Science.gov

Sample records for gastrointestinal stromal tumors

  1. Genetics Home Reference: gastrointestinal stromal tumor

    MedlinePlus

    ... cells in the gastrointestinal tract and patches of dark skin on various areas of the body. Some ... Cancer Society: Treating Gastrointestinal Stromal Tumor (GIST) Cancer.Net: Gastrointestinal Stromal Tumor--Diagnosis Genetic Testing Registry: Gastrointestinal ...

  2. Gastrointestinal Stromal Tumors: A Case Report

    PubMed Central

    Sashidharan, Palankezhe; Matele, Apoorva; Matele, Usha; Al Felahi, Nowfel; Kassem, Khalid F.

    2014-01-01

    Advances in the identification of gastrointestinal stromal tumors, its molecular and immunohiostochemical basis, and its management have been a watershed in the treatment of gastrointestinal tumors. This paradigm shift occurred over the last two decades and gastrointestinal stromal tumors have now come to be understood as rare gastrointestinal tract tumors with predictable behavior and outcome, replacing the older terminologies like leiomyoma, schwannoma or leiomyosarcoma. This report presents a case of gastric gastrointestinal stromal tumor operated recently in a 47-year-old female patient and the outcome, as well as literature review of the pathological identification, sites of origin, and factors predicting its behavior, prognosis and treatment. PMID:24715944

  3. What Are the Key Statistics about Gastrointestinal Stromal Tumors?

    MedlinePlus

    ... for gastrointestinal stromal tumors? What are the key statistics about gastrointestinal stromal tumors? Gastrointestinal stromal tumors (GISTs) ... They are slightly more common in men. Survival statistics for GIST are discussed in “ Survival rates for ...

  4. What's New in Gastrointestinal Stromal Tumor Research and Treatment?

    MedlinePlus

    ... Topic Additional resources for gastrointestinal stromal tumor What’s new in gastrointestinal stromal tumor research and treatment? There ... GIST) Talking With Your Doctor After Treatment What`s New in Gastrointestinal Stromal Tumor (GIST) Research? Other Resources ...

  5. Gastrointestinal stromal tumor (gist) of the duodenum.

    PubMed

    Ghazanfar, Shahriyar; Sial, Khadim S; Quraishy, M S

    2007-06-01

    This is a report of a rare gastrointestinal stromal tumor of the duodenum in a 75 years old man who presented with recurrent episodes of intestinal obstruction and melena. The patient underwent successful Whipple's procedure. PMID:17623589

  6. Multicentric malignant gastrointestinal stromal tumor.

    PubMed

    Shukla, Shailaja; Singh, Sanjeet K; Pujani, Mukta

    2009-01-01

    Malignant gastrointestinal stromal tumor (GIST) is a rare type of sarcoma that is found in the digestive system, most often in the wall of the stomach. Multiple GISTs are extremely rare and usually associated with type 1 neurofibromatosis and familial GIST.We report here a case of a 70-year-old woman who reported pain in the abdomen, loss of appetite, and weight loss for six months. Ultrasound examination showed a small bowel mass along with multiple peritoneal deposits and a mass within the liver. Barium studies were suggestive of a neoplastic pathology of the distal ileum. A differential diagnosis of adenocarcinoma/lymphoma with metastases was entertained. Perioperative findings showed two large growths arising from the jejunum and the distal ileum, along with multiple smaller nodules on the serosal surface and adjoining mesentery of the involved bowel segments. Segmental resection of the involved portions of the intestine was performed. Histopathological features were consistent with those of multicentric malignant GIST-not otherwise specified (GIST-NOS). Follow-up examination three months after surgery showed no evidence of recurrence. PMID:19568556

  7. Surgical Treatment of Gastric Gastrointestinal Stromal Tumor

    PubMed Central

    Kong, Seong-Ho

    2013-01-01

    Gastrointestinal stromal tumor is the most common mesenchymal tumor in the gastrointestinal tract and is most frequently developed in the stomach in the form of submucosal tumor. The incidence of gastric gastrointestinal stromal tumor is estimated to be as high as 25% of the population when all small and asymptomatic tumors are included. Because gastric gastrointestinal stromal tumor is not completely distinguished from other submucosal tumors, a surgical excisional biopsy is recommended for tumors >2 cm. The surgical principles of gastrointestinal stromal tumor are composed of an R0 resection with a normal mucosa margin, no systemic lymph node dissection, and avoidance of perforation, which results in peritoneal seeding even in cases with otherwise low risk profiles. Laparoscopic surgery has been indicated for gastrointestinal stromal tumors <5 cm, and the indication for laparoscopic surgery is expanded to larger tumors if the above mentioned surgical principles can be maintained. A simple exogastric resection and various transgastric resection techniques are used for gastrointestinal stromal tumors in favorable locations (the fundus, body, greater curvature side). For a lesion at the gastroesophageal junction in the posterior wall of the stomach, enucleation techniques have been tried preserve the organ's function. Those methods have a theoretical risk of seeding a ruptured tumor, but this risk has not been evaluated by well-designed clinical trials. While some clinical trials are still on-going, neoadjuvant imatinib is suggested when marginally unresectable or multiorgan resection is anticipated to reduce the extent of surgery and the chance of incomplete resection, rupture or bleeding. PMID:23610714

  8. What Should You Ask Your Doctor about Gastrointestinal Stromal Tumors?

    MedlinePlus

    ... gastrointestinal stromal tumors? What should you ask your doctor about gastrointestinal stromal tumors? As you cope with ... we encourage you to talk openly with your doctor, nurse, and cancer care team. You should feel ...

  9. What Are the Risk Factors for Gastrointestinal Stromal Tumors?

    MedlinePlus

    ... what causes gastrointestinal stromal tumors? What are the risk factors for gastrointestinal stromal tumors? A risk factor is ... disease like cancer. Different cancers have different risk factors. Some risk factors, like smoking, can be changed. Others, like ...

  10. Gastrointestinal Stromal Tumor: May Mimic Adnexal Mass

    PubMed Central

    Karaca, Nilay; Akpak, Yaşam Kemal; Tatar, Zeynep; Batmaz, Gonca; Erken, Aslihan

    2016-01-01

    Gastrointestinal stromal tumors (GISTs) are rare tumor of the gastrointestinal tract. GISTs occur in the entire gastrointestinal tract and may also arise from the retroperitoneum, omentum and mesenteries. They are originated from gastrointestinal pacemaker cells (Cajal’s interstitial cells) and range from benign tumors to sarcomas at all sites of occurrence. Diagnosis of GIST could be deceptive because of their similarity in appearance to gynecological neoplasms. We would like to present a case of a woman with GIST in the small intestine giving a imprint of an adnexal mass was diagnosed correctly during surgery. The diagnosis and treatment of GIST has been reformed over the past years. It is crucial to separate GISTs from possible misdiagnosis because their prognosis and treatment could be unlike clearly. The purpose of this case is to evaluate this rarely seen clinical entity, and thus, make some contribution to the literature. PMID:26383211

  11. Gastrointestinal Stromal Tumor: May Mimic Adnexal Mass.

    PubMed

    Karaca, Nilay; Akpak, Yasam Kemal; Tatar, Zeynep; Batmaz, Gonca; Erken, Aslihan

    2016-02-01

    Gastrointestinal stromal tumors (GISTs) are rare tumor of the gastrointestinal tract. GISTs occur in the entire gastrointestinal tract and may also arise from the retroperitoneum, omentum and mesenteries. They are originated from gastrointestinal pacemaker cells (Cajal's interstitial cells) and range from benign tumors to sarcomas at all sites of occurrence. Diagnosis of GIST could be deceptive because of their similarity in appearance to gynecological neoplasms. We would like to present a case of a woman with GIST in the small intestine giving a imprint of an adnexal mass was diagnosed correctly during surgery. The diagnosis and treatment of GIST has been reformed over the past years. It is crucial to separate GISTs from possible misdiagnosis because their prognosis and treatment could be unlike clearly. The purpose of this case is to evaluate this rarely seen clinical entity, and thus, make some contribution to the literature. PMID:26383211

  12. What Are Gastrointestinal Stromal Tumors?

    MedlinePlus

    ... the digestive system. The gastrointestinal system The gastrointestinal (GI) system (or digestive system) processes food for energy ... bloodstream. This is the longest section of the GI tract, measuring more than 20 feet. The small ...

  13. Gastrointestinal stromal tumor of the rectum.

    PubMed

    Hama, Y; Okizuka, H; Odajima, K; Hayakawa, M; Kusano, S

    2001-01-01

    Gastrointestinal stromal tumors (GISTs) are characterized by remarkable variability in their differentiation potential, but most of these lesions do not display convincing smooth muscle or neuronal differentiation. The GISTs arising from the rectum or anal canal are extremely uncommon. We present a case of immunohistochemically proven GIST of the rectum, which was characterized by homogenous isointensity mass without necrosis or hemorrhage on T2-weighted image and by enhancement on gadolinium-enhanced study. PMID:11218017

  14. Gastrointestinal Stromal Tumor – An Evolving Concept

    PubMed Central

    Tornillo, Luigi

    2014-01-01

    Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal tumors of the gastrointestinal tract. The discovery that these tumors, formerly thought of smooth muscle origin, are indeed better characterized by specific activating mutation in genes coding for the receptor tyrosine kinases (RTKs) CKIT and PDGFRA and that these mutations are strongly predictive for the response to targeted therapy with RTK inhibitors has made GISTs the typical example of the integration of basic molecular knowledge in the daily clinical activity. The information on the mutational status of these tumors is essential to predict (and subsequently to plan) the therapy. As resistant cases are frequently wild type, other possible oncogenic events, defining other “entities,” have been discovered (e.g., succinil dehydrogenase mutation/dysregulation, insuline growth factor expression, and mutations in the RAS-RAF-MAPK pathway). The classification of disease must nowadays rely on the integration of the clinico-morphological characteristics with the molecular data. PMID:25593916

  15. Combined Therapy of Gastrointestinal Stromal Tumors.

    PubMed

    Rutkowski, Piotr; Hompes, Daphne

    2016-10-01

    Radical surgery is the mainstay of therapy for primary resectable, localized gastrointestinal stromal tumors (GIST). Nevertheless, approximately 40% to 50% of patients with potentially curative resections develop recurrent or metastatic disease. The introduction of imatinib mesylate has revolutionized the therapy of advanced (inoperable and/or metastatic) GIST and has become the standard of care in treatment of patients with advanced GIST. This article discusses the proper selection of candidates for adjuvant and neoadjuvant treatment in locally advanced GIST, exploring the available evidence behind the combination of preoperative imatinib and surgery. PMID:27591496

  16. [Soft tissue sarcomas and gastrointestinal stromal tumors].

    PubMed

    Reichardt, P

    2016-03-01

    Soft tissue sarcomas are rare tumors that represent a major challenge due to varying clinical presentations and often interdisciplinary treatment concepts. Gold standard for the treatment of localized resectable soft tissue sarcomas is complete surgical removal. In metastatic soft tissue sarcoma, systemic therapy is the treatment of choice. The most active drugs are anthracyclines and ifosfamide. Combination chemotherapy has improved both response rate and progression-free survival at the cost of increased toxicity. Imatinib at a dose of 400 mg/day is the gold standard for patients with advanced or metastatic gastrointestinal stromal tumors (GIST). In patients with a mutation in KIT exon 9, 800 mg/day is the recommended dose. In imatinib refractory or intolerant patients, sunitinib is recommended. Regorafenib has been approved for third-line therapy. PMID:26907871

  17. Targeting Disease Persistence in Gastrointestinal Stromal Tumors

    PubMed Central

    Zörnig, Martin; Hayashi, Yujiro

    2015-01-01

    Summary Gastrointestinal stromal tumors (GISTs) represent 20%–40% of human sarcomas. Although approximately half of GISTs are cured by surgery, prognosis of advanced disease used to be poor due to the high resistance of these tumors to conventional chemo- and radiotherapy. The introduction of molecularly targeted therapy (e.g., with imatinib mesylate) following the discovery of the role of oncogenic mutations in the receptor tyrosine kinases KIT and platelet-derived growth factor α (PDGFRA) significantly increased patient survival. However, GIST cells persist in 95%–97% of imatinib-treated patients who eventually progress and die of the disease because of the emergence of clones with drug-resistant mutations. Because these secondary mutations are highly heterogeneous, even second- and third-line drugs that are effective against certain genotypes have only moderately increased progression-free survival. Consequently, alternative strategies such as targeting molecular mechanisms underlying disease persistence should be considered. We reviewed recently discovered cell-autonomous and microenvironmental mechanisms that could promote the survival of GIST cells in the presence of tyrosine kinase inhibitor therapy. We particularly focused on the potential role of adult precursors for interstitial cells of Cajal (ICCs), the normal counterpart of GISTs. ICC precursors share phenotypic characteristics with cells that emerge in a subset of patients treated with imatinib and in young patients with GIST characterized by loss of succinate dehydrogenase complex proteins and lack of KIT or PDGFRA mutations. Eradication of residual GIST cells and cure of GIST will likely require individualized combinations of several approaches tailored to tumor genotype and phenotype. Significance Gastrointestinal stromal tumors (GISTs) are one of the most common connective tissue cancers. Most GISTs that cannot be cured by surgery respond to molecularly targeted therapy (e.g., with imatinib

  18. LAPAROSCOPIC RESECTION OF GASTROINTESTINAL STROMAL TUMORS (GIST)

    PubMed Central

    LOUREIRO, Marcelo de Paula; de ALMEIDA, Rômulo Augusto Andrade; CLAUS, Christiano Marlo Paggi; BONIN, Eduardo Aimoré; CURY-FILHO,, Antônio Moris; DIMBARRE, Daniellson; da COSTA, Marco Aurélio Raeder; VITAL, Marcílio Lisboa

    2016-01-01

    Background Gastrointestinal mesenchymal or stromal tumors (GIST) are lesions originated on digestive tract walls, which are treated by surgical resection. Several laparoscopic techniques, from gastrectomies to segmental resections, have been used successfully. Aim Describe a single center experience on laparoscopic GIST resection. Method Charts of 15 operated patients were retrospectively reviewed. Thirteen had gastric lesions, of which ten were sub epithelial, ranging from 2-8 cm; and three were pure exofitic growing lesions. The remaining two patients had small bowel lesions. Surgical laparoscopic treatment consisted of two distal gastrectomies, 11 wedge gastric resections and two segmental enterectomies. Mechanical suture was used in the majority of patients except on six, which underwent resection and closure using manual absorbable sutures. There were no conversions to open technique. Results Mean operative time was 1h 29 min±92 (40-420 min). Average lenght of hospital stay was three days (2-6 days). There were no leaks, postoperative bleeding or need for reintervention. Mean postoperative follow-up was 38±17 months (6-60 months). Three patients underwent adjuvant Imatinib treatment, one for recurrence five months postoperatively and two for tumors with moderate risk for recurrence . Conclusion Laparoscopic GIST resection, not only for small lesions but also for tumors above 5 cm, is safe and acceptable technique. PMID:27120729

  19. Succinate dehydrogenase-deficient gastrointestinal stromal tumors

    PubMed Central

    Wang, Ya-Mei; Gu, Meng-Li; Ji, Feng

    2015-01-01

    Most gastrointestinal stromal tumors (GISTs) are characterized by KIT or platelet-derived growth factor alpha (PDGFRA) activating mutations. However, there are still 10%-15% of GISTs lacking KIT and PDGFRA mutations, called wild-type GISTs (WT GISTs). Among these so-called WT GISTs, a small subset is associated with succinate dehydrogenase (SDH) deficiency, known as SDH-deficient GISTs. In addition, GISTs that occur in Carney triad and Carney-Stratakis syndrome represent specific examples of SDH-deficient GISTs. SDH-deficient GISTs locate exclusively in the stomach, showing predilection for children and young adults with female preponderance. The tumor generally pursues an indolent course and exhibits primary resistance to imatinib therapy in most cases. Loss of succinate dehydrogenase subunit B expression and overexpression of insulin-like growth factor 1 receptor (IGF1R) are common features of SDH-deficient GISTs. In WT GISTs without succinate dehydrogenase activity, upregulation of hypoxia-inducible factor 1α may lead to increased growth signaling through IGF1R and vascular endothelial growth factor receptor (VEGFR). As a result, IGF1R and VEGFR are promising to be the novel therapeutic targets of GISTs. This review will update the current knowledge on characteristics of SDH-deficient GISTs and further discuss the possible mechanisms of tumorigenesis and clinical management of SDH-deficient GISTs. PMID:25741136

  20. Drug repurposing for gastrointestinal stromal tumor.

    PubMed

    Pessetto, Ziyan Y; Weir, Scott J; Sethi, Geetika; Broward, Melinda A; Godwin, Andrew K

    2013-07-01

    Despite significant treatment advances over the past decade, metastatic gastrointestinal stromal tumor (GIST) remains largely incurable. Rare diseases, such as GIST, individually affect small groups of patients but collectively are estimated to affect 25 to 30 million people in the United States alone. Given the costs associated with the discovery, development, and registration of new drugs, orphan diseases such as GIST are often not pursued by mainstream pharmaceutical companies. As a result, "drug repurposing" or "repositioning," has emerged as an alternative to the traditional drug development process. In this study, we screened 796 U.S. Food and Drug Administration (FDA)-approved drugs and found that two of these compounds, auranofin (Ridaura) and fludarabine phosphate, effectively and selectively inhibited the proliferation of GISTs, including imatinib-resistant cells. One of the most notable drug hits, auranofin, an oral, gold-containing agent approved by the FDA in 1985 for the treatment of rheumatoid arthritis, was found to inhibit thioredoxin reductase activity and induce reactive oxygen species (ROS) production, leading to dramatic inhibition of GIST cell growth and viability. Importantly, the anticancer activity associated with auranofin was independent of imatinib-resistant status, but was closely related to the endogenous and inducible levels of ROS. Coupled with the fact that auranofin has an established safety profile in patients, these findings suggest for the first time that auranofin may have clinical benefit for patients with GIST, particularly in those suffering from imatinib-resistant and recurrent forms of this disease. PMID:23657945

  1. Drug Repurposing for Gastrointestinal Stromal Tumor

    PubMed Central

    Pessetto, Ziyan Y.; Weir, Scott J.; Sethi, Geetika; Broward, Melinda A.; Godwin, Andrew K.

    2013-01-01

    Despite significant treatment advances over the past decade, metastatic gastrointestinal stromal tumor (GIST) remains largely incurable. Rare diseases, such as GIST, individually affect small groups of patients but collectively are estimated to affect 25–30 million people in the U.S. alone. Given the costs associated with the discovery, development and registration of new drugs, orphan diseases such as GIST are often not pursued by mainstream pharmaceutical companies. As a result, “drug repurposing” or “repositioning”, has emerged as an alternative to the traditional drug development process. In this study we screened 796 FDA-approved drugs and found that two of these compounds, auranofin and fludarabine phosphate, effectively and selectively inhibited the proliferation of GISTs including imatinib-resistant cells. One of the most notable drug hits, auranofin (Ridaura®), an oral, gold-containing agent approved by the FDA in 1985 for the treatment of rheumatoid arthritis (RA), was found to inhibit thioredoxin reductase (TrxR) activity and induce reactive oxygen species (ROS) production, leading to dramatic inhibition of GIST cell growth and viability. Importantly, the anti-cancer activity associated with auranofin was independent of IM resistant status, but was closely related to the endogenous and inducible levels of ROS, therefore is prior to IM response. Coupled with the fact auranofin has an established safety profile in patients, these findings suggest for the first time that auranofin may have clinical benefit for GIST patients, particularly in those suffering from imatinib-resistant and recurrent forms of this disease. PMID:23657945

  2. [Gastrointestinal stromal tumors. A case of small intestine stromal tumor (SIST) with an uncertain biological aspect].

