147,214 research outputs found
Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression.
Gastrointestinal stromal tumors (GIST) arise within the interstitial cell of Cajal (ICC) lineage due to activating KIT/PDGFRA mutations. Both ICC and GIST possess primary cilia (PC), which coordinate PDGFRA and Hedgehog signaling, regulators of gastrointestinal mesenchymal development. Therefore, we hypothesized that Hedgehog signaling may be altered in human GIST and controls KIT expression. Quantitative RT-PCR, microarrays, and next generation sequencing were used to describe Hedgehog/PC-related genes in purified human ICC and GIST. Genetic and pharmacologic approaches were employed to investigate the effects of GLI manipulation on KIT expression and GIST cell viability. We report that Hedgehog pathway and PC components are expressed in ICC and GIST and subject to dysregulation during GIST oncogenesis, irrespective of KIT/PDGFRA mutation status. Using genomic profiling, 10.2% of 186 GIST studied had potentially deleterious genomic alterations in 5 Hedgehog-related genes analyzed, including in the PTCH1 tumor suppressor (1.6%). Expression of the predominantly repressive GLI isoform, GLI3, was inversely correlated with KIT mRNA levels in GIST cells and non-KIT/non-PDGFRA mutant GIST. Overexpression of the 83-kDa repressive form of GLI3 or small interfering RNA-mediated knockdown of the activating isoforms GLI1/2 reduced KIT mRNA. Treatment with GLI1/2 inhibitors, including arsenic trioxide, significantly increased GLI3 binding to the KIT promoter, decreased KIT expression, and reduced viability in imatinib-sensitive and imatinib-resistant GIST cells. These data offer new evidence that genes necessary for Hedgehog signaling and PC function in ICC are dysregulated in GIST. Hedgehog signaling activates KIT expression irrespective of mutation status, offering a novel approach to treat imatinib-resistant GIST
Gastrointestinal stromal tumour as a rare association with neurofibromatosis type 1
Gastrointestinal stromal tumours (GIST) are rare tumours of mesenchymal origin. These can be associated with neurofibromatosis type 1 (NF1), which is an autosomal dominant disorder. The prevalence of GIST in NF1 is estimated at 3.9-25%. This paper describes the presentation of a GIST arising from the jejenum in a 75-year-old lady with NF1, who presented with gastrointestinal bleeding. This was diagnosed by CT angiography. She was managed with laparotomy, with resection of small bowel, and an ischaemic segment of large bowel with two primary anastomoses. Pathology showed GIST of spindle cell type (Figs 3 and 4), 90 mm in size, with complete local excision. The patient was discharged on the eighth post-operative day and is currently undergoing regular clinic follow-up after multidisciplinary team meeting discussion
Role for targeted resection in the multidisciplinary treatment of metastatic gastrointestinal stromal tumor
The management of advanced gastrointestinal stromal tumors (GISTs) has evolved in the modern era due to the discovery of c-kit mutations and the development of tyrosine kinase inhibitors (TKIs). Until the advent of TKIs such as imatinib, the median survival reported for patients with advanced GIST was 19 months. Although surgery is the treatment of choice for resectable primary GIST, its role in cases of recurrence and metastasis remains to be unclear. This review outlines the potential beneficial role of repeat surgical resection in the multidisciplinary treatment of advanced GIST in the era of TKIs
Six years survival on imatinib with no disease progression after diagnosis of metastatic duodenal gastrointestinal stromal tumour: a case report
Introduction: A duodenal Gastrointestinal Stromal Tumour (GIST) is a rare finding and until recently advanced disease had a poor prognosis. A PubMed search revealed no reports of more than five years survival of inoperable GIST on chemotherapy with WHO performance status zero.
Case Presentation: A 68 year old female was diagnosed with unresectable GIST in the duodenum with metastasis to liver, pancreas and omentum in November 2001. She was
commenced on imatinib mesylate (Glivec) chemotherapy. This case report was prepared from the medical records and radiology reports. She had good tolerance with stable disease. After six years her CT scan showed no disease progression and her WHO performance status was zero.
