odds of CRC (OR, 1.11; 95% CI, 1.01-1.22), and this association was particularly strong among African Americans (OR, 1.45; 95% CI, 1.08-1.95). Additionally, odds of CRC increased with level of VacA antibody in the overall cohort (P = .008) and specifically among African Americans (P = .007).
CONCLUSIONS - In an analysis of a large consortium of cohorts representing diverse populations, we found serologic responses to H pylori VacA to associate with increased risk of CRC risk, particularly for African Americans. Future studies should seek to understand whether this marker is related to virulent H pylori strains carried in these populations.
Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.
Triple negative breast cancer (TNBC) is the deadliest form of breast cancer because it is more aggressive, diagnosed at later stage and more likely to develop local and systemic recurrence. Many patients do not experience adequate tumor control after current clinical treatments involving surgical removal, chemotherapy and/or radiotherapy, leading to disease progression and significantly decreased quality of life. Here we report a new combinatory therapy strategy involving cannabinoid-based medicine and photodynamic therapy (PDT) for the treatment of TNBC. This combinatory therapy targets two proteins upregulated in TNBC: the cannabinoid CB2 receptor (CBR, a G-protein coupled receptor) and translocator protein (TSPO, a mitochondria membrane receptor). We found that the combined CBR agonist and TSPO-PDT treatment resulted in synergistic inhibition in TNBC cell and tumor growth. This combinatory therapy approach provides new opportunities to treat TNBC with high efficacy. In addition, this study provides new evidence on the therapeutic potential of CBR agonists for cancer.
Copyright © 2018 Elsevier B.V. All rights reserved.
Solute carrier family 7 member 2 (SLC7A2, also known as CAT2) is an inducible transporter of the semi-essential amino acid L-arginine (L-Arg), which has been implicated in wound repair. We have reported that both SLC7A2 expression and L-Arg availability are decreased in colonic tissues from inflammatory bowel disease patients and that mice lacking Slc7a2 exhibit a more severe disease course when exposed to dextran sulfate sodium (DSS) compared to wild-type (WT) mice. Here, we present evidence that SLC7A2 plays a role in modulating colon tumorigenesis in the azoxymethane (AOM)-DSS model of colitis-associated carcinogenesis (CAC). SLC7A2 was localized predominantly to colonic epithelial cells in WT mice. Utilizing the AOM-DSS model, Slc7a2 mice had significantly increased tumor number, burden, and risk of high-grade dysplasia vs. WT mice. Tumors from Slc7a2 mice exhibited significantly increased levels of the proinflammatory cytokines/chemokines IL-1β, CXCL1, CXCL5, IL-3, CXCL2, CCL3, and CCL4, but decreased levels of IL-4, CXCL9, and CXCL10 compared to tumors from WT mice. This was accompanied by a shift toward pro-tumorigenic M2 macrophage activation in Slc7a2-deficient mice, as marked by increased colonic CD11bF4/80ARG1 cells with no alteration in CD11bF4/80NOS2 cells by flow cytometry and immunofluorescence microscopy. The shift toward M2 macrophage activation was confirmed in bone marrow-derived macrophages from Slc7a2 mice. In bone marrow chimeras between Slc7a2 and WT mice, the recipient genotype drove the CAC phenotype, suggesting the importance of epithelial SLC7A2 in abrogating neoplastic risk. These data reveal that SLC7A2 has a significant role in the protection from CAC in the setting of chronic colitis, and suggest that the decreased SLC7A2 in inflammatory bowel disease (IBD) may contribute to CAC risk. Strategies to enhance L-Arg availability by supplementing L-Arg and/or increasing L-Arg uptake could represent a therapeutic approach in IBD to reduce the substantial long-term risk of colorectal carcinoma.
Immune checkpoint inhibitors are a new class of anticancer therapies that amplify T-cell-mediated immune responses against cancer cells. Immune checkpoint inhibitors have shown important benefits in phase 3 trials, and several agents have been approved for specific malignancies. Although adverse events from immune checkpoint inhibitors are a common occurrence, cardiotoxic effects are uncommon, but are often serious complications with a relatively high mortality. Most cardiotoxic effects appear to be inflammatory in nature. Clinical assessment of a combination of biomarkers, electrocardiography, cardiac imaging, and endomyocardial biopsy can be used to confirm a possible diagnosis. In this Review, we discuss the epidemiology of immune checkpoint inhibitor-mediated cardiotoxic effects, as well as their clinical presentation, subtypes, risk factors, pathophysiology, and clinical management, including the introduction of a new surveillance strategy.
Copyright © 2018 Elsevier Ltd. All rights reserved.