    PubMed

    Quaglino, F; Borello, M; Cumbo, P; Pietribiasi, F; Poma, A; Seglie, E; Do, D

    2000-05-01

    Tumors of the small intestine are relatively rare. The diagnosis is difficult to establish because the symptoms are vague and non-specific. Although the small intestine constitutes 75% of the length and over 90% of the mucosal surface area of the gastrointestinal tract, only 1 to 2% of gastrointestinal malignancies occur in this segment. Metastases are usually present at the time of diagnosis. The outcome of these patients can be improved if the possibility of a malignant small bowel tumor is considered in all cases of unexplained abdominal pain or gastrointestinal bleeding, especially in younger age. Malignant tumors occur with increasing frequency in distal small bowel with a preponderance of malignant lesions in the ileum compared with the jejunum and the duodenum. Adenocarcinoma is the most common tumor of the primary malignant small bowel tumors, followed by carcinoid, lymphoma and leiomyosarcoma. Mesenchymal tumors of the gastrointestinal tract, traditionally regarded as smooth muscle tumors, have demonstrated different cellular differentiations based on immunohistochemical and ultrastructural features. Therefore the terms leiomyoma and leiomyosarcoma have been replaced by a more encompassing term, gastrointestinal stromal tumor (GIST). The majority of GISTs occurs in the stomach; stromal tumors involving the small intestine (SISTs) are far less common but seem to have greater malignant potential. The clinical a case of a small intestinal stromal tumor (SIST), localised in the jejunum and characterised by an uncertain histological aspect, is presented and a review of the literature is made. PMID:10953571

  3. [Gastrointestinal stromal tumor (GIST)--medical rarities?].

    PubMed

    Predescu, D; Gheorghe, M; Predoiu, I; Iosif, C; Constantin, A; Chiru, F; Cociu, L; Constantinoiu, S

    2010-01-01

    Although their overall incidence is low, GISTs are distinctive subgroup of gastrointestinal mesenchymal tumors which express CD117 or platelet derived growth factor receptor alpha (PDGFRA). Considered as rare digestive cancers, tumors like schwannomas, neurofibromas, gastrointestinal leiomiomas are now reclassified as GIST based on immunohistochemistry studies. GIST are more frequent in stomach (40-70%), small bowel (20-40%), colon (5-15%), meanwhile locations such as mesentery, omentum, retro peritoneum in less of 5%. 10 GIST patients were surgically managed during 2004-2009. 5 gastric and 5 small bowel GIST. Most with symptomatic disease: palpable tumor, abdominal pain, anemia, fatigue, superior digestive hemorrhage or occlusion. Imagistic diagnosis consisted of: barium swallow, abdominal sonography, CT and PET-CT. Confirmation was made by hystopathological exam and immunohistochemistry. All patients had more or less wide surgical resections. For some patients there was also a specific adjuvant treatment. All patients survived after surgery. The principle of surgery for GIST is RO resection of the tumor. Tumor rupture or R1 resection of the primary tumor has a negative impact on disease free survival. Some patients (great volume tumors, R1 or R2 resection) had adjuvant treatment. Imatinib mesylate and derivates showed a significant improvement of recurrence free survival with one condition: permanent treatment. Surgery remains the mainstay of treatment in patients with localized, resectable GIST. Recurrence rate of 17-21% and 5 years survival rate of 48-70%, even in resectable GIST, impose an adjuvant treatment. PMID:20941986

  4. ULTRASONOGRAPHIC FEATURES OF CANINE GASTROINTESTINAL STROMAL TUMORS COMPARED TO OTHER GASTROINTESTINAL SPINDLE CELL TUMORS.

    PubMed

    Hobbs, Joshua; Sutherland-Smith, James; Penninck, Dominique; Jennings, Samuel; Barber, Lisa; Barton, Bruce

    2015-01-01

    Canine gastrointestinal stromal tumors (GISTs) are a recent subtype of gastrointestinal spindle cell tumor recognized with the increasing use of immunohistochemistry. To our knowledge, no imaging features have been described in immunostochemically confirmed canine GISTs. The objective of this retrospective, cross-sectional study was to describe ultrasonographic features of canine GISTs compared with other spindle cell tumors. Thirty-seven dogs with an ultrasonographically visible gastrointestinal mass and a histopathologic diagnosis of spindle cell neoplasia were examined. Immunohistochemistry staining was performed for retrieved tissue samples to further differentiate the tumor type and each sample was interpreted by a single veterinary pathologist. Ultrasonographic features recorded examined included mass echogenicity, homogeneity, presence of cavitation, layer of origin, bowel wall symmetry, and loss of wall layering, location, size, vascularity, and evidence of perforation or ulceration. Tumor types included 19 GISTs, eight leiomyosarcomas, six leiomyomas, and four nonspecified sarcomas. Gastrointestinal stromal tumors were significantly more likely to be associated (P < 0.03) with abdominal effusion than other tumor types. There was overlap between the anatomical locations of all tumors types with the exception of the cecum where all eight tumors identified were GISTs. Besides location, there were no unique ultrasound features of GISTs that would allow distinction from other gastrointestinal spindle cell tumors. Similar to previous studies, GISTs appeared to be the most common spindle cell tumor associated with the cecum in our sample of dogs. The high frequency of abdominal effusion with GIST's was of unknown etiology could possibly have been due to septic peritonitis. PMID:25846814

  5. [Surgical principles of gastrointestinal stromal tumors at different locations].

    PubMed

    Ye, Yingjiang; Gao, Zhidong; Wang, Shan

    2015-04-01

    Gastrointestinal stromal tumors(GIST) are the most common mesenchymal tumors in gastrointestinal tract. At present, surgical and molecular targeted therapies are the main treatments. Operation is properly the only way of radical resection. The general principles of surgery are complete resection of the tumor, negative margins, as well as no intraoperative tumor rupture. The choice of surgical skills for GIST is obviously affected by different locations. This paper reviews current literatures combined with our experiences, and elaborates relevant contents in detail. PMID:25940165

  6. Knowns and Known Unknowns of Gastrointestinal Stromal Tumor Adjuvant Therapy.

    PubMed

    Martínez-Marín, Virginia; Maki, Robert G

    2016-09-01

    The first 15 years of management of gastrointestinal stromal tumor (GIST) have led to 3 lines of therapy for metastatic disease: imatinib, sunitinib, and regorafenib. In the adjuvant setting, imatinib is usually given for 3 years postoperatively to patients with higher-risk primary tumors that are completely resected. In this review, issues regarding GIST adjuvant therapy are discussed. It is hoped this review will help the reader understand the present standard of care to improve upon it in years to come. PMID:27546844

  7. How Are Gastrointestinal Stromal Tumors Staged?

    MedlinePlus

    ... spread to nearby lymph nodes (any N). The cancer has spread to distant sites, such as the liver or the lungs (M1). The tumor can have any mitotic rate. Resectable versus unresectable tumors The AJCC staging system provides a detailed summary of how far ...

  8. Targeting gastrointestinal stromal tumors: the role of regorafenib

    PubMed Central

    Schroeder, Brett; Li, Zula; Cranmer, Lee D; Jones, Robin L; Pollack, Seth M

    2016-01-01

    Gastrointestinal stromal tumor (GIST) is a devastating disease in the metastatic setting, but its natural history has been dramatically altered by the development of small molecule tyrosine kinase inhibitors, most notably imatinib. Although patients with advanced GIST live much longer today than they did in the past, imatinib-refractory disease remains a tremendous problem. For disease that is refractory to imatinib and sunitinib, regorafenib is an excellent option. In this review, we discuss the biology and clinical work establishing regorafenib as the standard of care for advanced GIST refractory to both imatinib and sunitinib. PMID:27284251

  9. Targeting gastrointestinal stromal tumors: the role of regorafenib.

    PubMed

    Schroeder, Brett; Li, Zula; Cranmer, Lee D; Jones, Robin L; Pollack, Seth M

    2016-01-01

    Gastrointestinal stromal tumor (GIST) is a devastating disease in the metastatic setting, but its natural history has been dramatically altered by the development of small molecule tyrosine kinase inhibitors, most notably imatinib. Although patients with advanced GIST live much longer today than they did in the past, imatinib-refractory disease remains a tremendous problem. For disease that is refractory to imatinib and sunitinib, regorafenib is an excellent option. In this review, we discuss the biology and clinical work establishing regorafenib as the standard of care for advanced GIST refractory to both imatinib and sunitinib. PMID:27284251

  10. Gastrointestinal Stromal Tumor Arising From a Gastric Duplication Cyst

    PubMed Central

    Machicado, Jorge; Davogustto, Giovanni

    2016-01-01

    Gastric duplication cysts (GDC) are rarely diagnosed in adults, but previous cases have been associated with malignancy. We present a case of gastrointestinal stromal tumor (GIST) arising from a GDC in a 71-year-old woman who presented with 3 years of early satiety, anorexia, abdominal distention, and weight loss. Abdominal CT showed a 9.3 x 5.2 x 9.5-cm well-circumscribed cystic mass arising 3 cm above the gastroduodenal junction. The cyst was resected, and histopathology was consistent with GDC. Future studies are needed to clarify the malignant potential of GDC and the molecular pathways for its development. PMID:27144196

  11. Primary gastrointestinal stromal tumor of the liver: A case report

    PubMed Central

    Luo, Xiao-Li; Liu, Dan; Yang, Jian-Jun; Zheng, Min-Wen; Zhang, Jing; Zhou, Xiao-Dong

    2009-01-01

    We report a case of primary gastrointestinal stromal tumor (GIST) of the liver. A 17-year-old man with a solid mass in the anterior segment of the right liver was asymptomatic with negative laboratory examinations with the exception of positive HBV. Contrast-enhanced ultrasound (CEUS) revealed a hypervascular lesion in the arterial phase and hypoechoic features during the portal and late phases. However, enhanced spiral computed tomography (CT) showed hypoattenuation in all three phases. Following biopsy, immunohistochemical evaluation demonstrated positive CD117. Different imaging features of primary GISTs of the liver are due to pathological properties and different working systems between CEUS and enhanced spiral CT. PMID:19653356

  12. Gastrointestinal stromal tumors: molecular markers and genetic subtypes.

    PubMed

    Barnett, Christine M; Corless, Christopher L; Heinrich, Michael C

    2013-10-01

    Mutation-activated signaling from the KIT and PDGFRA kinases has been successfully targeted in gastrointestinal stromal tumors (GISTs), with subtle differences between the mutations serving to refine prognosis and more precisely tailor therapy. There is a growing understanding of the molecular drivers of GISTs lacking mutations in KIT or PDGFRA, so called wild-type GISTs, further aiding in management decisions. This article provides an overview of all the known molecular subtypes of GIST and provides information about clinical correlates, treatment, and prognosis depending on the subtype. PMID:24093165

  13. Management of early asymptomatic gastrointestinal stromal tumors of the stomach

    PubMed Central

    Scherübl, Hans; Faiss, Siegbert; Knoefel, Wolfram-Trudo; Wardelmann, Eva

    2014-01-01

    Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the digestive tract. Approximately two thirds of clinically manifest tumors occur in the stomach, nearly one third in the small bowel, and the rest in the colorectal region with a few cases in the esophagus. GIST originate within the smooth muscle layer in the wall of the tubular gastrointestinal tract and grow mostly toward the serosa, far less often toward the mucosa. In the latter case, ulceration may develop and can cause gastrointestinal bleeding as the cardinal symptom. However, most GIST of the stomach are asymptomatic. They are increasingly detected incidentally as small intramural or submucosal tumors during endoscopy and particularly during endoscopic ultrasound. Epidemiological and molecular genetic findings suggest that early asymptomatic GIST of the stomach (< 1 cm) show self-limiting tumorigenesis. Thus, early (< 1 cm) asymptomatic gastric GIST (synonym: micro-GIST) are found in 20%-30% of the elderly. The mostly elderly people with early gastric GIST have an excellent GIST-specific prognosis. Patients with early GIST of the stomach can therefore be managed by endoscopic surveillance. PMID:25031785

  14. The neo-adjuvant treatment in gastrointestinal stromal tumor.

    PubMed

    Catania, V; Consoli, A; Cavallaro, A; Liardo, R L E; Malaguarnera, M

    2010-08-01

    Gastrointestinal Stromal Tumor (GIST) is a rare intra-abdominal tumor, characterized by a specific histological and immunohistochemical pattern. These tumors affect with higher frequency stomach and small bowel and occur at a median age of 60 years with a slight male predominance. An early stage of GIST often don't cause any symptoms, so most GISTs are diagnosed in later stages of the disease. We report a case of GIST diagnosed only with clinical data and positron emission tomography (PET). We demonstrate the usefulness of neoadjuvant treatment with Imatinib mesylate, a newly developed tyrosine kinase receptor inhibitor. The neoadjuvant treatment with Imatinib reduced the mass size and vascularization, making possible a surgical approach. PMID:20707293

  15. Acute Pancreatitis and Gastroduodenal Intussusception Induced by an Underlying Gastric Gastrointestinal Stromal Tumor: A Case Report

    PubMed Central

    Doğan, Ahmet; Koparan, Ibrahim Halil; Adin, Mehmet Emin

    2016-01-01

    Gastrointestinal stromal tumors (GISTs) are rare tumors of the gastrointestinal system and comprise only 1% to 3% of all gastrointestinal tract tumors, with the majority of them arising in the stomach. In this report, we present the unique findings of a case of gastroduodenal intussusception caused by an underlying gastric GIST and complicated with severe acute pancreatitis. PMID:27104028

  16. Gastric Schwannoma: A Benign Tumor Often Misdiagnosed as Gastrointestinal Stromal Tumor.

    PubMed

    Shah, Apurva S; Rathi, Pravin M; Somani, Vaibhav S; Mulani, Astha M

    2015-09-28

    Gastric schwannomas are rare mesenchymal tumors that arise from the nerve plexus of gut wall. They present with nonspecific symptoms and are often detected incidentally. Preoperative investigation is not pathognomic and many are therefore misdiagnosed as gastrointestinal stromal tumors. We report a rare case of a 37-year old woman who underwent laparotomy for complex bilateral ovarian cyst with resection of gastric-gastrointestinal stromal tumor preoperatively, but confirmed to have a gastric schwannomas postoperatively. This case underscores the differential diagnosis of submucosal, exophytic gastric mass as schwannoma. PMID:26664714

  17. Gastric Schwannoma: A Benign Tumor Often Misdiagnosed as Gastrointestinal Stromal Tumor

    PubMed Central

    Rathi, Pravin M.; Somani, Vaibhav S.; Mulani, Astha M.

    2015-01-01

    Gastric schwannomas are rare mesenchymal tumors that arise from the nerve plexus of gut wall. They present with nonspecific symptoms and are often detected incidentally. Preoperative investigation is not pathognomic and many are therefore misdiagnosed as gastrointestinal stromal tumors. We report a rare case of a 37-year old woman who underwent laparotomy for complex bilateral ovarian cyst with resection of gastric-gastrointestinal stromal tumor preoperatively, but confirmed to have a gastric schwannomas postoperatively. This case underscores the differential diagnosis of submucosal, exophytic gastric mass as schwannoma. PMID:26664714

  18. Immune infiltrates are prognostic factors in localized gastrointestinal stromal tumors.

    PubMed

    Rusakiewicz, Sylvie; Semeraro, Michaela; Sarabi, Matthieu; Desbois, Mélanie; Locher, Clara; Mendez, Rosa; Vimond, Nadège; Concha, Angel; Garrido, Federico; Isambert, Nicolas; Chaigneau, Loic; Le Brun-Ly, Valérie; Dubreuil, Patrice; Cremer, Isabelle; Caignard, Anne; Poirier-Colame, Vichnou; Chaba, Kariman; Flament, Caroline; Halama, Niels; Jäger, Dirk; Eggermont, Alexander; Bonvalot, Sylvie; Commo, Frédéric; Terrier, Philippe; Opolon, Paule; Emile, Jean-François; Coindre, Jean-Michel; Kroemer, Guido; Chaput, Nathalie; Le Cesne, Axel; Blay, Jean-Yves; Zitvogel, Laurence

    2013-06-15

    Cancer immunosurveillance relies on effector/memory tumor-infiltrating CD8(+) T cells with a T-helper cell 1 (TH1) profile. Evidence for a natural killer (NK) cell-based control of human malignancies is still largely missing. The KIT tyrosine kinase inhibitor imatinib mesylate markedly prolongs the survival of patients with gastrointestinal stromal tumors (GIST) by direct effects on tumor cells as well as by indirect immunostimulatory effects on T and NK cells. Here, we investigated the prognostic value of tumor-infiltrating lymphocytes (TIL) expressing CD3, Foxp3, or NKp46 (NCR1) in a cohort of patients with localized GIST. We found that CD3(+) TIL were highly activated in GIST and were especially enriched in areas of the tumor that conserve class I MHC expression despite imatinib mesylate treatment. High densities of CD3(+) TIL predicted progression-free survival (PFS) in multivariate analyses. Moreover, GIST were infiltrated by a homogeneous subset of cytokine-secreting CD56(bright) (NCAM1) NK cells that accumulated in tumor foci after imatinib mesylate treatment. The density of the NK infiltrate independently predicted PFS and added prognostic information to the Miettinen score, as well as to the KIT mutational status. NK and T lymphocytes preferentially distributed to distinct areas of tumor sections and probably contributed independently to GIST immunosurveillance. These findings encourage the prospective validation of immune biomarkers for optimal risk stratification of patients with GIST. PMID:23592754

  19. Molecular targets in Gastrointestinal Stromal Tumors (GIST) therapy.

    PubMed

    Braconi, C; Bracci, R; Cellerino, R

    2008-08-01

    Gastrointestinal Stromal Tumors (GISTs) are the most common mesenchimal tumors of the gastrointestinal tract. Such tumors usually have activating mutations in either KIT (75-80%) or Platelet Derived Growth Factor Receptor alpha (PDGFRa) (5-10%) which lead to ligand-independent signal transduction. Targeting these activated proteins with Imatinib mesylate, a small-molecule kinase inhibitor, has proven useful in the treatment of recurrent or metastatic GISTs. However, more than half of patients develop resistance to Imatinib after about 2 years. Therefore, other targets have been studying in order to implement the therapeutical armamentarium for this disease. Sunitinib malate is an oral multikinase inhibitor that targets several receptor tyrosine kinases and has proved to prolong survival in Imatinib-resistant patients. Other molecules, such as Nilotinib, Sorafenib and Dasatinib were shown to be useful in Imatinib resistant mutant cell lines and the results of their activity in humans are being awaited. Recent evidence suggests that GIST cells acquire the capability to escape from the control of KIT and PDGFRa through the activation of alternative pathways. Therefore, further effort should be invested in the discovery of new signaling pathways, such as AXL, MET, IGF-R, which might be involved in the evolution of the disease. After a description of KIT and PDGFRa as known targets of anti-GIST treatments, we review other mechanisms and mediators that might be potential targets of new therapies, providing a comprehensive revision of the new molecular strategies under investigation. PMID:18690842

  20. Ectopic Pancreas Imitating Gastrointestinal Stromal Tumor (GIST) In The Stomach.

    PubMed

    Zińczuk, Justyna; Bandurski, Roman; Pryczynicz, Anna; Konarzewska-Duchnowska, Emilia; Kemona, Andrzej; Kędra, Bogusław

    2015-05-01

    Ectopic pancreas is a rare congenital disorder defined as pancreatic tissue lacking vascular or anatomic communication with the normal body of the pancreas. Most cases of ectopic pancreas are asymptomatic, but it may become clinically evident depending on the size, location and the pathological changes similar to those observed in case of the normal pancreas. It is often an incidental finding and can be located at different sites in the gastrointestinal tract. The most common locations are: the stomach, duodenum or the proximal part of small intestine. The risk of malignancy, bleeding and occlusion are the most serious complications. Despite the development in diagnostics, it still remains a challenge for the clinician to differentiate it from neoplasm. In this report, we described a case of 28-years old woman who presented recurrent epigastric pain. The upper gastrointestinal endoscopy revealed gastrointestinal stromal tumor on the border of the body and antrum of the back wall of great curvature of the stomach. The histopathological examination after surgery showed heterotopic pancreatic tissue. Ectopic pancreas should be considered in the differential diagnosis of gastric mass lesions. PMID:26172167

  1. Gastrointestinal stromal tumors: what do we know now?

    PubMed

    Corless, Christopher L

    2014-01-01

    Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the GI tract, arising from the interstitial cells of Cajal, primarily in the stomach and small intestine. They manifest a wide range of morphologies, from spindle cell to epithelioid, but are immunopositive for KIT (CD117) and/or DOG1 in essentially all cases. Although most tumors are localized at presentation, up to half will recur in the abdomen or spread to the liver. The growth of most GISTs is driven by oncogenic mutations in either of two receptor tyrosine kinases: KIT (75% of cases) or PDGFRA (10%). Treatment with tyrosine kinase inhibitors (TKIs) such as imatinib, sunitinib, and regorafenib is effective in controlling unresectable disease; however, drug resistance caused by secondary KIT or PDGFRA mutations eventually develops in 90% of cases. Adjuvant therapy with imatinib is commonly used to reduce the likelihood of disease recurrence after primary surgery, and for this reason assessing the prognosis of newly resected tumors is one of the most important roles for pathologists. Approximately 15% of GISTs are negative for mutations in KIT and PDGFRA. Recent studies of these so-called wild-type GISTs have uncovered a number of other oncogenic drivers, including mutations in neurofibromatosis type I, RAS genes, BRAF, and subunits of the succinate dehydrogenase complex. Routine genotyping is strongly recommended for optimal management of GISTs, as the type and dose of TKI used for treatment is dependent on the mutation identified. PMID:24384849