Conclusion: This report supports the view that imatinib is a safe and effective drug in controlling
disease progression in advanced metastatic GIST and plays an important role in improving the patient's quality of life
Gastrointestinal Stromal Tumor (GIST) in Long Standing Crohn’s disease on Anti-TNF Therapy
Introduction
Patients suffering from inflammatory bowel disease (IBD) are at increased risk for developing cancer. Adenocarcinomas are the most commonly observed tumors of the gastrointestinal tract whereas data on gastrointestinal stromal tumor (GIST) in IBD patients is limited. GIST is a neoplasm that originates from the interstitial cells of Cajal in the smooth muscle layers of the gastrointestinal tract. [1] The association between GIST and Crohn’s disease (CD) is debated, as the tumor inconsistently present in areas of inflammatory activity. We report an interesting case of CD maintained on Infliximab, who presented with a flare that revealed GIST in the stomach. To our knowledge, this is the first reported occurrence of GIST in stomach in a patient with CD maintained on anti-TNF therapy.
Case Report
A 40-year-old Caucasian man with a history of small bowel Crohn’s disease on infliximab therapy presented with a two-day history of abdominal pain, hematochezia, and diffuse joint pain. Upon admission, the patient was hemodynamically stable and afebrile, with a blood pressure of 140/70 mmHg, heart rate of 90 beats per minute, and respiratory rate of 14 per minute. Physical exam was remarkable for abdominal distension and diffuse abdominal tenderness. Complete blood count, comprehensive metabolic panel, and C-reactive protein were within normal range. The patient reported no history of alcohol abuse, smoking, recent abdominal procedures, or trauma. The patient had computed tomography (CT) of the abdomen done that revealed a 2.5-centimeter exophytic mass in the stomach with possible liver metastases (Fig. 1). Endoscopic ultrasound (EUS) guided biopsies of the exophytic mass confirmed gastrointestinal stromal tumor (GIST) on fine needle aspiration and flow cytometry results (Fig. 2,3). The patient underwent surgical resection without complication and is back to his usual state of health.
Discussion
GIST is the most common mesenchymal neoplasm in the gastrointestinal tract [1,2]. The annual incidence of GIST has been reported as 11-19.6 per million [3,4], however a more recent analysis in 2015 estimates the annual incidence to be 6.8 per million with a 53% predominance in males and 73% predominance in Caucasians [5]. Individuals are typically diagnosed with GIST in their seventh decade of life [5].
Immunologically, it is reported that 70-80% of GIST have a mutation in the KIT gene, leading to a continuously active KIT receptor, independent of its activating ligand [1]. KIT activation leads to overexpression of the protein CD117. In KIT-negative GIST, a small number are observed to have a mutation in platelet-derived growth factor receptor-a (PDGFRA). Dysregulated activation of either of these genes results in uncontrolled cell growth and survival. It is estimated that 10-15% of GIST do not have mutations in either KIT or PDGRFA, and while they are considered wild-type, they are shown to express high levels of KIT [1]. More recently, Novelli et al. found that the presence of proteins CD117 and DOG1 had the highest sensitivity and specificity for GIST [6].
The majority of GIST develop in the stomach (60%), with the jejunum and ileum representing the next most common site of involvement (30%) [7]. Several prognostic factors have been researched, most notably tumor location and mitotic index. Emory et al. found that GIST originating from the esophagus had the highest survival rate, followed by those that arose from the stomach, small bowel, colon/rectum, and omentum/mesentery in decreasing order [8]. Additionally, mitotic index, defined as the number of mitotic figures per high-power field (HPF), is reported an independent prognostic factor, with greater than 10 mitotic figures per 50 HPF showing the largest difference in survival in gastric GIST [8]. Small bowel GIST exhibited minimally different survival curves with respect to mitotic index. Age was also found to be an independent prognostic factor of survival in GIST [8].
Later research by Miettinen demonstrated that larger gastric GIST with a diameter of 10cm and 5 mitotic figures per 50 HPF carried a lower metastatic risk in comparison to gastric GIST with diameter of \u3e 5cm but with \u3e 5 mitotic figures per 50 HPF [9]. This may suggest that in gastric GIST, mitotic index carries the most prognostic value. Miettinen found that in intestinal GIST, a diameter of \u3e 5cm and \u3e 5 mitotic figures per HPF each independently carried a moderate or high risk of metastasis, respectively. Intestinal GIST carried a 39% tumor-related mortality rate, compared to 17% for gastric GIST [10,11].