Esophageal adenocarcinoma (EAC) is a highly aggressive malignancy that is characterized by resistance to chemotherapy and a poor clinical outcome. The overexpression of the receptor tyrosine kinase AXL is frequently associated with unfavorable prognosis in EAC. Although it is well documented that AXL mediates cancer cell invasion as a downstream effector of epithelial-to-mesenchymal transition, the precise molecular mechanism underlying this process is not completely understood. Herein, we demonstrate for the first time that AXL mediates cell invasion through the regulation of lysosomes peripheral distribution and cathepsin B secretion in EAC cell lines. Furthermore, we show that AXL-dependent peripheral distribution of lysosomes and cell invasion are mediated by extracellular acidification, which is potentiated by AXL-induced secretion of lactate through AKT-NF-κB-dependent MCT-1 regulation. Our novel mechanistic findings support future clinical studies to evaluate the therapeutic potential of the AXL inhibitor R428 (BGB324) in highly invasive EAC.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
Within the course of a single minute, millions of cells in the human body will undergo programmed cell death in response to physiological or pathological cues. The diminished energetic capacity of an apoptotic cell renders the cell incapable of sustaining plasma membrane integrity. Under these circumstances, intracellular contents that might leak into the surrounding tissue microenvironment, a process referred to as secondary necrosis, could induce inflammation and tissue damage. Remarkably, in most cases of physiologically rendered apoptotic cell death, inflammation is avoided because a mechanism to swiftly remove apoptotic cells from the tissue prior to their secondary necrosis becomes activated. This mechanism, referred to as efferocytosis, uses phagocytes to precisely identify and engulf neighboring apoptotic cells. In doing so, efferocytosis mantains tissue homeostasis that would otherwise be disrupted by normal cellular turnover and exacerbated further when the burden of apoptotic cells becomes elevated due to disease or insult. Efferocytosis also supports the resolution of inflammation, restoring tissue homesostasis. The importance of efferocytosis in health and disease underlies the increasing research efforts to understand the mechanisms by which efferocytosis occurs, and how a failure in the efferocytic machinery contributes to diseases, or conversely, how cancers effectively use the existing efferocytic machinery to generate a tumor-tolerant, immunosuppressive tumor microenvironment. We discuss herein the molecular mechanisms of efferocytosis, how the process of efferocytosis might support a tumor 'wound healing' phenotype, and efforts to target efferocytosis as an adjunct to existing tumor treatments.
AIMS - Colorectal carcinoma (CRC) often has a mucinous component, with more than 50% mucin by volume defining the mucinous subtype of CRC. The prognostic impact of the mucinous phenotype remains unclear.
METHODS AND RESULTS - We evaluated 224 CRC with at least 5% mucinous component (herein 'mCRC') for patient sex, age, race and outcome; tumour size, location, stage and microsatellite instability (MSI) status; percentage of glands producing mucin; percentage of tumour volume composed of mucin; whether tumoral epithelium floated in mucin pools; tumour budding; signet ring cells (SRCs); and peritumoural inflammation (PI). We related these features to disease-specific survival and compared outcomes to 499 stage-matched, conventional colorectal adenocarcinomas. Factors predicting worse prognosis in mCRC on univariable analysis included non-MSI-high status (P = 0.0008), SRC (P = 0.0017) and lack of PI (P = 0.0034). No parameters were independently associated with outcome after adjusting for tumour stage in multivariate analysis. The percentage of glands producing mucin and percentage tumour volume composed of mucin did not affect prognosis, including at the recommended 50% cut-off for subtyping mCRC. Disease-specific survival for mCRC and adenocarcinomas were similar after accounting for stage.
CONCLUSIONS - Stage-matched mCRCs and adenocarcinomas have similar outcomes, with no prognostic significance to morphological subtyping. Histological characteristics of mCRC, including percentage of tumour volume comprised of mucin, were not predictive of outcome.
© 2018 John Wiley & Sons Ltd.
BACKGROUND - Wilms tumor (WT) is the most common childhood kidney cancer worldwide, yet its incidence and clinical behavior vary according to race and access to adequate healthcare resources. To guide and streamline therapy in the war-torn and resource-constrained city of Baghdad, Iraq, we conducted a first-ever molecular analysis of 20 WT specimens to characterize the biological features of this lethal disease within this challenged population.
METHODS - Next-generation sequencing of ten target genes associated with WT development and treatment resistance (WT1, CTNNB1, WTX, IGF2, CITED1, SIX2, p53, N-MYC, CRABP2, and TOP2A) was completed. Immunohistochemistry was performed for 6 marker proteins of WT (WT1, CTNNB1, NCAM, CITED1, SIX2, and p53). Patient outcomes were compiled.
RESULTS - Mutations were detected in previously described WT "hot spots" (e.g., WT1 and CTNNB1) as well as novel loci that may be unique to the Iraqi population. Immunohistochemistry showed expression domains most typical of blastemal-predominant WT. Remarkably, despite the challenges facing families and care providers, only one child, with combined WT1 and CTNNB1 mutations, was confirmed dead from disease. Median clinical follow-up was 40.5 months (range 6-78 months).
CONCLUSIONS - These data suggest that WT biology within a population of Iraqi children manifests features both similar to and unique from disease variants in other regions of the world. These observations will help to risk stratify WT patients living in this difficult environment to more or less intensive therapies and to focus treatment on cell-specific targets.