  2. Clinicopathologic Features and Clinical Outcomes of Esophageal Gastrointestinal Stromal Tumor

    PubMed Central

    Feng, Fan; Tian, Yangzi; Liu, Zhen; Xu, Guanghui; Liu, Shushang; Guo, Man; Lian, Xiao; Fan, Daiming; Zhang, Hongwei

    2016-01-01

    Abstract Clinicopathologic features and clinical outcomes of gastrointestinal stromal tumors (GISTs) in esophagus are limited, because of the relatively rare incidence of esophageal GISTs. Therefore, the aim of the current study was to investigate the clinicopathologic features and clinical outcomes of esophageal GISTs, and to investigate the potential factors that may predict prognosis. Esophageal GIST cases were obtained from our center and from case reports and clinical studies extracted from MEDLINE. Clinicopathologic features and survivals were analyzed and compared with gastric GISTs from our center. The most common location was lower esophagus (86.84%), followed by middle and upper esophagus (11.40% and 1.76%). The majority of esophageal GISTs were classified as high-risk category (70.83%). Mitotic index was correlated with histologic type, mutational status, and tumor size. The 5-year disease-free survival and disease-specific survival were 65.1% and 65.9%, respectively. Tumor size, mitotic index, and National Institutes of Health risk classification were associated with prognosis of esophageal GISTs. Only tumor size, however, was the independent risk factor for the prognosis of esophageal GISTs. In comparison to gastric GISTs, the distribution of tumor size, histologic type, and National Institutes of Health risk classification were significantly different between esophageal GISTs and gastric GISTs. The disease-free survival and disease-specific survival of esophageal GISTs were significantly lower than that of gastric GISTs. The most common location for esophageal GISTs was lower esophagus, and most of the esophageal GISTs are high-risk category. Tumor size was the independent risk factor for the prognosis of esophageal GISTs. Esophageal GISTs differ significantly from gastric GISTs in respect to clinicopathologic features. The prognosis of esophageal GISTs was worse than that of gastric GISTs. PMID:26765432

  3. CCI-779 in Treating Patients With Soft Tissue Sarcoma or Gastrointestinal Stromal Tumor

    ClinicalTrials.gov

    2013-06-03

    Gastrointestinal Stromal Tumor; Recurrent Adult Soft Tissue Sarcoma; Stage I Adult Soft Tissue Sarcoma; Stage II Adult Soft Tissue Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma

  4. Gastrointestinal tract spindle cell tumors with interstitial cells of Cajal: Prevalence excluding gastrointestinal stromal tumors

    PubMed Central

    Lee, So Jung; Hwang, Chung Su; Kim, Ahrong; Kim, Kyungbin; Choi, Kyung Un

    2016-01-01

    Leiomyomas and schwannomas of the gastrointestinal tract (GIT) are mainly comprised of spindle-shaped tumor cells and should always be differentiated from gastrointestinal stromal tumors (GISTs). Mast/stem cell growth factor receptor Kit (KIT) and discovered on GIST-1 (DOG1) are well-known diagnostic markers for the detection of a GIST by immunohistochemical staining. The aim of the present study was to assess the prevalence and significance of spindle cell tumors of the GIT with KIT- or DOG1-positive spindle-shaped cells, presumed to be interstitial cells of Cajal (ICCs), other than GISTs. A total of 71 leiomyomas and 35 schwannomas were examined and clinicopathological information was obtained. KIT and DOG1 immunostaining was performed to determine the proportions of positive cells. Mutation screening of KIT exons 9, 11, 13 and 17, and platelet-derived growth factor receptor α (PDGFRA) exons 12 and 18 was performed in cases with a relatively high proportion of either KIT- or DOG1-positive cells. The frequency of leiomyomas and schwannomas with KIT- and DOG1-positive ICCs was 35.2% (25/71 cases) and 5.7% (2/35 cases), respectively. Among the esophageal leiomyomas with KIT- and DOG-positive ICCs (14/25; 56.0%), 5 leiomyomas involved the muscularis mucosa and 9 leiomyomas involved the muscularis propria. All gastric leiomyomas with KIT- and DOG1-positive ICCs (11/25; 44%) involved the muscularis propria. All schwannomas with an increased proportion of KIT- or DOG1-positive ICCs were of gastric origin. No KIT or PDGFRA mutations were detected in 7 leiomyomas and 2 schwannomas. In conclusion, the majority of leiomyomas and the minority of schwannomas in the GIT had a significant portion of KIT- and DOG1-positive cells. All of the tumors were located in the upper GIT, and could be present in the muscularis propria or muscularis mucosa. The tumors represented a non-neoplastic proliferation of KIT- and DOG1-positive cells in the GIT. Careful evaluation of KIT- or DOG1

  5. Optimizing Adherence to Adjuvant Imatinib in Gastrointestinal Stromal Tumor

    PubMed Central

    Tetzlaff, Eric D.; Davey, Monica P.

    2013-01-01

    The increasing use of patient-administered oral anticancer drugs is paralleled by new challenges in maintaining treatment adherence. These challenges are particularly significant with adjuvant therapies for prevention of disease recurrence, where the benefits of ongoing treatment are not readily apparent to patients. Nurse practitioners and physician assistants (collectively referred to as advanced practitioners) play integral roles in providing education on disease and treatment to patients that can increase adherence to oral therapies and ideally improve outcomes. For patients with gastrointestinal stromal tumor (GIST), the oral targeted therapy imatinib has become the mainstay of treatment for advanced and recurrent disease and as adjuvant therapy following surgical resection. Recent data indicate significantly improved overall survival with 3 years vs. 1 year of adjuvant imatinib therapy. Continuous dosing with imatinib is needed for optimal efficacy and to limit additional health-care costs associated with management of disease progression in GIST. However, longer duration of therapy increases the risk of nonadherence. Imatinib adherence rates, as well as factors contributing to nonadherence to adjuvant therapy in routine clinical practice, are discussed in this review. Also explored are practical approaches for improving adherence to adjuvant imatinib therapy through greater patient education, in light of the increased duration of therapy in select patients. PMID:25032004

  6. Succinate Dehydrogenase Deficiency in Pediatric and Adult Gastrointestinal Stromal Tumors

    PubMed Central

    Belinsky, Martin G.; Rink, Lori; von Mehren, Margaret

    2013-01-01

    Gastrointestinal stromal tumors (GISTs) in adults are generally driven by somatic gain-of-function mutations in KIT or PDGFRA, and biological therapies targeted to these receptor tyrosine kinases comprise part of the treatment regimen for metastatic and inoperable GISTs. A minority (10–15%) of GISTs in adults, along with ∼85% of pediatric GISTs, lacks oncogenic mutations in KIT and PDGFRA. Not surprisingly these wild type (WT) GISTs respond poorly to kinase inhibitor therapy. A subset of WT GISTs shares a set of distinguishing clinical and pathological features, and a flurry of recent reports has convincingly demonstrated shared molecular characteristics. These GISTs have a distinct transcriptional profile including over-expression of the insulin-like growth factor-1 receptor, and exhibit deficiency in the succinate dehydrogenase (SDH) enzyme complex. The latter is often but not always linked to bi-allelic inactivation of SDH subunit genes, particularly SDHA. This review will summarize the molecular, pathological, and clinical connections that link this group of SDH-deficient neoplasms, and offer a view toward understanding the underlying biology of the disease and the therapeutic challenges implicit to this biology. PMID:23730622

  7. Recurrent epimutation of SDHC in gastrointestinal stromal tumors.

    PubMed

    Killian, J Keith; Miettinen, Markku; Walker, Robert L; Wang, Yonghong; Zhu, Yuelin Jack; Waterfall, Joshua J; Noyes, Natalia; Retnakumar, Parvathy; Yang, Zhiming; Smith, William I; Killian, M Scott; Lau, C Christopher; Pineda, Marbin; Walling, Jennifer; Stevenson, Holly; Smith, Carly; Wang, Zengfeng; Lasota, Jerzy; Kim, Su Young; Boikos, Sosipatros A; Helman, Lee J; Meltzer, Paul S

    2014-12-24

    Succinate dehydrogenase (SDH) is a conserved effector of cellular metabolism and energy production, and loss of SDH function is a driver mechanism in several cancers. SDH-deficient gastrointestinal stromal tumors (dSDH GISTs) collectively manifest similar phenotypes, including hypermethylated epigenomic signatures, tendency to occur in pediatric patients, and lack of KIT/PDGFRA mutations. dSDH GISTs often harbor deleterious mutations in SDH subunit genes (SDHA, SDHB, SDHC, and SDHD, termed SDHx), but some are SDHx wild type (WT). To further elucidate mechanisms of SDH deactivation in SDHx-WT GIST, we performed targeted exome sequencing on 59 dSDH GISTs to identify 43 SDHx-mutant and 16 SDHx-WT cases. Genome-wide DNA methylation and expression profiling exposed SDHC promoter-specific CpG island hypermethylation and gene silencing in SDHx-WT dSDH GISTs [15 of 16 cases (94%)]. Six of 15 SDHC-epimutant GISTs occurred in the setting of the multitumor syndrome Carney triad. We observed neither SDHB promoter hypermethylation nor large deletions on chromosome 1q in any SDHx-WT cases. Deep genome sequencing of a 130-kbp (kilo-base pair) window around SDHC revealed no recognizable sequence anomalies in SDHC-epimutant tumors. More than 2000 benign and tumor reference tissues, including stem cells and malignancies with a hypermethylator epigenotype, exhibit solely a non-epimutant SDHC promoter. Mosaic constitutional SDHC promoter hypermethylation in blood and saliva from patients with SDHC-epimutant GIST implicates a postzygotic mechanism in the establishment and maintenance of SDHC epimutation. The discovery of SDHC epimutation provides a unifying explanation for the pathogenesis of dSDH GIST, whereby loss of SDH function stems from either SDHx mutation or SDHC epimutation. PMID:25540324

  8. Imaging and Clinicopathologic Features of Esophageal Gastrointestinal Stromal Tumors

    PubMed Central

    Winant, Abbey J.; Gollub, Marc J.; Shia, Jinru; Antonescu, Christina; Bains, Manjit S.; Levine, Marc S.

    2016-01-01

    OBJECTIVE The purpose of this article is to describe the imaging and clinicopathologic characteristics of esophageal gastrointestinal stromal tumors (GISTs) and to emphasize the features that differentiate esophageal GISTs from esophageal leiomyomas. MATERIALS AND METHODS A pathology database search identified all surgically resected or biopsied esophageal GISTs, esophageal leiomyomas, and esophageal leiomyosarcomas from 1994 to 2012. Esophageal GISTs were included only if imaging studies (including CT, fluoroscopic, or 18F-FDG PET/CT scans) and clinical data were available. RESULTS Nineteen esophageal mesenchymal tumors were identified, including eight esophageal GISTs (42%), 10 esophageal leiomyomas (53%), and one esophageal leiomyosarcoma (5%). Four patients (50%) with esophageal GIST had symptoms, including dysphagia in three (38%), cough in one (13%), and chest pain in one (13%). One esophageal GIST appeared on barium study as a smooth submucosal mass. All esophageal GISTs appeared on CT as well-marginated predominantly distal lesions, isoattenuating to muscle, that moderately enhanced after IV contrast agent administration. Compared with esophageal leiomyomas, esophageal GISTs tended to be more distal, larger, and more heterogeneous and showed greater IV enhancement on CT. All esophageal GISTs showed marked avidity (mean maximum standardized uptake value, 16) on PET scans. All esophageal GISTs were positive for c-KIT (a cell-surface transmembrane tyrosine kinase also known as CD117) and CD34. On histopathology, six esophageal GISTs (75%) were of the spindle pattern and two (25%) were of a mixed spindle and epithelioid pattern. Five esophageal GISTs had exon 11 mutations (with imatinib sensitivity). Clinical outcome correlated with treatment strategy (resection plus adjuvant therapy or resection alone) rather than risk stratification. CONCLUSION Esophageal GISTs are unusual but clinically important mesenchymal neoplasms. Although esophageal GISTs and

  9. Current Techniques for Treating Gastrointestinal Stromal Tumors in the Upper Gastrointestinal Tract

    PubMed Central

    Ko, Weon Jin; Cho, Joo Young

    2016-01-01

    Most gastrointestinal stromal tumors (GISTs) arise from the proper muscle layer of the upper gastrointestinal (GI) tract and have a low malignant potential. They are sometimes accompanied by symptoms, but in most cases are detected by chance. Endoscopic surgery of subepithelial tumors in the upper GI tract has been actively performed, and its merits include the need for fewer medical devices compared with other surgical procedures and post-resection organ preservation. However, because endoscopic procedures are still limited to small or pilot studies, a multidisciplinary approach combining laparoscopy and endoscopy is needed for more effective and pathologically acceptable management of GISTs. Many new endoscopic surgeries have been developed, and this review describes the current status of and the new approaches for endoscopic surgery of GISTs in the upper GI tract. PMID:27214386

  10. Leiomyoma of the gastrointestinal tract with interstitial cells of Cajal: a mimic of gastrointestinal stromal tumor.

    PubMed

    Deshpande, Anita; Nelson, Dylan; Corless, Christopher L; Deshpande, Vikram; O'Brien, Michael J

    2014-01-01

    Leiomyomas (LMs) of the gastrointestinal tract arise within the muscularis mucosae (superficial) and muscularis propria (deep). There are isolated reports of KIT-positive cells, presumed interstitial cells of Cajal (ICCs), within gastrointestinal LMs. We have encountered esophageal LMs with a high proportion of KIT-positive and DOG1-positive spindle-shaped cells, an appearance that mimicked gastrointestinal stromal tumor. Our aim was to explore the prevalence of ICCs in LMs of the gastrointestinal tract and the etiopathogenic significance of these cells in this benign neoplasm. We identified 34 esophageal LMs (28 deep, 6 superficial), 8 gastric LMs, and 5 small-bowel LMs (all lesions in muscularis propria). We performed immunohistochemical staining studies for desmin, DOG1, and KIT on these neoplasms. We also evaluated 12 superficial colonic LMs. ICCs were distinguished from mast cells on the basis of morphology (elongated and occasionally branching spindle-shaped cells) and the presence of DOG1 reactivity. Four cases were screened for mutations in PDGFRA exons 12, 14, and 18 and KIT exons 9, 11, 13, and 17. ICCs were identified in all deep esophageal LMs and constituted an average of 20% of the lesional cells; focally, these cells comprised >50% of cells. The density of these cells was significantly higher than the background muscularis propria, and hyperplasia of ICCs was not identified in the adjacent muscle. ICCs were identified in 6 of 8 gastric LMs and 1 of 5 small-bowel LMs and were entirely absent in all superficial esophageal and colonic/rectal LMs. There were no mutations in KIT or PDGFRA. ICCs are universally present in deep esophageal LMs, and thus these neoplasms could be mistaken for gastrointestinal stromal tumors, particularly on biopsy samples, an error associated with adverse clinical consequences. ICCs are also identified in gastric and intestinal LMs, albeit in a smaller proportion of cases. Colonization and hyperplasia by non-neoplastic ICCs

  11. Gastrointestinal stromal tumor with KIT mutation in neurofibromatosis type 1.

    PubMed

    Namgung, Hwan

    2011-10-01

    Multiple jejunalgastrointestinal stromal tumors (GISTs) were found in a 52-year-old woman with a history of neurofibromatosis type 1. These tumors were composed of interlacing fascicles of uniform spindle cells with eosinophilic cytoplasm. Immunohistochemically, the tumor cells were positive for CD117, CD34 and negative for S-100, smooth muscle actin. Molecular analysis for activating mutations of KIT and PDGFRA was performed in two tumors. Contrary to sporadic GISTs, the NF1-associated GISTs are characterized by rare mutations of KIT or PDGFRA. But, one missense point mutation (Trp557Gly) was identified in KIT exon 11 of the extramural portion of the largest tumor in this case. The intramural portion of the largest tumor and the other tumor had wild type KIT and PDGFRA. PMID:22111084

  12. Immune cells in primary and metastatic gastrointestinal stromal tumors (GIST)

    PubMed Central

    Cameron, Silke; Gieselmann, Marieke; Blaschke, Martina; Ramadori, Giuliano; Füzesi, Laszlo

    2014-01-01

    We have previously described immune cells in untreated primary gastrointestinal stromal tumors (GIST). Here we compare immune cells in metastatic and primary GIST, and describe their chemoattractants. For this purpose, tissue microarrays from 196 patients, 188 primary and 51 metastasized GIST were constructed for paraffin staining. Quantitative analysis was performed for cells of macrophage lineage (Ki-M1P, CD68), T-cells (CD3, CD56) and B-cells (CD20). Chemokine gene-expression was evaluated by real-time RT-PCR. Immuno-localisation was verified by immunofluorescence. Ki-M1P+ cells were the predominant immune cells in both primary and metastatic GIST (2 8.8% ± 7.1, vs. 26.7% ± 6.3). CD68+ macrophages were significantly fewer, with no significant difference between primary GIST (3.6% ± 2.1) and metastases (4.6% ± 1.5). CD3+ T-cells were the most dominant lymphocytes with a significant increase in metastases (7.3% ± 2.3 vs. 2.2% ± 1.8 in primary GIST, P < 0.01). The percentage of CD56+ NK-cells was 1.1% ± 0.9 in the primary, and 2.4 ± 0.7 (P < 0.05) in the metastases. The number of CD20+ B-cells was generally low with 0.6% ± 0.7 in the primary and 1.8% ± 0.3 (P < 0.05) in the metastases. Analysis of the metastases showed significantly more Ki-M1P+ cells in peritoneal metastases (31.8% ± 7.4 vs. 18.2% ± 3.7, P < 0.01), whilst CD3+ T-cells were more common in liver metastases (11.7% ± 1.8 vs. 4.4% ± 2.6, P < 0.01). The highest transcript expression was seen for monocyte chemotactic protein 1 (MCP1/CCL2), macrophage inflammatory protein 1α (MIP-1α/CCL3) and the pro-angiogenic growth-related oncoprotein 1 (Gro-α/CXCL-1). Whilst the ligands were predominantly expressed in tumor cells, their receptors were mostly present in immune cells. This locally specific microenvironment might influence neoplastic progression of GIST at the different metastatic sites. PMID:25120735

  13. Small Intestinal and Mesenteric Multiple Gastrointestinal Stromal Tumors Causing Occult Bleeding

    PubMed Central

    Dinc, Tolga; Kayilioglu, Selami Ilgaz; Erdogan, Ahmet; Cetinkaya, Erdinc; Akgul, Ozgur; Coskun, Faruk

    2016-01-01

    Gastrointestinal stromal tumors are the meseancymal neoplasms which may involve any part of gastrointestinal tract. C-Kit and platelet derived factor receptor alpha polypeptide are believed to be responsible for the genetic basis. This case presentation aimed to discuss the diagnostic and therapeutic modality of multiple small intestinal, omental, and mesenteric GISTs with different sizes which caused occult bleeding in a 43-year-old male patient. PMID:26989528

  14. [Evaluation and endoscopic treatment of small and micro gastrointestinal stromal tumors].

    PubMed

    Shen, Kuntang; Gao, Xiaodong

    2015-04-01

    The incidence of small and micro gastrointestinal stromal tumors is increasing significantly because of the enhanced health consciousness and advanced endoscopic technology. But there still is controversial in the biological behavior and clinical treatment of GIST. The treatment of the GIST with endoscopic technology has obvious advantages. This method can remove tumor and avoid significant trauma. In this paper, the biological behavior, clinical evaluation and endoscopic treatment of the GIST are discussed. PMID:25940172

  15. Cytokeratin expression in gastrointestinal stromal tumor: a clinicopathologic and immunohistochemical study of 687 cases.