Currently, surgery is the primary treatment modality for nonmetastatic GIST that is technically amenable to resection. Imatinib, a tyrosine kinase inhibitor (TKI), may be used as neoadjuvant therapy or as initial therapy for nonresectable disease [12]. Imatinib directly binds to the KIT protein and prevents further signaling [1]. This medication first demonstrated favorable treatment effects in 2002, with over 50% of the 147 patients showing at least a partial response to therapy [13]. Some patients develop resistance to Imatinib, prompting the development of alternative TKI therapy. Currently, Sunitinib is FDA approved for Imatinib-resistant GIST [14], with a host of other TKI’s and alternative therapies under investigation [1].
In 2012, Körner examined glucagon-like peptide-2 receptor (GLP-2) expression in a variety of neoplasm and found that 68% of the GISTs expressed this receptor in the intestinal myenteric plexus [15]. Additionally, this receptor was expressed in high density in patients with Crohn’s disease. Interestingly, this expression was absent in active or inactive ulcerative colitis as well as Hirschsprung’s disease [15].
Table 1: GIST with concurrent IBD.
Author (ref)
Age, Sex
IBD
Symptoms
Location of GIST
Imaging or operative findings
Pfeffela, 1999 [16]
51, M
CD
Weight loss, Abdominal pain, Fever, Fatigue
Ileum
Large tumorous lesions in the right lower abdomen (terminal ileum) measuring 8 Ă— 5 Ă— 6 cm
Grieco, 2002 [17]
57, F
UC
Melena, progressive anemia
Ileum
Solid mass in the left pelvic cavity with a diameter of 7 cm
Mijandrusić Sincić, 2005 [18]
81, M
CD
Ileus
Meckel’s diverticulum
Dilated loops of intestine with large packets of gas and anti-peristalsis
Kaiser, 2006 [19]
64, M
UC
Severe bleeding, abdominal distension
Omentum
8 cm mass attached to greater omentum
Ruffolo, 2010 [20]
59, M
UC
Rectal bleeding
Rectum
0.5 cm GIST located 20 cm from anal adenocarcinoma
Theodoropoulos, 2009 [21]
45, M
CD
Abdominal pain, vomiting, constipation, bloating
Jejunum and Ileum
6 mm GIST within jejunoileal intussusception
Bocker U, 2008
[22]
26, F
CD
Abdominal cramping, gastrointestinal bleeding
Duodenum
Ulcerated lesion noted 140 cm past proximal duodenum on enteroscopy
Gianluca, 2016 [7]
38, M
CD
Asymptomatic
Small bowel
A mass found along the small bowel
Gianluca, 2016 [7]
53, M
UC
Abrupt postoperative bleeding
Stomach
No evidences of masses at surgery. Gastric bleeding at endoscopy
Present paper
40, M
CD
Abdominal pain, hematochezia
Stomach
2.5 cm exophytic mass in the stomach with possible liver metastases
CONCLUSION
Our case of Crohn’s disease diagnosed with gastric GIST sheds light on a rare link between two separate disease entities native to the gastrointestinal system. While there exists a well-known association between inflammatory bowel disease and colon cancer, other malignancies are described much less frequently in the literature. The development of gastric GIST with underlying Crohn’s disease is a rare occurrence, but is one that should be kept in mind when evaluating patients with inflammatory bowel disease found to have new masses on imaging.
References:
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ARTSCENE: A Neural System for Natural Scene Classification
How do humans rapidly recognize a scene? How can neural models capture this biological competence to achieve state-of-the-art scene classification? The ARTSCENE neural system classifies natural scene photographs by using multiple spatial scales to efficiently accumulate evidence for gist and texture. ARTSCENE embodies a coarse-to-fine Texture Size Ranking Principle whereby spatial attention processes multiple scales of scenic information, ranging from global gist to local properties of textures. The model can incrementally learn and predict scene identity by gist information alone and can improve performance through selective attention to scenic textures of progressively smaller size. ARTSCENE discriminates 4 landscape scene categories (coast, forest, mountain and countryside) with up to 91.58% correct on a test set, outperforms alternative models in the literature which use biologically implausible computations, and outperforms component systems that use either gist or texture information alone. Model simulations also show that adjacent textures form higher-order features that are also informative for scene recognition.National Science Foundation (NSF SBE-0354378); Office of Naval Research (N00014-01-1-0624
Generation of orthotopic patient-derived xenografts from gastrointestinal stromal tumor.