    PubMed

    Lopes, Lisandro F; Bacchi, Carlos E

    2012-01-01

    Gastrointestinal stromal tumor is the most common clinically significant mesenchymal neoplasm of the gastrointestinal tract. The expression of the intermediate filament cytokeratin in gastrointestinal stromal tumor is not frequently reported in the literature. The aim of this study was to investigate the immunohistochemical expression of several types of cytokeratin in a large number of cases (n=687), including a pan-cytokeratin marker (AE1/AE3 cocktail antibodies), high-molecular weight cytokeratins (34ßE12 antibody), and individual cytokeratins 8 (35ßH11 and CAM5.2 antibodies), 7, 14, and 20. Ki-67 antigen was used for the determination of cell proliferation index, and the correlation between Ki-67 and cytokeratin expression was evaluated. Cytokeratin expression was also correlated with several clinicopathologic parameters. The expression of pan-cytokeratin was observed in 24 (3.5%) cases, with variable intensity. Only 1 of 687 (0.1%) cases showed cytokeratin 14 expression. All 687 cases revealed no expression of high-molecular weight cytokeratins, cytokeratins 7, 8, and 20. No significant statistical association was found between AE1/AE3 immunoreactivity and several clinicopathologic parameters, including sex, tumor location and size, cell morphology, mitotic count, risk of aggressive behavior, and Ki-67 antigen cell proliferation index. However, statistical correlation between AE1/AE3 immunoreactivity and a higher age at diagnosis was detected. These results show that cytokeratin expression is not frequent in gastrointestinal stromal tumor, but caution is necessary to avoid erroneous diagnoses. PMID:22157057

  16. CT and MR imaging of gastrointestinal stromal tumor of stomach: a pictorial review.

    PubMed

    Gong, Jingshan; Kang, Wenyan; Zhu, Jin; Xu, Jianmin

    2012-12-01

    This pictorial review illustrates CT and MR imaging appearance of gastrointestinal stromal tumor (GIST) of the stomach and other lesions with similar imaging appearance. GIST of the stomach appears as well-defined enhanced masses with characteristics of subeppthial neoplasms. Majority are exophytic growth, but can also be of intra-luminal growth. GIST can growth into a large mass without gastrointestinal tract obstruction. Necrosis is often seen in GIST and results in heterogeneous enhancement and communication with gastrointestinal tract. CT and MRI features of several other neoplasms mimicking GISTs in the stomach are also described in this review. PMID:23289087

  17. SLITRK3 expression correlation to gastrointestinal stromal tumor risk rating and prognosis

    PubMed Central

    Wang, Chao-Jie; Zhang, Zi-Zhen; Xu, Jia; Wang, Ming; Zhao, Wen-Yi; Tu, Lin; Zhuang, Chun; Liu, Qiang; Shen, Yan-Yin; Cao, Hui; Zhang, Zhi-Gang

    2015-01-01

    AIM: To assess the influence of SLIT and NTRK-like family member 3 (SLITRK3) on the prognosis of gastrointestinal stromal tumor (GIST) and determine whether SLITRK3 can help improve current risk stratification systems. METHODS: We hypothesized that SLITRK3 could be used as a prognostic molecular biomarker for GIST. 35 fresh tumor samples and 417 paraffin-embedded specimens from GIST patients were utilized. SLITRK3 mRNA expression in GIST tumor tissue was detected by real-time polymerase chain reaction, and SLITRK3 protein levels were estimated by immunohistochemistry. The correlation of SLITRK3 expression with various tumor clinicopathological characteristics and follow-up data were analyzed. RESULTS: GIST tumors had high expression of SLITRK3 compared with adjacent normal tissues and the expression level gradually increased with risk grade. SLITRK3 protein expression was closely associated with gastrointestinal bleeding, tumor site, tumor size, mitotic index, and National Institutes of Health (NIH) classification. Survival analysis showed that SLITRK3 expression was closely correlated with overall survival and disease-free survival of GIST patients. Multivariate analysis also identified SLITRK3 expression, mitotic index, and NIH stage as significant risk factors of GIST recurrence. CONCLUSION: SLITRK3 expression is a highly significant predictor of GIST recurrence and metastasis. Combinations of SLITRK3 and NIH stage have strong predictive and prognostic value, and are feasible markers for clinical practice in gastrointestinal stromal tumor. PMID:26217092

  18. Gastrointestinal stromal tumors presenting as pelvic masses: report of two cases.

    PubMed

    Erkanli, S; Kayaselcuk, F; Törer, N; Bolat, F; Tarim, E; Simsek, E; Kuscu, E

    2006-01-01

    We present two cases of gastrointestinal stromal tumors (GISTs) that presented as pelvic masses. These tumors can present diagnostic problems and they may be difficult to discover preoperatively. GISTs are neoplasms that can be diagnosed utilizing immunohistochemistry, especially detecting CD117 (c-kit) reactivity along with associated histological features. GISTs, should be considered in the differential diagnosis of ovarian tumors especially when imaging studies and rectovaginal examination findings are inconclusive and vague. Histologic diagnosis of these tumors are important considering the efficacy of tyrosine kinase inhibitor therapy after surgery in such cases. PMID:16550984

  19. [Gastrointestinal stromal tumors: molecular aspects and therapeutic implications].

    PubMed

    Italiano, Antoine; Bui, Binh

    2008-01-01

    Approximately 90 % of gastrointestinal tumors (GISTs) harbor an activating mutation in KIT or PDGFR alpha oncogene known to confer imatinib sensitivity. Imatinib is a tyrosine kinase inhibitor of KIT and PDGFRs that yields a 6-months progression-free survival (PFS) rate of 80 % in patients with advanced GISTs. Several studies have shown that response to imatinib in GIST patients mainly depends on the mutational status of KIT or PDGFR alpha. Moreover, most if not all patients treated with imatinib for advanced GIST will secondarily develop progressive disease under treatment. In the majority of cases, such progressions are the result of acquired resistance due to occurrence of secondary C-KIT mutations; especially for GIST with primary exon 11 mutations. Sunitinib is another approved drug and an inhibitor of multiple tyrosine kinases including KIT, PDGFR alpha as well as PDGFR beta and VEGFRs which are associated with angiogenesis. Sunitinib, in phase II and III trials was associated with durable clinical benefit in nearly 25 % of patients with advanced GIST resistant/intolerant to imatinib. Clearly, a better knowledge of the molecular mechanisms underlying the resistance to imatinib as well as the development of a new class of broad-spectrum tyrosine kinase inhibitors may allow in the near future new individualized therapeutic strategies for GISTs patients. PMID:18230576

  20. Synchronous colorectal adenocarcinoma and gastrointestinal stromal tumor in Meckel's diverticulum; an unusual association

    PubMed Central

    Kosmidis, Christopher; Efthimiadis, Christopher; Levva, Sofia; Anthimidis, George; Baka, Sofia; Grigoriou, Marios; Tzeveleki, Ioanna; Masmanidou, Maria; Zaramboukas, Thomas; Basdanis, Georgios

    2009-01-01

    Background Coexistence of gastrointestinal stromal tumor with synchronous or metachronous colorectal cancer represents a phenomenon with increasing number of relative reports in the last 5 years. Synchronous occurence of GISTs with other gastrointestinal tumors of different histogenesis presents a special interest. We herein report a case of GIST in Meckel's diverticulum synchronous with colorectal adenocarcinoma. Case presentation A 69 year old man, presented with abdominal distension and anal bleeding on defecation. Colonoscopy revealed colorectal cancer and a low anterior resection was performed, during which a tumor in Meckel's diverticulum was discovered. Histologic examination revealed GIST in Meckel's diverticulum and a rectosigmoid adenocarcinoma. Conclusion Whenever GIST is encountered, the surgeon should be alert to recognize a possible coexistent tumor with different histological origin. Correct diagnosis of synchronous tumors of different origin is the cornerstone of treatment. PMID:19309498

  1. The DREAM complex in anti-tumor activity of imatinib mesylate in gastrointestinal stromal tumors (GISTs)

    PubMed Central

    DeCaprio, James A.; Duensing, Anette

    2014-01-01

    Purpose of review Although most gastrointestinal stromal tumors (GISTs) respond well to treatment with the small molecule kinase inhibitor imatinib mesylate (Gleevec), the majority of patients achieve disease stabilization and complete remissions are rare. Furthermore, discontinuation of treatment in the presence of residual tumor mass almost inevitably leads to tumor progression. These observations suggest that a subset of tumor cells not only persists under imatinib treatment, but remains viable. The current article reviews the molecular basis for these findings and explores strategies to exploit them therapeutically. Recent findings Although imatinib can induce apoptosis in a subset of GIST cells, it can induce a reversible exit from the cell division cycle and entry into G0, a cell cycle state called quiescence, in the remaining cells. Mechanistically, this process involves the DREAM complex, a newly identified key regulator of quiescence. Interfering with DREAM complex formation either by siRNA-mediated knockdown or by pharmacological inhibition of the regulatory kinase DYRK1A was shown to enhance imatinib-induced GIST cell death. Summary Targeting the DREAM complex and imatinib-induced quiescence could provide opportunities for future therapeutic interventions toward more efficient imatinib responses. PMID:24840522

  2. Pancreatic Gastrointestinal Stromal Tumor after Upper Gastrointestinal Hemorrhage and Performance of Whipple Procedure: A Case Report and Literature Review

    PubMed Central

    Aziret, Mehmet; Çetinkünar, Süleyman; Aktaş, Elife; İrkörücü, Oktay; Bali, İlhan; Erdem, Hasan

    2015-01-01

    Patient: Male, 56 Final Diagnosis: Pancreatic GIST Symptoms: Abdominal pain Medication: None Clinical Procedure: Whipple procedure Specialty: Surgery Objective: Rare disease Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal system. These types of tumors originate from any part of the tract as well as from the intestine, colon, omentum, mesentery or retroperitoneum. GIST is a rare tumor compared to other types of tumors, accounting for less than 1% of all gastrointestinal tumors. Case Report: A 56-year-old male patient was hospitalized due to an upper gastrointestinal hemorrhage and the start of abdominal pain on the same day. In the upper gastrointestinal endoscopy that was performed, a solitary mass was found in the second section of the duodenum and a blood vessel (Forrest type 2a) was seen. The extent and location of the mass was detected by abdominal tomography. After hemodynamic recovery, a Whipple procedure was performed without any complications. A subsequent histopathological examination detected a c-kit-positive (CD117) pancreatic GIST with high mitotic index. Conclusions: The most effective treatment method for GISTs is surgical resection. In patients with a head of pancreatic GIST, the Whipple procedure can be used more safely and effectively. PMID:26237079

  3. Gastrointestinal stromal tumor masquerading as a lung neoplasm. A case presentation and literature review

    PubMed Central

    Papaspyros, S; Papagiannopoulos, K

    2008-01-01

    Gastrointestinal stromal tumors (GISTs) are rare neoplasms of the gastrointestinal tract. Their incidence in the esophagus is 1%–3%. Never has a GIST been documented to directly invade the lung. We report a primary esophageal GIST with direct invasion into the lung parenchyma, presenting predominantly with respiratory symptoms. We include a retrospective literature review. Although the principle 'common things are common' usually guides our everyday clinical practice, this case emphasizes that rare entities can mimic common pathologies and underlines the importance of having a clearly defined differential diagnostic list which should be meticulously scrutinized. PMID:18495011

  4. Dedifferentiated gastrointestinal stromal tumor arising de novo from the small intestine.

    PubMed

    Choi, Jacqueline J; Sinada-Bottros, Laura; Maker, Ajay V; Weisenberg, Elliot

    2014-04-01

    Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and usually display monotonous cytologic features and immunoactivity for CD117. Anaplastic GIST, with pleomorphic cells and loss of CD117, until recently have only been reported in patients with chronic imatinib mesylate treatment. Dedifferentiated GISTs arising de novo is a newly identified entity that may prove to be difficult to diagnose. We present the case of a 52-year-old female found to have a dedifferentiated GIST without prior imatinib mesylate therapy. This case is the first reported dedifferentiated GIST arising de novo from the small bowel, and at 30cm in greatest diameter, the largest reported to date. Additionally, we demonstrate for the first time the loss of DOG1 in the anaplastic component of the tumor. De novo dedifferentiated GIST is a rare and diagnostically challenging tumor that may be mischaracterized unless considered in the differential diagnosis. PMID:24484970

  5. Gastric Schwannoma Mimicking Malignant Gastrointestinal Stromal Tumor Exhibiting Increased Fluorodeoxyglucose Uptake

    PubMed Central

    Oh, Sung Jin; Suh, Byoung Jo; Park, Jong Kwon

    2016-01-01

    A schwannoma is a kind of neurogenic tumor that rarely occurs in the gastrointestinal tract. Gastric schwannomas make up 0.2% of all gastric neoplasms. Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors and up to 60–70% of GIST occur in the stomach. Schwannoma and GIST are similar in clinical features, so they are difficult to differentiate preoperatively. Differential diagnosis of these two submucosal tumors is important because of the malignant potential of GIST and the relatively benign course of gastric schwannomas. We report a 49-year-old woman who was diagnosed after operation with a gastric schwannoma, which was suspected a malignant GIST by fluorine-18-fluorodeoxyglucose positron emission computed tomography imaging. PMID:27194983

  6. Metachronous Primary Adenocarcinoma of Lung During Adjuvant Imatinib Mesylate Therapy for Gastrointestinal Stromal Tumor of Stomach

    PubMed Central

    Jiang, Meng-jie; Weng, Shan-Shan; Cao, Ying; Li, Xiao-Fen; Wang, Liu-Hong; Xu, Jing-Hong; Yuan, Ying

    2015-01-01

    Abstract Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor in gastrointestinal tracts; however, the synchronous or metachronous coexistence of GIST with additional primary malignancy is not common. Here, we present an unusual case of gastric GIST with metachronous primary lung adenocarcinoma diagnosed during his adjuvant treatment with oral receptor tyrosine kinase inhibitor imatinib mesylate (400 mg daily). After 6-month use of imatinib, the patient suffered from dry cough and dyspnea. Subsequent lung biopsy demonstrated adenocarcinoma with diffuse interstitial changes. Our research emphasizes the possibility of an additional primary tumor with GIST, and reminds the clinicians to strengthen the surveillance of the additional cancer during the follow-up of GIST patients. PMID:26356712

  7. Gastrointestinal and Extragastrointestinal Stromal Tumors: Report of Two Cases and Review of the Literature

    PubMed Central

    Antonopoulos, Petros; Leonardou, Polytimi; Barbagiannis, Nikolaos; Alexiou, Konstantinos; Demonakou, Maria; Economou, Nikolaos

    2014-01-01

    We present two cases, one of a gastrointestinal stromal tumor (GIST) in the stomach and one of an extragastrointestinal stromal tumor (EGIST) in the hepatogastric ligament, which were discovered as incidental findings during computed tomography (CT) scans performed for other reasons. In both cases the diagnosis of the tumor was confirmed histologically and immunohistochemically. During the follow-up CT examinations these tumors proved to have a completely different natural course. The first case refers to an 82-year-old male patient with GIST of the stomach who refused to be operated and was followed by CT scans for a 4-year period. This patient did not show any significant changes in the morphology, size and density of the lesion. The second case refers to a 58-year-old female patient with EGIST of the hepatogastric ligament who presented with simultaneous liver metastases and remained healthy for 2 years after surgical resection, but developed local recurrence later. As a conclusion, both GISTs/EGISTs can be revealed as incidental findings in a CT scan performed for other purposes. Moreover, an untreated GIST located in the stomach can remain unchanged and without metastatic lesions for a long period of time, as in our case for a 4-year period. To our knowledge, this is the first report in the literature in whom a GIST was proved to remain almost unchanged for many years without any treatment, and we therefore attempt a further review of the current literature on stromal tumors. PMID:24707244

  8. Synchronous occurrence of gastrointestinal stromal tumor and intrahepatic cholangiocarcinoma: A case report

    PubMed Central

    NAM, SEUNG-JOO; CHOI, HYUK SOON; KIM, EUN SUN; KEUM, BORA; JEEN, YOON TAE; CHUN, HOON JAI

    2015-01-01

    Various cases of gastrointestinal stromal tumor (GIST) coinciding with other gastrointestinal malignancies have been reported to date, however, the synchronous occurrence of GIST and intrahepatic cholangiocarcinoma (ICC) is exceptionally rare and, to the best of our knowledge, has only been reported once. The coinciding malignancy has usually been encountered incidentally during surgical exploration. Thus, this is the first report where a targeted biopsy of the clinically suspicious lesion was used to determine the diagnosis of ICC concurrent with GIST. The liver is the most frequent metastatic site of GIST, therefore, additional hepatic masses may be mistakenly diagnosed as metastatic disease, rather than the presentation of multiple primary tumors. This subsequently delays the accurate diagnosis and complicates the performance of a curable resection. The current study reports a case of advanced synchronous GIST and ICC, which was operable at initial presentation, but progressed to become surgically unresectable. PMID:25435952

  9. An Adult Gastric Duplication Cyst Mimicking a Gastrointestinal Stromal Tumor.

    PubMed

    Yoda, Takenori; Furihata, Makoto; Nagao, Sayaka; Wada, Tomonori

    2016-01-01

    We herein describe a rare case of a 24-year-old man who presented with severe epigastralgia after consuming a considerable amount of broiled meat. Computed tomography revealed a cystic lesion adjacent to the distal stomach, with high intensity on T2-weighted magnetic resonance imaging. Upper endoscopy showed a cystic mass measuring 6 cm in diameter, mimicking a submucosal tumor adjacent to the pyloric valve, with duodenum invagination, characteristic of ball valve syndrome. Endoscopic ultrasonography showed that the lesion was contiguous through the first to the third layer of the stomach. Therefore, we performed distal gastrectomy. Pathology showed that the lesion was a gastric duplication cyst without malignancy. PMID:27580540

  10. Large mesenteric gastrointestinal stromal tumor in a patient with familial adenomatous polyposis syndrome.

    PubMed

    Moschos, John; Tzilves, Dimitrios; Paikos, Dimitrios; Tagarakis, Georgios; Pilpilidis, Ioannis; Antonopoulos, Zissis; Kadis, Savvas; Katsos, Ioannis; Tarpagos, Anestis

    2006-06-01

    We report a case of a 30-year-old man who presented with severe debilitation, anemia and diarrhea over two months. Colonoscopy revealed many (>100) polyps (familial adenomatous polyposis syndrome). Abdominal CT scan showed a large mass at the left upper abdomen in conjunction with the splenic flexure. Total colectomy with mesenteric mass and adjacent small bowel removal and ileoanal pouch was performed. Examination of the resected mesenteric mass showed a gastrointestinal stromal tumor (GIST) with scarce mitosis and infiltration of the adjacent small bowel. We describe for the first time in medical literature the coexistence of familial adenomatous polyposis syndrome and GIST in a 30-year-old man. PMID:16855925

  11. Key Issues in the Clinical Management of Gastrointestinal Stromal Tumors: An Expert Discussion

    PubMed Central

    Blay, Jean-Yves; Demetri, George D.; Fletcher, Jonathan A.; Joensuu, Heikki; Martín-Broto, Javier; Nishida, Toshirou; Reichardt, Peter; Schöffski, Patrick; Trent, Jonathan C.

    2015-01-01

    After the revelation of kinase targeting with orally available small molecules, the use of imatinib in chronic myelogenous leukemia and in gastrointestinal stromal tumor (GIST) has now become commonplace and just two of many examples of the use of kinase inhibitors in cancer. In this article, we discuss important practice points that may impact upon questions of therapy of primary and metastatic GIST, with the hope that the questions addressed in this rare solid tumor can serve as examples of what can be achieved with kinase-directed therapies in other cancers. We present cases that highlight some of the key issues in GIST management and afterward discuss both points of consensus and controversial issues in what is now recognized as one of the most common forms of sarcoma. Implications for Practice: The treatment of gastrointestinal stromal tumor (GIST) has become sophisticated with the availability of three approved agents in many countries and 15 years of experience with primary and metastatic disease. Important lessons from tyrosine-kinase inhibitors in GIST can be gleaned from this experience and will impact implementation of similar agents for other cancers. PMID:26070915

  12. Endoscopic en bloc resection of an exophytic gastrointestinal stromal tumor with suction excavation technique.

    PubMed

    Choi, Hyuk Soon; Chun, Hoon Jai; Kim, Kyoung-Oh; Kim, Eun Sun; Keum, Bora; Jeen, Yoon-Tae; Lee, Hong Sik; Kim, Chang Duck

    2016-06-21

    Here, we report the first successful endoscopic resection of an exophytic gastrointestinal stromal tumor (GIST) using a novel perforation-free suction excavation technique. A 49-year-old woman presented for further management of a gastric subepithelial tumor on the lesser curvature of the lower body, originally detected via routine upper gastrointestinal endoscopy. Abdominal computed tomography and endoscopic ultrasound showed a 4-cm extraluminally protruding mass originating from the muscularis propria layer. The patient firmly refused surgical resection owing to potential cardiac problems, and informed consent was obtained for endoscopic removal. Careful dissection and suction of the tumor was repeated until successful extraction was achieved without serosal injury. We named this procedure the suction excavation technique. The tumor's dimensions were 3.5 cm × 2.8 cm × 2.5 cm. The tumor was positive for C-KIT and CD34 by immunohistochemical staining. The mitotic count was 6/50 high-power fields. The patient was followed for 5 years without tumor recurrence. This case demonstrated the use of endoscopic resection of an exophytic GIST using the suction excavation technique as a potential therapy without surgical resection. PMID:27340363

  13. Brain Metastasis from Gastrointestinal Stromal Tumor: A Case Report and Review of the Literature

    PubMed Central

    Naoe, Hideaki; Kaku, Eisuke; Ido, Yumi; Gushima, Rika; Maki, Yoko; Saito, Hirokazu; Yokote, Seiichiro; Gushima, Ryosuke; Nonaka, Kouichi; Hoshida, Yohmei; Murao, Tetsuya; Ozaki, Tetsu; Yokomine, Kazunori; Tanaka, Hideki; Nagahama, Hiroyasu; Sakurai, Kouichi; Tanaka, Motohiko; Iyama, Ken-ichi; Baba, Hideo; Sasaki, Yutaka

    2011-01-01

    Metastasis of gastrointestinal stromal tumor (GIST) into the central nervous system is extremely rare. We report a patient with synchronous GIST and brain metastasis. At disease onset, there was left hemiplegia and ptosis of the right eyelids. Resection cytology of the brain tumor was reported as metastasis of GIST. After positron emission tomography examination, another tumor in the small bowel was discovered, which suggested a small bowel GIST associated with intracranial metastasis. Immunohistochemical analysis of the intestinal tumor specimen obtained by double balloon endoscopy showed a pattern similar to the brain tumor, with the tumors subsequently identified as intracranial metastases of jejunal GIST. After surgical resection of one brain tumor, the patient underwent whole brain radiation therapy followed by treatment with imatinib mesylate (Gleevec; Novartis Pharma, Basel, Switzerland). Mutational analysis of the original intestinal tumor revealed there were no gene alterations in KIT or PDGFRα. Since the results indicated the treatment had no apparent effect on either of the tumors, and because ileus developed due to an intestinal primary tumor, the patient underwent surgical resection of the intestinal lesion. However, the patient's condition gradually worsen and she subsequently died 4 months after the initial treatment. PMID:22110419

  14. Successful treatment with personalized dosage of imatinib in elderly patients with gastrointestinal stromal tumors.

    PubMed

    Saponara, Maristella; Gatto, Lidia; Di Nunno, Vincenzo; Tabacchi, Elena; Fanti, Stefano; Di Scioscio, Valerio; Nannini, Margherita; Gruppioni, Elisa; Altimari, Annalisa; Fiorentino, Michelangelo; Santini, Donatella; Ceccarelli, Claudio; Zompatori, Maurizio; Biasco, Guido; Pantaleo, Maria Abbondanza

    2016-04-01

    Imatinib is the standard first-line therapy for metastatic gastrointestinal stromal tumors. It has markedly improved the prognosis and outcome of patients affected by gastrointestinal stromal tumors, especially in the case of exon 11 KIT mutations. Imatinib-associated adverse events are generally mild to moderate; however, in clinical practice, intolerance caused by chronic toxicities frequently leads to breaks in treatment. This is particularly true in elderly patients in whom age, decline in drug metabolism, and polypharmacy, with a possible drug-drug interaction, may influence the tolerability of imatinib. In the present article, we report our extensive experience with the management of imatinib therapy in a 'real' population, in particular in very elderly patients, discussing whether the use of personalized imatinib dosage could be a safe and advantageous option, enabling continuous administration, thus ensuring effective treatment. Only a few case reports in the literature provide data on outcome with low tailored dosage of imatinib and none of them has been carried out on a Western population. Here, we report four cases treated with low imatinib dosage as a safe and useful option enabling continued treatment with imatinib, improving tolerance, and maintaining good and lasting disease control. PMID:26720290

  15. Endoscopic en bloc resection of an exophytic gastrointestinal stromal tumor with suction excavation technique

    PubMed Central

    Choi, Hyuk Soon; Chun, Hoon Jai; Kim, Kyoung-Oh; Kim, Eun Sun; Keum, Bora; Jeen, Yoon-Tae; Lee, Hong Sik; Kim, Chang Duck

    2016-01-01

    Here, we report the first successful endoscopic resection of an exophytic gastrointestinal stromal tumor (GIST) using a novel perforation-free suction excavation technique. A 49-year-old woman presented for further management of a gastric subepithelial tumor on the lesser curvature of the lower body, originally detected via routine upper gastrointestinal endoscopy. Abdominal computed tomography and endoscopic ultrasound showed a 4-cm extraluminally protruding mass originating from the muscularis propria layer. The patient firmly refused surgical resection owing to potential cardiac problems, and informed consent was obtained for endoscopic removal. Careful dissection and suction of the tumor was repeated until successful extraction was achieved without serosal injury. We named this procedure the suction excavation technique. The tumor’s dimensions were 3.5 cm × 2.8 cm × 2.5 cm. The tumor was positive for C-KIT and CD34 by immunohistochemical staining. The mitotic count was 6/50 high-power fields. The patient was followed for 5 years without tumor recurrence. This case demonstrated the use of endoscopic resection of an exophytic GIST using the suction excavation technique as a potential therapy without surgical resection. PMID:27340363

  16. The role of surgery in the multidisciplinary management of patients with localized gastrointestinal stromal tumors.

    PubMed

    Bednarski, Brian K; Pisters, Peter W T; Hunt, Kelly K

    2012-08-01

    Surgical resection of localized gastrointestinal stromal tumors (GISTs) is associated with recurrence rates of approximately 50% at 5 years of follow-up. The introduction of tyrosine kinase inhibitors, such as imatinib, improved overall survival rates in advanced disease, while in the adjuvant setting, improved recurrence-free survival following resection of high-risk GIST. The demonstration of the clinical benefit of tyrosine kinase inhibitors in both the metastatic and adjuvant settings generated interest in neoadjuvant approaches for patients with operable locally advanced disease, particularly in difficult anatomic locations. The potential impact of tumor downsizing in areas such as the gastroesophageal junction, the duodenum or the rectum, on the extent of surgical resection and morbidity is real. The ongoing research regarding neoadjuvant therapy, the duration of adjuvant therapy and the optimal means by which to risk stratify patients with GIST continues to keep the treatment of this disease at the forefront of personalized cancer care. PMID:23030225

  17. The management of gastrointestinal stromal tumors: a model for targeted and multidisciplinary therapy of malignancy.

    PubMed

    Joensuu, Heikki; DeMatteo, Ronald P

    2012-01-01

    Gastrointestinal stromal tumor (GIST) has become a model for targeted therapy in cancer. The vast majority of GISTs contain an activating mutation in either the KIT or platelet-derived growth factor A (PDGFRA) gene. GIST is highly responsive to several selective tyrosine kinase inhibitors. In fact, this cancer has been converted to a chronic disease in some patients. Considerable progress has been made recently in our understanding of the natural history and molecular biology of GIST, risk stratification, and drug resistance. Despite the efficacy of targeted therapy, though, surgery remains the only curative primary treatment and cures >50% of GIST patients who present with localized disease. Adjuvant therapy with imatinib prolongs recurrence-free survival and may improve overall survival. Combined or sequential use of tyrosine kinase inhibitors with other agents following tumor molecular subtyping is an attractive next step in the management of GIST. PMID:22017446

  18. miRNA profiling in gastrointestinal stromal tumors: implication as diagnostic and prognostic markers.

    PubMed

    Nannini, Margherita; Ravegnini, Gloria; Angelini, Sabrina; Astolfi, Annalisa; Biasco, Guido; Pantaleo, Maria A

    2015-01-01

    MicroRNAs are a class of short noncoding RNAs, that play a relevant role in multiple biological processes, such as differentiation, proliferation and apoptosis. Gastrointestinal stromal tumors (GIST) are considered as a paradigm of molecular biology in solid tumors worldwide, and after the discovery of specific alterations in the KIT and PDGFRA genes, they have emerged from anonymity to become a model for targeted therapy. Epigenetics have an emerging and relevant role in different steps of GIST biology such as tumorigenesis, disease progression, prognosis and drug resistance. The aim of the present review was to summarize the current evidence about the role of microRNAs in GIST, including their potential application as well as their limits. PMID:26447534

  19. Status of the gastric mucosa with endoscopically diagnosed gastrointestinal stromal tumor.

    PubMed

    Nonaka, Kouichi; Ban, Shinichi; Hiejima, Yoshimitsu; Narita, Rei; Shimizu, Michio; Aikawa, Masayasu; Ohata, Ken; Matsuhashi, Nobuyuki; Arai, Shin; Kita, Hiroto

    2014-01-01

    Background. Since gastrointestinal stromal tumor (GIST) is a mesenchymal submucosal tumor, the endosonographic, CT, and MRI features of gastric GISTs have been widely investigated. However, the GIST-bearing gastric mucosa status has not been reported. Objective. To characterize the GIST-bearing gastric mucosa status in terms of the degree of inflammation and atrophy, assessed endoscopically. Subjects and Methods. The subjects were 46 patients with submucosal tumors (histologically proven gastric GISTs) who had undergone upper gastrointestinal endoscopy in our hospital between April 2007 and September 2012. They were retrospectively evaluated regarding clinicopathological features, the endoscopically determined status of the entire gastric mucosa (presence or absence and degree of atrophy), presence or absence and severity of endoscopic gastritis/atrophy (A-B classification) at the GIST site, and presence or absence of H. pylori infection. Results. Twenty-three patients had no mucosal atrophy, but 17 and 6 had closed- and open-type atrophy, respectively. Twenty-six, 5, 12, 1, 1, and 1 patients had grades B0, B1, B2, B3, A0, and A1 gastritis/atrophy at the lesion site, respectively, with no grade A2 gastritis/atrophy. Conclusion. The results suggest that gastric GISTs tend to arise in the stomach wall with H. pylori-negative, nonatrophic mucosa or H. pylori-positive, mildly atrophic mucosa. PMID:25104899

  20. Differentiating gastrointestinal stromal tumors from gastric adenocarcinomas and normal mucosae using confocal Raman microspectroscopy

    NASA Astrophysics Data System (ADS)

    Hsu, Chih-Wei; Huang, Chia-Chi; Sheu, Jeng-Horng; Lin, Chia-Wen; Lin, Lien-Fu; Jin, Jong-Shiaw; Chen, Wenlung

    2016-07-01

    Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract, and gastric adenocarcinomas are a common cancer worldwide. To differentiate GISTs from adenocarcinomas is important because the surgical processes for both are different; the former excises the tumor with negative margins, while the latter requires radical gastrectomy with lymph node dissection. Endoscopy with biopsy is used to distinguish GISTs from adenocarcinomas; however, it may cause tumor bleeding in GISTs. We reported here the confocal Raman microspectroscopy as an effective tool to differentiate GISTs, adenocarcinomas, and normal mucosae. Of 119 patients enrolled in this study, 102 patients underwent gastrectomy (40 GISTs and 62 adenocarcinomas), and 17 patients with benign lesions were obtained as normal mucosae. Raman signals were integrated for 100 s for each spot on the specimen, and 5 to 10 spots, depending on the sample size, were chosen for each specimen. There were significant differences among those tissues as evidenced by different Raman signal responding to phospholipids and protein structures. The spectral data were further processed and analyzed by using principal component analysis. A two-dimensional plot demonstrated that GISTs, adenocarcinomas, and normal gastric mucosae could be effectively differentiated from each other.

  1. A case of diffuse infiltrating gastrointestinal stromal tumor of sigmoid colon with perforation.

    PubMed

    Yamashita, Daisuke; Usami, Yu; Toyosawa, Satoru; Hirota, Seiichi; Imai, Yukihiro

    2014-01-01

    Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract, and typically present as discrete well-circumscribed but non-encapsulated tumor masses. In this report, we describe a case of colonic perforation caused by an unusual form of GIST. A 72-year-old Japanese woman presented to the emergency department with acute abdominal pain. Under the provisional diagnosis of sigmoid colon perforation, a laparoscopic sigmoidectomy was performed. Although the tumor mass was undetectable during the preoperative examination, a spindle cell lesion with a diffuse longitudinal growth pattern replacing the muscularis propria was revealed by microscopic examination. The spindle cell lesion was exposed at the perforation, suggesting a causal relationship between the lesion and the perforation. The spindle cell lesion was KIT-positive and had a mutation in the C-KIT gene at exon 11. We diagnosed it as diffuse infiltrating GIST. We consider that the lesion would be a cause of the colonic perforation, and emphasize the importance of accurate diagnosis of the lesion by histological, immunohistochemical and genetic examinations. PMID:24471968

  2. Imaging of Gastrointestinal Stromal Tumors: From Diagnosis to Evaluation of Therapeutic Response.

    PubMed

    Vernuccio, Federica; Taibbi, Adele; Picone, Dario; LA Grutta, Ludovico; Midiri, Massimo; Lagalla, Roberto; Lo Re, Giuseppe; Bartolotta, Tommaso Vincenzo

    2016-06-01

    Once considered an obscure tumor entity with poor prognosis, gastrointestinal stromal tumors (GISTs) are nowadays recognized as the most common mesenchymal tumors of the alimentary tract. GISTs differ from other mesenchymal neoplasms at pathology since 90% of them exhibit strong immunohistochemical staining for KIT, a tyrosinase kinase growth factor receptor. In the early 2000s, the ability of imatinib mesylate, a tyrosine kinase inhibitor, to inhibit KIT established a new paradigm for cancer treatment. A reduction in lesion size may not be observed or may appear many months after therapy; thus, tumor response criteria alternative to the Response Evaluation Criteria in Solid Tumors were developed. This review highlights the role of imaging in the detection, characterization, preoperative staging, postoperative assessment, therapy-response evaluation and treatment-related toxicities. All this information is crucial in optimizing patient management. Contrast-enhanced computed tomography is the most commonly used modality for staging the disease and assessing treatment response, whereas positron-emission tomography adds valuable functional information. Magnetic resonance imaging (MRI) may also be useful, especially in ano-rectal GISTs. Diffusion-weighted MRI may provide promising indicators of tumor response to targeted molecular therapy. Radiologists and oncologists should be aware of all these issues related to GISTs, since multidisciplinary teams gathering different expertise are usually needed to properly treat patients with GISTs. PMID:27272772

  3. State of the Art in the Treatment of Gastrointestinal Stromal Tumors

    PubMed Central

    Garlipp, Benjamin; Bruns, Christiane J.

    2014-01-01

    Background Gastrointestinal stromal tumors (GISTs) are the most frequently diagnosed mesenchymal neoplasms of the gastrointestinal tract. Despite their biological and clinical heterogeneity, the majority of these tumors are positive for the receptor tyrosine kinase KIT and are driven by KIT- or platelet-derived growth factor receptor alpha (PDGFRA)-activating mutations. There are still uncertainties regarding their clinical and molecular characterization and the optimal treatment regimens, making it difficult to establish a universal treatment algorithm for these tumors. Summary From a clinical perspective, the main difference between GISTs and other gastrointestinal neoplasms is that the benign or malignant behavior of GISTs cannot be predicted from histopathology, but instead relies on empirically established scoring systems. Clinical data suggest that malignant potential may be an inherent quality of some GISTs rather than a feature acquired by the tumor during disease progression. Thus, some patients may require prolonged anti-tumor treatment even after complete surgical removal of the tumor. Key Message Although GISTs are the most frequently occurring mesenchymal neoplasms in the gastrointestinal tract, no universal treatment algorithms exist. This paper reviews the current evidence that guides the management of GISTs. Practical Implications The management of localized GISTs involves the use of surgical resection, with the inclusion of preoperative tyrosine kinase inhibitor treatment for locally advanced, primarily unresectable tumors and for resectable cases requiring extensive surgery. Imatinib is also indicated as adjuvant therapy after complete surgical removal of GISTs with a high estimated risk of recurrence unless specific mutations conferring imatinib resistance are present. The optimal duration of adjuvant treatment is still controversial. For patients with metastatic imatinib-sensitive GISTs, imatinib constitutes the first-line standard treatment

  4. Neurofibromatosis type 1 associated with pheochromocytoma and gastrointestinal stromal tumors: A case report and literature review

    PubMed Central

    PAN, DONGFENG; LIANG, PEIFENG; XIAO, HONGYAN

    2016-01-01

    Neurofibromatosis type 1 (NF1) is a genetic disorder associated with neurofibromin 1 (NF1) gene mutation, which generates an increased risk of variety of tumor types. The current study reports a case involving NF1, pheochromocytoma (PHEO) and gastrointestinal stromal tumors (GIST). A 56-year-old man presented with abdominal pain and polypnea. Clinical investigation revealed multiple diffuse soft-tissue lesions throughout his body, and pigmented macules on the skin. Imaging analyses revealed thoracic scoliosis, multiple subcutaneous nodules in the abdomen and trunk, and a 7.0×7.7×8.9-cm oval-shaped, cystic mass in the left upper abdominal cavity. Immunohistochemical staining indicated that S-100 protein and synaptophysin were highly expressed in adrenal gland neoplasm, whilst CD117 and CD34 were highly expressed in small intestine tumors. The overall clinical and pathological finding suggested a diagnosis of NF1, giant PHEO and small intestinal stromal tumor. In addition, a literature review was conducted to identify the specific clinical features of patients with this condition. Only 11 similar cases have been reported worldwide. In the present study, paroxysmal hypertension occurred in the majority of patients, and GISTs tended to be located in the small intestine. In addition, the present study demonstrated that many of the patients had a poor prognosis. Therefore, the present study indicates that NF1-PHEO-GIST is a special type tumor with varied clinical symptoms, which may be associated with an increased risk for poor prognosis; however, more studies are required to confirm this. PMID:27347193

  5. Spontaneous intraperitoneal hemorrhage as the initial presentation of a gastrointestinal stromal tumor: a case report

    PubMed Central

    Critchlow, Jonathan F.; Cohen, Steven; Edlow, Jonathan A.