BackgroundGastrointestinal stromal tumor (GIST) is the most common sarcoma and its treatment with imatinib has served as the paradigm for developing targeted anti-cancer therapies. Despite this success, imatinib-resistance has emerged as a major problem and therefore, the clinical efficacy of other drugs has been investigated. Unfortunately, most clinical trials have failed to identify efficacious drugs despite promising in vitro data and pathological responses in subcutaneous xenografts. We hypothesized that it was feasible to develop orthotopic patient-derived xenografts (PDXs) from resected GIST that could recapitulate the genetic heterogeneity and biology of the human disease.MethodsFresh tumor tissue from three patients with pathologically confirmed GISTs was obtained immediately following tumor resection. Tumor fragments (4.2-mm3) were surgically xenografted into the liver, gastric wall, renal capsule, and pancreas of immunodeficient mice. Tumor growth was serially assessed with ultrasonography (US) every 3-4 weeks. Tumors were also evaluated with positron emission tomography (PET). Animals were sacrificed when they became moribund or their tumors reached a threshold size of 2500-mm3. Tumors were subsequently passaged, as well as immunohistochemically and histologically analyzed.ResultsHerein, we describe the first model for generating orthotopic GIST PDXs. We have successfully xenografted three unique KIT-mutated tumors into a total of 25 mice with an overall success rate of 84% (21/25). We serially followed tumor growth with US to describe the natural history of PDX growth. Successful PDXs resulted in 12 primary xenografts in NOD-scid gamma or NOD-scid mice while subsequent successful passages resulted in 9 tumors. At a median of 7.9 weeks (range 2.9-33.1 weeks), tumor size averaged 473 ± 695-mm³ (median 199-mm3, range 12.6-2682.5-mm³) by US. Furthermore, tumor size on US within 14 days of death correlated with gross tumor size on necropsy. We also demonstrated that these tumors are FDG-avid on PET imaging, while immunohistochemically and histologically the PDXs resembled the primary tumors.ConclusionsWe report the first orthotopic model of human GIST using patient-derived tumor tissue. This novel, reproducible in vivo model of human GIST may enhance the study of GIST biology, biomarkers, personalized cancer treatments, and provide a preclinical platform to evaluate new therapeutic agents for GIST
Knowledge-rich Image Gist Understanding Beyond Literal Meaning
We investigate the problem of understanding the message (gist) conveyed by
images and their captions as found, for instance, on websites or news articles.
To this end, we propose a methodology to capture the meaning of image-caption
pairs on the basis of large amounts of machine-readable knowledge that has
previously been shown to be highly effective for text understanding. Our method
identifies the connotation of objects beyond their denotation: where most
approaches to image understanding focus on the denotation of objects, i.e.,
their literal meaning, our work addresses the identification of connotations,
i.e., iconic meanings of objects, to understand the message of images. We view
image understanding as the task of representing an image-caption pair on the
basis of a wide-coverage vocabulary of concepts such as the one provided by
Wikipedia, and cast gist detection as a concept-ranking problem with
image-caption pairs as queries. To enable a thorough investigation of the
problem of gist understanding, we produce a gold standard of over 300
image-caption pairs and over 8,000 gist annotations covering a wide variety of
topics at different levels of abstraction. We use this dataset to
experimentally benchmark the contribution of signals from heterogeneous
sources, namely image and text. The best result with a Mean Average Precision
(MAP) of 0.69 indicate that by combining both dimensions we are able to better
understand the meaning of our image-caption pairs than when using language or
vision information alone. We test the robustness of our gist detection approach
when receiving automatically generated input, i.e., using automatically
generated image tags or generated captions, and prove the feasibility of an
end-to-end automated process
Verbatim and Gist Extraction Among University Colleges
Fuzzy Trace Theory (FTT) posits that individuals use two different cognitive processes in encoding, storing, and retrieving information. One process (verbatim) encodes the details of the information, applying cost/benefit analysis when used for a decision. The other process (gist) encodes relational information extracted from the information and uses more intuition when applied to decisions. Often, use of one process over another can lead to different decisions. Further, there exists individual differences in the skill and preference for using these processes.
The current study examined whether differences in verbatim, and gist skill or preference would vary by university college (STEM, or Liberal and Applied Arts). FTT states differences in verbatim or gist affect performance on learning tasks. Given the preponderance of verbatim type requirements in the STEM fields versus other majors, it was hypothesized that STEM majors would have higher preference and performance in verbatim processing
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