    2010-01-01

    Background Spontaneous hemoperitoneum is rare. The most common etiologies are gynecologic, splenic, and hepatic. Gastrointestinal stromal tumors (GISTs) are commonly associated with intraluminal bleeding, but rarely with spontaneous hemoperitoneum. We report a case of spontaneous hemoperitoneum caused by a gastric GIST. Case report A 54-year-old male presented with the acute onset of abdominal pain and a drop in hemoglobin. Subsequent evaluation, including a CT, MRI, and EUS, revealed a 1.2-cm mass along the greater curvature of the stomach and associated hemoperitoneum. The patient was taken electively to the operating room for laparoscopic removal of the mass. Pathology confirmed that it was a GIST. Conclusion GIST is a rare clinical entity that infrequently presents with spontaneous hemoperitoneum. Emergent treatment should be guided towards treating the spontaneous hemoperitoneum. PMID:20414383

  6. A Case of Malignant Gastrointestinal Stromal Tumor Initially Misdiagnosed as Malignant B-Cell Lymphoma

    PubMed Central

    Suh, Byoung Jo

    2016-01-01

    Errors that occur in anatomic pathology influence the treatment strategy of patients with malignancy. There are four general types of error with three subtypes in the category of defective interpretation. The first subtype is a false-negative diagnosis or undercall of the extent or severity of the lesion, the second is a false-positive diagnosis, and the third is misclassification. We herein report a 65-year-old female patient with malignant gastrointestinal stromal tumor that was diagnosed after reevaluation of the lesion at our hospital – and treated with proximal gastrectomy – after initial diagnosis as malignant B-cell lymphoma on esophagogastroduodenoscopy biopsy of a small gastric fundic mass and subsequent treatment with six cycles of CHOP chemotherapy with aggravation of the mass at another hospital. PMID:27462236

  7. A Pleural Solitary Fibrous Tumor, Multiple Gastrointestinal Stromal Tumors, Moyamoya Disease, and Hyperparathyroidism in a Patient Associated with NF1

    PubMed Central

    Yamamoto, Yoko; Kodama, Ken; Yokoyama, Shigekazu; Takeda, Masashi; Michishita, Shintaro

    2015-01-01

    Neurofibromatosis type 1 (NF1), also called von Recklinghausen's disease, is a multisystemic disease caused by an alteration of the NF1 gene, a tumor suppressor located on the long arm of chromosome 17 (17q11.2). Loss of the gene function, due to a point mutation, leads to an increase in cell proliferation and the development of several tumors. We report a 60-year-old female patient manifesting hypercalcemia due to hyperparathyroidism, a solitary fibrous tumor (SFT) of the pleura, multiple gastrointestinal stromal tumors (GISTs), and moyamoya disease associated with NF1. The SFT and GISTs were removed by staged operations. Then, hypercalcemia was successfully controlled after resection of the parathyroid adenoma. Based on a literature review, these combinations have never been reported, and the relevant literature is briefly discussed. PMID:26442164

  8. Successful surgical resection of advanced gastrointestinal stromal tumor post neoadjuvent therapy.

    PubMed

    Kamil, Sm; Biswas, M; Imran, Ak; Islam, R; Mukhtar, Aa; Joshi, Sc

    2009-01-01

    We report a case of a 48-year-old Indian male who presented with swelling and firmness in his left upper part of the abdomen of one month duration with anorexia and weight loss. Initial examination revealed an intra abdominal mass of around 16.8x11.0x24.5cm with minimal left sided pleural effusion. A biopsy from the mass confirmed the diagnosis of gastrointestinal stromal tumour (GISTs) as supported by immmunohistochemistry results which showed strong positivity for c-kit while stains for smooth muscle actin, desmin, myoglobin, S100 Protein and cytokerstin remained negative. The patient was not suitable for surgical intervention in view of advanced tumor, and Imatinib Mesylate 400mg daily was started with the aim of making the tumor operable. Such therapy lasted for twenty months and was tolerated well by the patient. It then resulted in gradual tumor regression, following which the patient underwent successful tumor resection. Post surgical resection patient had no radiological evidence of intra abdominal tumor but mild left sided pleural effusion with left lower lobe atelectasis. The patient had uneventful post operative recovery and he is currently on Imatinib mesylate and tolerating treatment well with mild skin rash. The experience with preoperative imatinib on surgical resection rates and post operative outcomes is limited especially with primary locally advanced GISTs. In our case successful surgical resection was possible for a huge locally advanced GIST with unusually prolonged treatment of twenty months with imatinib preoperatively. PMID:21483516

  9. KIT and PDGFRA mutations and PDGFRA immunostaining in gastrointestinal stromal tumors.

    PubMed

    Barreca, Antonella; Fornari, Alessandro; Bonello, Lisa; Tondat, Fabrizio; Chiusa, Luigi; Lista, Patrizia; Pich, Achille

    2011-01-01

    In the present study, we investigated the association of PDGFRA and KIT mutations as well as PDGFRA immunohistochemical expression with clinicopathologic features and prognosis in a series of gastrointestinal stromal tumors (GISTs). Tumor DNA from 40 GISTs was sequenced for the presence of mutations in KIT exons 9, 11, 13 and 17, and in PDGFRA exons 12 and 18. Tissue sections were stained with polyclonal anti-PDGFRA antibody. KIT mutations occurred in 26 cases. There were 13 deletions, 6 substitutions, 3 deletion-substitutions, 3 duplications and 1 insertion. Tumors with KIT deletions/insertion were large with a high mitotic index (MI), and were associated with a high rate of symptoms at diagnosis, invasion into adjacent organs, distant metastasis, relapse and a short disease-free survival (DFS). PDGFRA mutations occurred in 6 gastric GISTs. There were 4 deletions and 2 substitutions. Tumors with PDGFRA mutations were small, with a low MI and Ki67 score, and were associated with a very low rate of symptoms at diagnosis, invasion into adjacent organs and distant metastasis. PDGFRA immunopositivity was found in 23 cases: a peculiar 'dotlike' staining was found in 5 out of 6 PDGFRA mutated cases. Patients with positive PDGFRA immunostaining had a longer DFS than those with negative staining. Our data confirm that the type of KIT mutation is associated with various clinicopathologic features of GISTs, and indicate that PDGFRA mutations are associated with rather indolent tumors. PDGFRA immunopositivity reflects PDGFRA mutational status and is associated with a favorable outcome. PMID:21461555

  10. Co-occurrence of liver metastasis of gastrointestinal stromal tumor and hepatocellular carcinoma: a case report.

    PubMed

    Yamashita, Kohei; Baba, Yoshifumi; Kurashige, Junji; Iwatsuki, Masaaki; Imai, Katsunori; Hashimoto, Daisuke; Sakamoto, Yasuo; Chikamoto, Akira; Yoshida, Naoya; Beppu, Toru; Baba, Hideo

    2016-12-01

    Gastrointestinal stromal tumors (GISTs) are potentially malignant mesenchymal tumors that can give rise to distant metastases, mainly in the liver. The co-occurrence of synchronous primary liver tumors (e.g., hepatocellular carcinoma (HCC)) in patients with GIST is extremely rare. This report describes a 77-year-old male patient with liver metastasis of GIST originating in the small intestine and synchronous HCC. The patient had undergone resection of the small intestine for the primary GIST 3 years earlier and partial hepatectomy and radiofrequency ablation for liver metastases of GIST 1 year earlier. Despite the continuation of adjuvant therapy with imatinib, two new lesions in the liver were detected by follow-up computed tomography scanning, which showed the gradual enlargement of one tumor. A second hepatectomy was performed. Pathological examination revealed that one tumor was a liver metastasis of GIST and the other was a primary HCC. To our knowledge, this is the first report of the synchronous co-occurrence of a liver metastasis of GIST and a primary HCC. PMID:27586263

  11. Gastrointestinal Stromal Tumor of the Stomach Presenting as Multilobular with Diffuse Calcifications

    PubMed Central

    Kim, Sae Hee; Cho, Byung Sun; Park, Joo-Seung; Han, Hyun-Young; Kang, Dong-Wook

    2016-01-01

    Gastrointestinal stromal tumors (GISTs) are the most common primary mesenchymal neoplasms of the gastrointestinal tract and usually appear as a well-circumscribed mass. However, it may be difficult to confirm the extent of the disease for some GISTs. A 70-year-old asymptomatic female presented for a regular physical exam. An esophagogastroduodenoscopy showed a 2.0 cm protruding mass on the gastric fundus. Endoscopic ultrasound revealed an ill-defined heterogenous hypoechoic lesion (3.0×1.5 cm). A computed tomography (CT) scan demonstrated a 4.5 cm multifocal calcified mass at the gastric body as well as at the gastric fundus. Laparoscopic gastric wedge resection was performed according to the extent of multifocal calcifications that are shown on the CT. Intraoperative specimen mammography and intraoperative biopsy might be helpful to obtain a tumor-free margin. Final pathologic diagnosis was an intermediate risk GIST in multilobular form. In patients with diffuse multifocal calcifications in the stomach, the possibility of GIST should be considered. PMID:27104029

  12. Brunner's gland cyst in combination with gastrointestinal stromal tumor: A case report

    PubMed Central

    HUO, XIQIAN; WEI, JISHU; LIU, XINCHUN; WU, JUNLI; GAO, WENTAO; LI, QIANG; JIANG, KUIRONG; DAI, CUNCAI; MIAO, YI

    2016-01-01

    Brunner's gland cysts are rare benign lesions that are mainly observed in the first and the second regions of the duodenum. Patients with Brunner's gland cyst demonstrate no specific symptoms. The present study reports the case of a patient with Brunner's gland cyst located in the duodenum in combination with a gastrointestinal stromal tumor (GIST) in the same region. To the best of our knowledge, the present study reports the first case of Brunner's gland cyst with GIST. A 58-year-old female patient was referred to Tianchang Hospital of Traditional Chinese Medicine (Tianchang, China) with a one-month history of upper abdominal discomfort, diarrhea and recurrent vomiting following the intake of food. Upper gastrointestinal endoscopy and a computed tomography scan revealed the presence of a round, cystic-like lesion with internal low density located within the duodenum. Pathological examination revealed that the cyst measured 0.3 cm in diameter and was consistent with a diagnosis of Brunner's gland cyst. Histopathology revealed that the cyst possessed characteristics of GIST. The patient underwent surgical exploration and tumor resection, and was discharged 2 weeks post-surgery. During the 12 month post-operative follow-up period, the outcome of the patient was good. This case study of Brunner's gland cyst combined with GIST enriches the present literature and promotes better understanding of the two diseases. Further investigation is required to explain the mechanism and association between the two rare diseases. PMID:27123125

  13. Integrated genomic analyses identify frequent gene fusion events and VHL inactivation in gastrointestinal stromal tumors

    PubMed Central

    Sun, Choong-Hyun; Park, Inho; Lee, Seungmook; Kwon, Jekeun; Do, Ingu; Hong, Min Eui; Van Vrancken, Michael; Lee, Jeeyun; Park, Joon Oh; Cho, Jeonghee; Kim, Kyoung-Mee; Sohn, Tae Sung

    2016-01-01

    Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. We sequenced nine exomes and transcriptomes, and two genomes of GISTs for integrated analyses. We detected 306 somatic variants in nine GISTs and recurrent protein-altering mutations in 29 genes. Transcriptome sequencing revealed 328 gene fusions, and the most frequently involved fusion events were associated with IGF2 fused to several partner genes including CCND1, FUS, and LASP1. We additionally identified three recurrent read-through fusion transcripts: POLA2-CDC42EP2, C8orf42-FBXO25, and STX16-NPEPL1. Notably, we found intragenic deletions in one of three exons of the VHL gene and increased mRNAs of VEGF, PDGF-β, and IGF-1/2 in 56% of GISTs, suggesting a mechanistic link between VHL inactivation and overexpression of hypoxia-inducible factor target genes in the absence of hypoxia. We also identified copy number gain and increased mRNA expression of AMACR, CRIM1, SKP2, and CACNA1E. Mapping of copy number and gene expression results to the KEGG pathways revealed activation of the JAK-STAT pathway in small intestinal GISTs and the MAPK pathway in wild-type GISTs. These observations will allow us to determine the genetic basis of GISTs and will facilitate further investigation to develop new therapeutic options. PMID:25987131

  14. Malignant extra-gastrointestinal stromal tumor of the liver: A case report

    PubMed Central

    WANG, YINGCHAO; LIU, YAHUI; ZHONG, YANPING; JI, BAI

    2016-01-01

    Extra-gastrointestinal stromal tumors (EGISTs) predominantly occur outside of the gastrointestinal tract, and their biological and histological characteristics are similar to those of GISTs. Primary EGIST occurrence in the liver is extremely rare. The present study reports a case of primary EGIST in the caudate lobe of the liver in a 61-year-old Chinese man. Contrast-enhanced computed tomography revealed a 7.3×5.1-cm heterogeneously enhanced neoplasm with solid and cystic components located in the caudate lobe of the liver. The patient underwent caudate lobe (specifically, Spiegel lobe) resection. Immunohistochemical analysis of the resected tumor revealed a strong positivity for cluster of differentiation (CD)117, discovered on GIST-1 and CD34. Thus, based on the histological and immunohistochemical findings, the final diagnosis was primary hepatic EGIST. Follow up was conducted at 3-month intervals for the first year and 6-months thereafter. The patient was asymptomatic without any sign of recurrence during the follow-up period. Lab tests were in normal range, and no mass was found in CT scan. PMID:27313719

  15. Gastrointestinal stromal tumors regularly express synaptic vesicle proteins: evidence of a neuroendocrine phenotype.

    PubMed

    Bümming, Per; Nilsson, Ola; Ahlman, Håkan; Welbencer, Anna; Andersson, Mattias K; Sjölund, Katarina; Nilsson, Bengt

    2007-09-01

    Gastrointestinal stromal tumors (GISTs) are thought to originate from the interstitial cells of Cajal, which share many properties with neurons of the gastrointestinal tract. Recently, we demonstrated expression of the hormone ghrelin in GIST. The aim of the present study was therefore to evaluate a possible neuroendocrine phenotype of GIST. Specimens from 41 GISTs were examined for the expression of 12 different synaptic vesicle proteins. Expression of synaptic-like microvesicle proteins, e.g., Synaptic vesicle protein 2 (SV2), synaptobrevin, synapsin 1, and amphiphysin was demonstrated in a majority of GISTs by immunohistochemistry, western blotting, and quantitative reversetranscriptase PCR. One-third of the tumors also expressed the large dense core vesicle protein vesicular monoamine transporter 1. Presence of microvesicles and dense core vesicles in GIST was confirmed by electron microscopy. The expression of synaptic-like microvesicle proteins in GIST was not related to risk profile or to KIT/platelet derived growth factor alpha (PDGFRA) mutational status. Thus, GISTs regularly express a subset of synaptic-like microvesicle proteins necessary for the regulated secretion of neurotransmitters and hormones. Expression of synaptic-like micro-vesicle proteins, ghrelin and peptide hormone receptors in GIST indicate a neuroendocrine phenotype and suggest novel possibilities to treat therapy-resistant GIST. PMID:17914114

  16. Interventional digital subtraction angiography for small bowel gastrointestinal stromal tumors with bleeding

    PubMed Central

    Chen, Yao-Ting; Sun, Hong-Liang; Luo, Jiang-Hong; Ni, Jia-Yan; Chen, Dong; Jiang, Xiong-Ying; Zhou, Jing-Xing; Xu, Lin-Feng

    2014-01-01

    AIM: To retrospectively evaluate the diagnostic efficacy of interventional digital subtraction angiography (DSA) for bleeding small bowel gastrointestinal stromal tumors (GISTs). METHODS: Between January 2006 and December 2013, small bowel tumors in 25 consecutive patients undergoing emergency interventional DSA were histopathologically confirmed as GIST after surgical resection. The medical records of these patients and the effects of interventional DSA and the presentation and management of the condition were retrospectively reviewed. RESULTS: Of the 25 patients with an age range from 34- to 70-year-old (mean: 54 ± 12 years), 8 were male and 17 were female. Obscure gastrointestinal bleeding, including tarry or bloody stool and intermittent melena, was observed in all cases, and one case also involved hematemesis. Nineteen patients required acute blood transfusion. There were a total of 28 small bowel tumors detected by DSA. Among these, 20 were located in the jejunum and 8 were located in the ileum. The DSA characteristics of the GISTs included a hypervascular mass of well-defined, homogeneous enhancement and early developed draining veins. One case involved a complication of intussusception of the small intestine that was discovered during surgery. No pseudoaneurysms, arteriovenous malformations or fistulae, or arterial rupture were observed. The completely excised size was approximately 1.20 to 5.50 cm (mean: 3.05 ± 1.25 cm) in maximum diameter based on measurements after the resection. There were ulcerations (n = 8), erosions (n = 10), hyperemia and edema (n = 10) on the intra-luminal side of the tumors. Eight tumors in patients with a large amount of blood loss were treated with transcatheter arterial embolization with gelfoam particles during interventional DSA. CONCLUSION: Emergency interventional DSA is a useful imaging option for locating and diagnosing small bowel GISTs in patients with bleeding, and is an effective treatment modality. PMID:25548494

  17. Generation of orthotopic patient-derived xenografts from gastrointestinal stromal tumor

    PubMed Central

    2014-01-01

    Background Gastrointestinal 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. Methods Fresh 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. Results Herein, 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

  18. Combined presence of multiple gastrointestinal stromal tumors along with duodenal submucosal somatostatinoma in a patient with neurofibromatosis type 1.

    PubMed

    Kumar, Tarun; Gupta, Brijnandan; Das, Prasenjit; Jain, Deepali; Jain, Hemant Ashok; Madhusudhan, Kumble S; Dash, Nihar Ranjan; Gupta, Siddhartha Datta

    2016-01-01

    Neurofibromatosis type-1 (NF-1) is an autosomal dominant disorder, with increased risk of developing benign and malignant tumors of the gastrointestinal tract (GIT). However, the synchronous presence of multiple GIT stromal tumors and duodenal submucosal somatostatinoma, like in this 50-year-old female NF-1 patient, is very rare. She presented with hematemesis, malena, along with multiple neurofibromas all over the body. Thorough radiological and peroperative work-up revealed multiple ulcerated submucosal and serosal nodules in the proximal small intestine. Histological work-up revealed diagnosis of a duodenal submucosal somatostatinoma with multifocal serosal gastrointestinal stromal tumors. This case is being reported to highlight the rare coincidence of multiple GIT tumors in an NF-1 patient. PMID:27510677

  19. A meta-analysis of prognostic value of KIT mutation status in gastrointestinal stromal tumors

    PubMed Central

    Jiang, Zhiqiang; Zhang, Jian; Li, Zhi; Liu, Yingjun; Wang, Daohai; Han, Guangsen

    2016-01-01

    Numerous types of KIT mutations have been reported in gastrointestinal stromal tumors (GISTs); however, controversy still exists regarding their clinicopathological significance. In this study, we reviewed the publicly available literature to assess the data by a meta-analysis to characterize KIT mutations and different types of KIT mutations in prognostic prediction in patients with GISTs. Twenty-eight studies that included 4,449 patients were identified and analyzed. We found that KIT mutation status was closely correlated with size of tumors and different mitosis indexes, but not with tumor location. KIT mutation was also observed to be significantly correlated with tumor recurrence, metastasis, as well as the overall survival of patients. Interestingly, there was higher risk of progression in KIT exon 9-mutated patients than in exon 11-mutated patients. Five-year relapse-free survival (RFS) rate was significantly higher in KIT exon 11-deleted patients than in those with other types of KIT exon 11 mutations. In addition, RFS for 5 years was significantly worse in patients bearing KIT codon 557–558 deletions than in those bearing other KIT exon 11 deletions. Our results strongly support the hypothesis that KIT mutation status is another evaluable factor for prognosis prediction in GISTs. PMID:27350754

  20. Multiple Gastric Gastrointestinal Stromal Tumors in a Patient with Neurofibromatosis Type 1.

    PubMed

    Tomatsu, Makoto; Isogaki, Jun; Watanabe, Takahiro; Yajima, Kiyoshige; Okumura, Takuya; Yamashita, Kimihiro; Suzuki, Kenji; Kawabe, Akihiro; Komiyama, Akira; Hirota, Seiichi

    2016-01-01

    Gastrointestinal stromal tumors (GISTs) are relatively common in neurofibromatosis type 1 (NF 1) patients. Approximately 90% of GISTs associated with NF 1 are located in the small intestine, while sporadic GISTs are most commonly located in the stomach. Here we report an extremely rare case of an NF 1 patient with multiple gastric GITs (90 or more) but without multiple small intestinal tumors. A 63-year-old female patient who had a history of NF 1 underwent surgery for a gastric neuroendocrine tumor and gastric submucosal tumor (SMT). During the operation, multiple small nodules were identified on the serosal surface of the upper stomach. SMT and multiple nodules on the serosal surface were diagnosed as GISTs consisting of spindle cells positive for KIT, CD34, and DOG-1. Both GIST and the normal gastric mucosa showed no mutations not only in the c-kit gene (exons 8, 9, 11, 13, and 17) but also in the PDGFRA gene (exons 12, 14, and 18). This patient is being followed up without the administration of a tyrosine kinase inhibitor. PMID:27375917

  1. Multiple Gastric Gastrointestinal Stromal Tumors in a Patient with Neurofibromatosis Type 1

    PubMed Central

    Isogaki, Jun; Yajima, Kiyoshige; Yamashita, Kimihiro; Suzuki, Kenji; Hirota, Seiichi

    2016-01-01

    Gastrointestinal stromal tumors (GISTs) are relatively common in neurofibromatosis type 1 (NF 1) patients. Approximately 90% of GISTs associated with NF 1 are located in the small intestine, while sporadic GISTs are most commonly located in the stomach. Here we report an extremely rare case of an NF 1 patient with multiple gastric GITs (90 or more) but without multiple small intestinal tumors. A 63-year-old female patient who had a history of NF 1 underwent surgery for a gastric neuroendocrine tumor and gastric submucosal tumor (SMT). During the operation, multiple small nodules were identified on the serosal surface of the upper stomach. SMT and multiple nodules on the serosal surface were diagnosed as GISTs consisting of spindle cells positive for KIT, CD34, and DOG-1. Both GIST and the normal gastric mucosa showed no mutations not only in the c-kit gene (exons 8, 9, 11, 13, and 17) but also in the PDGFRA gene (exons 12, 14, and 18). This patient is being followed up without the administration of a tyrosine kinase inhibitor. PMID:27375917

  2. Genomic mapping of pathways in endometrial adenocarcinoma and a gastrointestinal stromal tumor located in Meckel's diverticulum

    PubMed Central

    ENGLERT-GOLON, MONIKA; BUDNY, BARTLOMIEJ; BURCHARDT, BARTOSZ; WROTKOWSKA, ELZBIETA; ZIEMNICKA, KATARZYNA; RUCHAŁA, MAREK; SAJDAK, STEFAN

    2016-01-01

    The present study reports the case of a 71-year-old female patient diagnosed with endometrial adenocarcinoma, which was confirmed by histopathology. In the course of performing an elective hysterectomy with adnexa removal, a solid tumor located in Meckel's diverticulum (MD) was identified and excised. Due to the unique nature of the lesion, the tumor tissue underwent broad mapping of any genomic alterations once the histopathological examination was completed. The genetic testing was conducted using a high-resolution microarray and resulted in the identification of 45 genomic abnormalities, including 4 chromosomal aneuploidies. Within those regions, alterations of 87 known cancer genes were assigned. The involvement of v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog gene alteration was noted to be a key player for triggering gastrointestinal stromal tumor transformation for this unusual case. A total of 12 genes, showing mutual interaction in different cancer types or involved in diverse cellular processes, were identified. These reported data may shed light on the carcinogenesis of a rare MD tumor. PMID:26893683

  3. Long-Term Outcomes after Endoscopic Treatment of Gastric Gastrointestinal Stromal Tumor

    PubMed Central

    Park, Jong-Jae

    2016-01-01

    Endoscopic resection of gastric subepithelial tumors (SETs) has several advantages over biopsy techniques, such as superior diagnostic yield and definite diagnosis. Removal of gastric SETs and histopathologic confirmation should be considered whenever gastric SETs are highly suspected to have malignant potential such as gastrointestinal stromal tumor (GIST) or neuroendocrine tumor. According to our clinical experience, we suggest that endoscopic resection of gastric SETs is feasible for GISTs less than 3.0 cm without positive endoscopic ultrasonography findings or for hypoechoic SETs less than 3.0 cm. However, serious complications such as macroperforation may occur during endoscopic resection, and this procedure is highly dependent on endoscopists’ skills. We recently reported the long-term clinical outcomes of endoscopic resection of gastric GIST, which showed a relatively low recurrence rate (2.2%) during long-term follow-up (46.0±28.5 months) despite the low R0 resection rate (25.0%). We suggest that endoscopic surveillance might be possible without additional surgical resection in completely resected GISTs without residual tumor confirmed to be lower risk, even if they show an R1 resection margin. PMID:27196737

  4. Coexisting and possible primary extra-gastrointestinal stromal tumors of the pancreas and liver: A single case report

    PubMed Central

    LIU, LEI; ZHU, YINGQIAO; WANG, DONGXUAN; YANG, CHANGBIN; ZHANG, QI; LI, XIUKUN; BAI, YANG

    2016-01-01

    Gastrointestinal stromal tumors (GIST) are mesenchymal neoplasms of the gastrointestinal tract (GI) that are defined, in part, by the expression of CD117, a c-Kit proto-oncogene protein. GISTs emerge outside of the GI at a very low frequency, typically in a single organ or location. GISTs that occasionally emerge outside of the GI are classified as extra-gastrointestinal stromal tumors (EGIST). The present study reports an extremely rare case of EGIST detected in the pancreas and the liver. The pancreatic and liver tumors were 4.5×2.5 cm and 2.0×1.5 cm in size, respectively. Both tumors consisted of CD117-positive spindle cells with a similar mitotic rate of 1–2 per 50 high power fields. The pancreatic and the hepatic EGISTs were at a low risk of malignancy, and both tumors were proposed to be primary stromal tumors. To the best of our knowledge, this is the first report of likely primary EGIST identified in the pancreas and liver of the same patient. PMID:27123107

  5. High Density DNA Array Analysis Reveals Distinct Genomic Profiles in a Subset of Gastrointestinal Stromal Tumors

    PubMed Central

    Belinsky, Martin G.; Skorobogatko, Yuliya V.; Rink, Lori; Pei, Jianming; Cai, Kathy Q.; Vanderveer, Lisa A.; Riddell, David; Merkel, Erin; Tarn, Chi; Eisenberg, Burton L.; von Mehren, Margaret; Testa, Joseph R.; Godwin, Andrew K.

    2010-01-01

    Gastrointestinal stromal tumors (GISTs) generally harbor activating mutations in KIT or PDGFRA. Mutations in these receptor tyrosine kinases lead to dysregulation of downstream signaling pathways that contribute to GIST pathogenesis. GISTs with KIT or PDGFRA mutations also undergo secondary cytogenetic alterations that may indicate the involvement of additional genes important in tumor progression. Approximately 10–15% of adult and 85% of pediatric GISTs do not have mutations in KIT or in PDGFRA. Most mutant adult GISTs display large-scale genomic alterations, but little is know about the mutation-negative tumors. Using genome-wide DNA arrays, we investigated genomic imbalances in a set of 31 GISTs, including 10 KIT/PDGFRA mutation-negative tumors from 9 adults and 1 pediatric case and 21 mutant tumors. While all 21 mutant GISTs exhibited multiple copy number aberrations, notably losses, 8 of the 10 KIT/PDGFRA mutation-negative GISTs exhibited few or no genomic alterations. One KIT/PDGFRA mutation-negative tumor exhibiting numerous genomic changes was found to harbor an alternate activating mutation, in the serine-threonine kinase BRAF. The only other mutation-negative GIST with significant chromosomal imbalances was a recurrent metastatic tumor found to harbor a homozygous deletion in chromosome 9p. Similar findings in several KIT-mutant GISTs identified a minimal overlapping region of deletion of ~0.28 Mbp in 9p21.3 that includes only the CDKN2A/2B genes, which encode inhibitors of cell-cycle kinases. These results suggest that GISTs without activating kinase mutations, whether pediatric or adult, generally exhibit a much lower level of cytogenetic progression than that observed in mutant GISTs. PMID:19585585

  6. Imaging features of primary anorectal gastrointestinal stromal tumors with clinical and pathologic correlation

    PubMed Central

    Koch, M.R.; Jagannathan, J.P.; Krajewski, K.M.; Raut, C.P.; Hornick, J.L.; Ramaiya, N.H.

    2012-01-01

    Abstract Purpose: To evaluate the imaging features of anorectal gastrointestinal stromal tumors (GISTs) with clinical and histopathologic correlation. Materials and methods: In this Institutional Review Board-approved, Health Insurance Portability and Accountability Act-compliant retrospective study, 16 patients (12 men; mean age 66 years (30–89 years)) with pathologically proven anorectal GISTs seen at our institution from January 2001 to July 2011 were identified. Electronic medical records were reviewed to obtain clinical data. Pretreatment imaging studies (computed tomography (CT) in 16 patients, magnetic resonance imaging (MRI) in 9 patients and fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT in 8 patients) were evaluated by 2 radiologists until consensus. The location, size and imaging features of the primary tumor and metastases at presentation, if any, were recorded, and correlated with clinical data and pathologic features (histologic type, presence of necrosis, mitotic activity, risk category, immunohistochemical profile). Results: The mean tumor size was 6.9 × 6.0 cm. Of the 16 tumors, 11 (68.7%) were infralevator, 4 (25%) supra and infralevator and 1 (6.3%) supralevator; 9 (56.2%) were exophytic, 6 (37.5%) both exophytic and intraluminal, and 1 (6.3%) was intraluminal. The tumors were iso- to minimally hypoattenuating to muscle on CT, iso- to minimally hypointense on T1-weighted images, hyperintense on T2-weighted images and showed variable enhancement. Necrosis was seen in 4 (25%), and hemorrhage and calcification in 2 (12.5%) patients each. The tumors were FDG avid with a mean maximum standardized uptake value of 11 (8.4–16.8). All tumors were positive for KIT and CD34. Distant metastasis to liver was seen in 1 patient (6.3%) at presentation. Conclusion: Anorectal GISTs are well-circumscribed, non-circumferential, predominantly infralevator, intramural or exophytic, FDG-avid, hypoattenuating masses, and present without

  7. Cutaneous and subcutaneous metastases of gastrointestinal stromal tumors: a series of 5 cases with molecular analysis.

    PubMed

    Wang, Wei-Lien; Hornick, Jason L; Mallipeddi, Raj; Zelger, Bettina G; Rother, Joshua D; Yang, Dan; Lev, Dina C; Trent, Jonathan C; Prieto, Victor G; Brenn, Thomas; Robson, Alistair; Calonje, Eduardo; Lazar, Alexander J F

    2009-05-01

    Gastrointestinal stromal tumors (GISTs) rarely metastasize to the skin. We describe 5 patients with GIST with subcutaneous and cutaneous metastases. The mean age at metastasis was 54 years (range 30-68 years) with a male predominance (4:1). Primary tumors occurred in the stomach (n = 3), small bowel (n = 1), and abdomen, not otherwise specified (n = 1). The average time from primary tumor resection to the resection of skin metastases was 59 months (range 11-155 months). The metastases occurred in the scalp (n = 2), cheek (n = 1), and abdomen (n = 2) with 3 patients presenting with solitary nodules and 2 patients with multiple nodules. The average size was 2 cm (range 0.6-4 cm). Histologically, 2 cases were spindled and 3 cases demonstrated mixed epithelioid and spindle cell morphology. All were confirmed to have CD117 reactivity. KIT genotyping was performed in 4 of 5 cases. Two cases harbored a mutation in exon 11, and the remaining 2 cases were wild type in exons 9, 11, 13, and 17. All 5 patients had multiple concurrent or subsequent abdominal and/or hepatic metastases. In 4 patients with an average follow-up of 32 months (range 6-75 months), after the resection of the metastases, 2 were alive with disease and 2 died of disease. Cutaneous metastases seem to be a late complication of GIST, but their presence does not necessarily herald a rapid demise of the patient. PMID:19384074

  8. Pharmacological inhibition of KIT activates MET signaling in gastrointestinal stromal tumors

    PubMed Central

    Cohen, Noah A.; Zeng, Shan; Seifert, Adrian M.; Kim, Teresa S.; Sorenson, Eric C.; Greer, Jonathan B.; Beckman, Michael J.; Santamaria-Barria, Juan A.; Crawley, Megan H.; Green, Benjamin L.; Rossi, Ferdinand; Besmer, Peter; Antonescu, Cristina R.; DeMatteo, Ronald P.

    2015-01-01

    Gastrointestinal stromal tumors (GIST) are the most common adult sarcomas and the oncogenic driver is usually a KIT or PDGFRA mutation. While GIST are often initially sensitive to imatinib or other tyrosine kinase inhibitors, resistance generally develops necessitating backup strategies for therapy. In this study, we determined that a subset of human GIST specimens that acquired imatinib resistance acquired expression of activated forms of the MET oncogene. MET activation also developed after imatinib therapy in a mouse model of GIST (KitV558del/+ mice), where it was associated with increased tumor hypoxia. MET activation also occurred in imatinib-sensitive human GIST cell lines after imatinib treatment in vitro. MET inhibition by crizotinib or RNA interference was cytotoxic to an imatinib-resistant human GIST cell population. Moreover, combining crizotinib and imatinib was more effective than imatinib alone in imatinib-sensitive GIST models. Lastly, cabozantinib, a dual MET and KIT small molecule inhibitor, was markedly more effective than imatinib in multiple preclinical models of imatinib-sensitive and imatinib-resistant GIST. Collectively, our findings showed that activation of compensatory MET signaling by KIT inhibition may contribute to tumor resistance. Furthermore, our work offered a preclinical proof of concept for MET inhibition by cabozantinib as an effective strategy for GIST treatment. PMID:25836719

  9. Gastrointestinal Stromal Tumors: A Review of Case Reports, Diagnosis, Treatment, and Future Directions

    PubMed Central

    Tan, Christopher B.; Zhi, Wanqing; Shahzad, Ghulamullah; Mustacchia, Paul

    2012-01-01

    Gastrointestinal stromal tumor (GIST) is a nonepithelial, mesenchymal tumor first described by Mazur and Clark in 1983. Since then, its molecular biology has been studied in great detail. Special interest in the role of tyrosine kinase in its regulation has been the target by different drug research. Mutation in c-kit exons 9, 11, 13, 17 and PDGFRA mutation in exons 12, 14, 18 are responsible for activation of gene signaling system resulting in uncontrolled phosphorylation and tissue growth. However, 5 to 15% of GISTs does not harbor these mutations, which raises additional questions in another alternate signaling pathway mutation yet to be discovered. Diagnosis of GISTs relies heavily on KIT/CD117 immunohistochemical staining, which can detect most GISTs except for a few 3% to 5% that harbors PDGFRA mutation. Newer staining against PKC theta and DOG-1 genes showed promising results but are not readily available. Clinical manifestation of GISTs is broad and highly dependent on tumor size. Surgery still remains the first-line treatment for GISTs. The advancement of molecular biology has revolutionized the availability of newer drugs, Imatinib and Sunitinib. Together with its advancement is the occurrence of Imatinib/Sunitinib drug resistance. With this, newer monoclonal antibody drugs are being developed and are undergoing clinical trials to hopefully improve survival in patients with GISTs. PMID:22577569

  10. RACK1 overexpression is linked to acquired imatinib resistance in gastrointestinal stromal tumor

    PubMed Central

    Gao, Xiaodong; Xue, Anwei; Fang, Yong; Shu, Ping; Ling, Jiaqian; Hou, Yingyong; Shen, Kuntang; Qin, Jing; Sun, Yihong; Qin, Xinyu

    2016-01-01

    Although treatment with imatinib, which inhibits KIT and PDGFR, controls advanced disease in about 80% of gastrointestinal stromal tumor (GIST) patients, resistance to imatinib often develops. RACK1 (Receptor for Activated C Kinase 1) is a ribosomal protein that contributes to tumor progression by affecting proliferation, apoptosis, angiogenesis, and migration. Here, we found that c-KIT binds to RACK1 and increases proteasome-mediated RACK1 degradation. Imatinib treatment inhibits c-KIT activity and prevents RACK1 degradation, and RACK1 is upregulated in imatinib-resistant GIST cells compared to non-resistant parental cells. Moreover, Erk and Akt signaling were reactivated by imatinib in resistant GIST cells. RACK1 functioned as a scaffold protein and mediated Erk and Akt reactivation after imatinib treatment, thereby promoting GIST cell survival even in the presence of imatinib. Combined inhibition of KIT and RACK1 inhibited growth in imatinib-resistant GIST cell lines and reduced tumor relapse in GIST xenografts. These findings provide new insight into the role of RACK1 in imatinib resistance in GIST. PMID:26893362

  11. Multimodality therapy of rectal gastrointestinal stromal tumors in the era of imatinib—an Indian series

    PubMed Central

    Pai, Vishwas D.; Demenezes, Jean L.; Patil, Prachi S.

    2016-01-01

    Background Primary objective was to determine if sphincter preservation is possible with the use of neoadjuvant imatinib in cases of rectal gastrointestinal stromal tumor (GIST). Secondary objectives were to determine clinicopathological characteristics and intermediate term oncological outcomes of the cases of rectal GIST. Methods This is a retrospective review of 13 cases of GIST of the rectum diagnosed between January 1, 2010 and June 30, 2015 at Tata Memorial Centre, Mumbai, India. Clinical parameters that were assessed were duration of the neoadjuvant imatinib therapy, type of surgery performed as well as perioperative morbidity. Pathological parameters that were assessed included the size of the tumor, completeness of resection, mitotic count and mutational analysis. Results Of the 13 patients included, 11 were nonmetastatic at the time of presentation. All the patients received neoadjuvant imatinib in view of locally advanced nature of the tumors. Median distance from anal verge was 2 cm. Median duration of imatinib was 9 months. Of the 9 patients who underwent surgery, three had sphincter preserving surgery (33%) whereas the rest had abdomino-perineal resection. Two patients had perineal wound infections. All the operated patients received adjuvant imatinib therapy for 3 years. Median follow up period was 34 months. One patient developed distant metastasis; otherwise rest had no local or distant recurrence. Conclusions In cases of rectal GIST, sphincter preservation may not be possible in spite of neoadjuvant therapy with imatinib. PMID:27034795

  12. A Case of a Gastrointestinal Stromal Tumor with Skeinoid Fibers of the Sigmoid Colon

    PubMed Central

    Sumi, Tetsuo; Katsumata, Kenji; Shibuya, Makoto; Katayanagi, Sou; Iwasaki, Kenichi; Kasuya, Kazuhiko; Serizawa, Hiromi; Shimazu, Motohide; Tsuchida, Akihiko

    2014-01-01

    An 80-year-old man was diagnosed with rectal cancer and underwent Hartmann's procedure. Although no tumors were identified during the preoperative examination, gross examination of the resected specimen incidentally revealed a submucosal tumor that was 9 mm in diameter at the oral side and located in the proximal stump of the specimen from the sigmoid colon. We suspected a concurrent gastrointestinal stromal tumor (GIST) and performed a histopathological examination. An L-shaped nodular lesion measuring 9 × 6 mm was histologically composed of a patternless proliferation of spindle cells intermingled with eosinophilic globules. Cellular atypia, prominent mitotic figures and necrotic foci were not observed in the nodule. The spindle cells were positive for CD34, CD117 and vimentin, but negative for CD56, smooth muscle actin and S-100 protein. MIB-1 positivity was estimated to be as low as approximately 1–2%. Electron microscopy showed a bundle of wool-like fibers with a periodicity of approximately 40 nm. We therefore considered the lesion to be a low-risk GIST with skeinoid fibers in the large intestine. Although numerous previous reports have reported skeinoid fibers in the stomach and small intestines, there have been only 9 cases (including the present case) of skeinoid fibers in the large intestine. PMID:25408627

  13. Nestin regulates proliferation and invasion of gastrointestinal stromal tumor cells by altering mitochondrial dynamics.

    PubMed

    Wang, J; Cai, J; Huang, Y; Ke, Q; Wu, B; Wang, S; Han, X; Wang, T; Wang, Y; Li, W; Lao, C; Song, W; Xiang, A P

    2016-06-16

    Nestin is widely expressed in numerous tumors and has become a diagnostic and prognostic indicator. However, the exact mechanism by which nestin contributes to tumor malignancy remains poorly understood. Here, we found marked upregulation of nestin expression in highly proliferative and invasive gastrointestinal stromal tumor (GIST) specimens. Nestin knockdown in GIST cells reduced the proliferative and invasive activity owing to a decrease of mitochondrial intracellular reactive oxygen species (ROS) generation. Furthermore, nestin was co-localized with mitochondria, and knockdown of nestin increased mitochondrial elongation and influenced the mitochondrial function, including oxygen consumption rates, ATP generation and mitochondrial membrane potential and so on. In exploring the underlying mechanism, we demonstrated nestin knockdown inhibited the mitochondrial recruitment of Dynamin-related protein1 and induced the change of mitochondrial dynamics. Thus, nestin may have an important role in GIST malignancy by regulating mitochondrial dynamics and altering intracellular ROS levels. The findings provide new clues to reveal mechanisms by which nestin mediates the proliferation and invasion of GISTs. PMID:26434586

  14. The endoscopic appearance of a gastrointestinal stromal tumor in a pediatric patient.

    PubMed

    Muniyappa, Pramodha; Kay, Marsha; Feinberg, Lisa; Mahajan, Lori; Stallion, Anthony; Wyllie, Robert

    2007-07-01

    Gastrointestinal stromal tumor (GIST) is a mesenchymal tumor that is rare in children. We report a case of GIST in a pediatric patient. A 16-year-old adolescent girl presented after an episode of syncope preceded by one episode of melena. Physical examination results were normal except for Hemoccult-positive stool. Laboratory studies included a hemoglobin level of 6.1 g/dL; complete metabolism profile and coagulation studies revealed normal results. She was transfused with 2 units of packed red blood cells, and an urgent esophagogastroduodenoscopy was performed. Esophagogastroduodenoscopy demonstrated 3 submucosal sessile masses in the gastric antrum ranging from 1 to 3 cm with normal overlying mucosa except for one of the lesions, which was ulcerated. Endoscopic biopsies stained positive for CD117 and were consistent with GIST. Radiologic imaging demonstrated the endoscopically visualized masses and also showed a solitary 1-cm lesion within the liver. She underwent partial gastrectomy and open biopsy of the hepatic lesion. Histologic examination confirmed GIST with hepatic metastasis. Typically with GIST, esophagogastroduodenoscopy will demonstrate a normal surface mucosa and a firm, smooth yellowish submucosal mass, which can be ulcerated. In some cases these tumors can be missed because of their frequent submucosal and extraluminal growth. This case, to our knowledge, is one of the first reports of the endoscopic appearance of GIST in a pediatric patient. Although a rare entity in children, GIST should be considered in pediatric patients with endoscopically visualized submucosal gastric masses. PMID:17618903

  15. Gastrointestinal stromal tumors as an incidental finding in patients with a presumptive diagnosis of ovarian cancer

    PubMed Central

    Muñoz, Mario; Ramirez, Pedro T.; Echeverri, Carolina; Álvarez, Luis Guillermo; Palomino, Maria Alejandra

    2012-01-01

    Objective To report the clinical presentation and oncologic outcomes of a series of patients who presented with an abdominal or pelvic mass and were diagnosed with a gastrointestinal stromal tumor (GIST). Methods Data were obtained on all patients who presented with an abdominal or pelvic mass between September 2007 and June 2010 and who were ultimately diagnosed with a GIST. The patients' medical records were reviewed. A literature review was also conducted. Results Six patients were identified who met the inclusion criteria. All six patients had a tumor in the intestinal tract arising from the small bowel. The mean tumor size was 12 cm (range, 6 to 22 cm). A complete resection was achieved in five of the six patients. There were no intraoperative complications; one patient had a postoperative complication. Two patients were treated with imatinib after surgery. The mean follow-up time was 32 months (range, 0.3 to 40 months). At the last follow-up, five of the six patients were without any evidence of disease. One patient died of an unrelated hepatic encephalopathy. The incidence in our institution is 3%. Conclusion GISTs are uncommon; however, they should be considered in the differential diagnosis of patients presenting with an abdominal or pelvic mass. PMID:22355467

  16. Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor.

    PubMed

    Killian, J Keith; Kim, Su Young; Miettinen, Markku; Smith, Carly; Merino, Maria; Tsokos, Maria; Quezado, Martha; Smith, William I; Jahromi, Mona S; Xekouki, Paraskevi; Szarek, Eva; Walker, Robert L; Lasota, Jerzy; Raffeld, Mark; Klotzle, Brandy; Wang, Zengfeng; Jones, Laura; Zhu, Yuelin; Wang, Yonghong; Waterfall, Joshua J; O'Sullivan, Maureen J; Bibikova, Marina; Pacak, Karel; Stratakis, Constantine; Janeway, Katherine A; Schiffman, Joshua D; Fan, Jian-Bing; Helman, Lee; Meltzer, Paul S

    2013-06-01

    Gastrointestinal stromal tumors (GIST) harbor driver mutations of signal transduction kinases such as KIT, or, alternatively, manifest loss-of-function defects in the mitochondrial succinate dehydrogenase (SDH) complex, a component of the Krebs cycle and electron transport chain. We have uncovered a striking divergence between the DNA methylation profiles of SDH-deficient GIST (n = 24) versus KIT tyrosine kinase pathway-mutated GIST (n = 39). Infinium 450K methylation array analysis of formalin-fixed paraffin-embedded tissues disclosed an order of magnitude greater genomic hypermethylation relative to SDH-deficient GIST versus the KIT-mutant group (84.9 K vs. 8.4 K targets). Epigenomic divergence was further found among SDH-mutant paraganglioma/pheochromocytoma (n = 29), a developmentally distinct SDH-deficient tumor system. Comparison of SDH-mutant GIST with isocitrate dehydrogenase-mutant glioma, another Krebs cycle-defective tumor type, revealed comparable measures of global hypo- and hypermethylation. These data expose a vital connection between succinate metabolism and genomic DNA methylation during tumorigenesis, and generally implicate the mitochondrial Krebs cycle in nuclear epigenomic maintenance. PMID:23550148

  17. Genetic variations in the TERT and CLPTM1L gene region and gastrointestinal stromal tumors risk

    PubMed Central

    Zhang, Rui; Zhao, Jian; Xu, Jian; Liu, Fang; Xu, Yongqing; Bu, Xianmin; Dai, Chaoliu; Song, Chun

    2015-01-01

    Recent studies have suggested polymorphisms in the TERT and CLPTM1L region are associated with carcinogenesis of many distinct cancer types, including gastrointestinal cancers. However, the contribution of polymorphisms in the TERT and CLPTM1L gene region to gastrointestinal stromal tumors (GISTs) risk is still unknown. We tested the six tagSNPs on TERT and CLPTM1L region with GIST risk, using a population-based, two-stage, case-control study in 2,000 subjects. Functional validation was conducted to validate our findings of TERT rs2736098 and explore its influence on relative telomere length (RTL) in GIST cells. It showed that variant rs2736098 was significantly associated with increased risk of GIST (per allele OR = 1.29, 95% CI: 1.14–1.47, P = 7.03 × 10−5). The difference remain significant after Bonferroni correction (P = 7.03 × 10−5 * 6 = 4.2 × 10−4). Real-time PCR showed carriers of genotype CC have the longest RTL, following by carriers of genotype CT, while carriers of genotype TT have the shortest RTL in GIST tissues (P < 0.001). Our data provide evidence to implicate TERT rs2736098 polymorphism as a novel susceptibility factor for GIST risk. PMID:26372813

  18. Gut wall replacing type of gastrointestinal stromal tumor presenting as a perforation of the ileal diverticulum.

    PubMed

    Ikemura, Masako; Kunita, Akiko; Miwa, Yoshiyuki; Jimbo, Keiichi; Mori, Kazuhiko; Seto, Yasuyuki; Fukayama, Masashi

    2015-11-01

    Gastrointestinal stromal tumors (GISTs) usually form a well-circumscribed mass. Very rarely, however, sporadic GISTs show gut-wall replacing growth, similar to the diffuse hyperplasia of interstitial cells of Cajal (ICC) observed in patients with neurofibromatosis type 1 (NF1) and hereditary GIST. Here we describe a patient with ileal perforation caused by this unusual type of GIST. An 82-year-old man was admitted to the emergency department with sudden abdominal pain. Following a provisional diagnosis of perforation of Meckel's diverticulum, he underwent segmental resection of the small intestine. Macroscopic examination revealed a diverticulum-like structure 2.5cm in size near the site of mesenteric attachment of the ileum. Histological examination showed diffuse and nodular proliferation of spindle cells positive for c-KIT and CD34 that had replaced the muscularis propria of the small intestine. Mutational analyses of the lesions revealed monoclonality of proliferating cells with a somatic mutation in c-kit exon 11 (p.Leu576Pro). Gut-wall replacing type of GIST should be recognized as a specific type of GIST causing diverticulum-like structures of the gastrointestinal tract. PMID:26298631

  19. Clinicopathologic Features and Clinical Outcomes of Esophageal Gastrointestinal Stromal Tumor: Evaluation of a Pooled Case Series.

    PubMed

    Feng, Fan; Tian, Yangzi; Liu, Zhen; Xu, Guanghui; Liu, Shushang; Guo, Man; Lian, Xiao; Fan, Daiming; Zhang, Hongwei

    2016-01-01

    Clinicopathologic features and clinical outcomes of gastrointestinal stromal tumors (GISTs) in esophagus are limited, because of the relatively rare incidence of esophageal GISTs. Therefore, the aim of the current study was to investigate the clinicopathologic features and clinical outcomes of esophageal GISTs, and to investigate the potential factors that may predict prognosis.Esophageal GIST cases were obtained from our center and from case reports and clinical studies extracted from MEDLINE. Clinicopathologic features and survivals were analyzed and compared with gastric GISTs from our center.The most common location was lower esophagus (86.84%), followed by middle and upper esophagus (11.40% and 1.76%). The majority of esophageal GISTs were classified as high-risk category (70.83%). Mitotic index was correlated with histologic type, mutational status, and tumor size. The 5-year disease-free survival and disease-specific survival were 65.1% and 65.9%, respectively. Tumor size, mitotic index, and National Institutes of Health risk classification were associated with prognosis of esophageal GISTs. Only tumor size, however, was the independent risk factor for the prognosis of esophageal GISTs. In comparison to gastric GISTs, the distribution of tumor size, histologic type, and National Institutes of Health risk classification were significantly different between esophageal GISTs and gastric GISTs. The disease-free survival and disease-specific survival of esophageal GISTs were significantly lower than that of gastric GISTs.The most common location for esophageal GISTs was lower esophagus, and most of the esophageal GISTs are high-risk category. Tumor size was the independent risk factor for the prognosis of esophageal GISTs. Esophageal GISTs differ significantly from gastric GISTs in respect to clinicopathologic features. The prognosis of esophageal GISTs was worse than that of gastric GISTs. PMID:26765432

  20. Comparison between air and carbon dioxide insufflation in the endoscopic submucosal excavation of gastrointestinal stromal tumors

    PubMed Central

    Shi, Wei-Bin; Wang, Zi-Hao; Qu, Chun-Ying; Zhang, Yi; Jiang, Han; Zhou, Min; Chen, Ying; Xu, Lei-Ming

    2012-01-01

    AIM: To evaluate the safety and efficacy of CO2 insufflation compared with air insufflation in the endoscopic submucosal excavation (ESE) of gastrointestinal stromal tumors. METHODS: Sixty patients were randomized to undergo endoscopic submucosal excavation, with the CO2 group (n = 30) and the air group (n = 30) undergoing CO2 insufflation and air insufflation in the ESE, respectively. The end-tidal CO2 level (pETCO2) was observed at 4 time points: at the beginning of ESE, at total removal of the tumors, at completed wound management, and 10 min after ESE. Additionally, the patients’ experience of pain at 1, 3, 6 and 24 h after the examination was registered using a visual analog scale (VAS). RESULTS: Both the CO2 group and air group were similar in mean age, sex, body mass index (all P > 0.05). There were no significant differences in PetCO2 values before and after the procedure (P > 0.05). However, the pain scores after the ESE at different time points in the CO2 group decreased significantly compared with the air group (1 h: 21.2 ± 3.4 vs 61.5 ± 1.7; 3 h: 8.5 ± 0.7 vs 42.9 ± 1.3; 6 h: 4.4 ± 1.6 vs 27.6 ± 1.2; 24 h: 2.3 ± 0.4 vs 21.4 ± 0.7, P < 0.05). Meanwhile, the percentage of VAS scores of 0 in the CO2 group after 1, 3, 6 and 24 h was significantly higher than that in the air group (60.7 ± 1.4 vs 18.9 ± 1.5, 81.5 ± 2.3 vs 20.6 ± 1.2, 89.2 ± 0.7 vs 36.8 ± 0.9, 91.3 ± 0.8 vs 63.8 ± 1.3, respectively, P < 0.05). Moreover, the condition of the CO2 group was better than that of the air group with respect to anal exsufflation. CONCLUSION: Insufflation of CO2 in the ESE of gastrointestinal stromal tumors will not cause CO2 retention and it may significantly reduce the level of pain, thus it is safe and effective. PMID:23326136

  1. Gastrointestinal stromal tumors: report of an audit and review of the literature.

    PubMed

    Biasco, Guido; Velo, Daniela; Angriman, Imerio; Astorino, Maria; Baldan, Anna; Baseggio, Matteo; Basso, Umberto; Battaglia, Giorgio; Bertin, Matteo; Bertorelle, Roberta; Bocus, Paolo; Brosolo, Piero; Bulzacchi, Andrea; Cannizzaro, Renato; Da Dalt, Gian Franco; Di Battista, Monica; Errante, Domenico; Fedrigo, Marny; Frustaci, Sergio; Lionetti, Ivana; Massani, Marco; Mencarelli, Roberto; Montesco, Maria Cristina; Norberto, Lorenzo; Pantaleo, Maria Abbondanza; Pasquali, Claudio; Pastorelli, Davide; Rossi, Carlo Remigio; Ruffolo, Cesare; Salvagno, Luigi; Saponara, Maria Stella; Vittadello, Fabrizio; Zaccaria, Francesco; Zovato, Stefania; Farinati, Fabio

    2009-04-01

    Gastrointestinal stromal tumors (GISTs), tumors characterized by c-KIT mutations, are the most frequent mesenchymal tumors of the digestive tract. The stomach is the most commonly involved site. Localization, size and mitotic rate are reliable predictors of survival and the two milestones of GISTs treatment are surgery and imatinib. This article is aimed to report the data of an audit, carried out on the morphological and clinical aspects of the disease and to review the present knowledge on GISTs. A total of 172 patients with GISTs (M : F=1 : 1; mean age 65 years) were recruited. The stomach was the most frequently involved site. In 50% of the cases the tumor was smaller than 5 cm, whereas major symptoms were observed in 43% of the cases. Predictors of progressive disease were present only in a small percentage of cases but the disease was in the metastatic phase in over 25% of the cases at diagnosis. Familial aggregation was rare but a consistent share of the patients (21%) had other synchronous or metachronous cancers. The most frequent mutations were in-frame deletions and point mutations of c-KIT exon 11. This report confirms in part the available data on GIST in a consecutive series of patients recruited in Italy and shows that only large collaborative multicenter studies provide data sound enough to enable making reasonable clinical and therapeutic choices, and suggests that, as a measure of secondary prevention, a diagnostic definition should be obtained in all submucosal lesions of the GI tract and that GIST patients should be screened for second tumors. PMID:19337057

  2. Robust linear regression model of Ki-67 for mitotic rate in gastrointestinal stromal tumors

    PubMed Central

    KEMMERLING, RALF; WEYLAND, DENIS; KIESSLICH, TOBIAS; ILLIG, ROMANA; KLIESER, ECKHARD; JÄGER, TARKAN; DIETZE, OTTO; NEUREITER, DANIEL

    2014-01-01

    Risk stratification of gastrointestinal stromal tumors (GISTs) by tumor size, lymph node and metastasis status is crucially affected by mitotic activity. To date, no studies have quantitatively compared mitotic activity in hematoxylin and eosin (H&E)-stained tissue sections with immunohistochemical markers, such as phosphohistone H3 (PHH3) and Ki-67. According to the TNM guidelines, the mitotic count on H&E sections and immunohistochemical PHH3-stained slides has been assessed per 50 high-power fields of 154 specimens of clinically documented GIST cases. The Ki-67-associated proliferation rate was evaluated on three digitalized hot spots using image analysis. The H&E-based mitotic rate was found to correlate significantly better with Ki-67-assessed proliferation activity than with PHH3-assessed proliferation activity (r=0.780; P<0.01). A linear regression model (analysis of variance; P<0.001) allowed reliable predictions of the H&E-associated mitoses based on the Ki-67 expression alone. Additionally, the Ki-67-associated proliferation revealed a higher and significant impact on the recurrence and metastasis rate of the GIST cases than by the classical H&E-based mitotic rate. The results of the present study indicated that the mitotic rate may be reliably and time-efficiently estimated by immunohistochemistry of Ki-67 using only three hot spots. PMID:24527082

  3. Beyond Standard Therapy: Drugs Under Investigation for The Treatment of Gastrointestinal Stromal Tumor

    PubMed Central

    Alturkmani, Hani J; Pessetto, Ziyan Y; Godwin, Andrew K

    2015-01-01

    Introduction Gastrointestinal stromal tumor (GIST) is the most common non-epithelial malignancy of the GI tract. With the discovery of KIT and later PDGFRA gain-of-function mutations as factors in the pathogenesis of the disease, GIST was the quintessential model for targeted therapy. Despite the successful clinical use of imatinib mesylate, a selective receptor tyrosine kinase (RTK) inhibitor that targets KIT, PDGFRA and BCR-ABL, we still do not have treatment for the long-term control of advanced GIST. Areas covered This review summarizes the drugs that are under investigation or have been assessed in trials for GIST treatment. The article focuses on their mechanisms of actions, the preclinical evidence of efficacy, and the clinical trials concerning safety and efficacy in humans. Expert opinion It is known that KIT and PDGFRA mutations in GIST patients influence the response to treatment. This observation should be taken into consideration when investigating new drugs. RECIST was developed to help uniformly report efficacy trials in oncology. Despite the usefulness of this system, many questions are being addressed about its validity in evaluating the true efficacy of drugs knowing that new targeted therapies do not affect the tumor size as much as they halt progression and prolong survival. PMID:26098203

  4. Crosstalk between KIT and FGFR3 Promotes Gastrointestinal Stromal Tumor Cell Growth and Drug Resistance.

    PubMed

    Javidi-Sharifi, Nathalie; Traer, Elie; Martinez, Jacqueline; Gupta, Anu; Taguchi, Takehiro; Dunlap, Jennifer; Heinrich, Michael C; Corless, Christopher L; Rubin, Brian P; Druker, Brian J; Tyner, Jeffrey W

    2015-03-01

    Kinase inhibitors such as imatinib have dramatically improved outcomes for patients with gastrointestinal stromal tumor (GIST), but many patients develop resistance to these treatments. Although in some patients this event corresponds with mutations in the GIST driver oncogenic kinase KIT, other patients develop resistance without KIT mutations. In this study, we address this patient subset in reporting a functional dependence of GIST on the FGF receptor FGFR3 and its crosstalk with KIT in GIST cells. Addition of the FGFR3 ligand FGF2 to GIST cells restored KIT phosphorylation during imatinib treatment, allowing sensitive cells to proliferate in the presence of the drug. FGF2 expression was increased in imatinib-resistant GIST cells, the growth of which was blocked by RNAi-mediated silencing of FGFR3. Moreover, combining KIT and FGFR3 inhibitors synergized to block the growth of imatinib-resistant cells. Signaling crosstalk between KIT and FGFR3 activated the MAPK pathway to promote resistance to imatinib. Clinically, an IHC analysis of tumor specimens from imatinib-resistant GIST patients revealed a relative increase in FGF2 levels, with a trend toward increased expression in imatinib-naïve samples consistent with possible involvement in drug resistance. Our findings provide a mechanistic rationale to evaluate existing FGFR inhibitors and multikinase inhibitors that target FGFR3 as promising strategies to improve treatment of patients with GIST with de novo or acquired resistance to imatinib. PMID:25432174

  5. A case for gastrointestinal stromal tumor (GIST) with reference to its ultrastructure and 'gain-of-function' mutation.

    PubMed

    Sakuma, Toshiyuki; Takayama, Ichiro; Zai, Hiroaki; Sekido, Yasutomo; Kijima, Hiroshi; Ogoshi, Kyoji; Makuuchi, Hiroyasu; Shirai, Takayuki; Mine, Tetsuya

    2003-07-01

    A case for primary gastrointestinal stromal tumor (GIST) is described with reference to its ultrastructural characteristics and mutation within the exon 11 of c-kit gene. A forty-seven years old woman complaining of dysphasia was examined by endoscopy, which depicted a submucosal tumor (70 mm in diameter) with ulcerations at the fundus of the stomach. Histopathologically, the tumor cells had large nuclei and eosinophilic cytoplasm and were frequently during mitosis phase. The tumor cells were immunopositive for KIT, CD 34 and vimentin, suggesting their fibroblast-like characteristics. In contrast, desmin and S-100, a smooth muscle and an enteroglial marker, were not immunopositive within the cells. At least 30 % of the tumor cells possessed MIB-I and 20 % of them possessed p53, which are compatible with fast development of the tumor. By electron microscopy, the tumor cells possessed large oval nuclei, abundant mitochondria, caveolae and smooth endoplasmic reticulums, while no gap junctions were seen on the cells: The tumor cells thus possessed interstitial cells-like characteristics at least in part. DNA mutation search for the tumor cells however realized no gain-of-function mutation within the exon 11 of the c-kit gene, suggesting existence of other mechanism for neoplasmic growth of the tumor cells classified as gastrointestinal stromal tumors. PMID:14714834

  6. Indian Council of Medical Research consensus document for the management of gastrointestinal stromal tumors.

    PubMed

    Shrikhande, Shailesh V; Sirohi, Bhawna; Barreto, Savio G; Chacko, Raju T; Parikh, Purvish M; Pautu, Jeremy; Arya, Supreeta; Patil, Prachi; Chilukuri, Srinivas C; Ganesh, B; Kaur, Tanvir; Shukla, Deepak; Rath, Goura Shankar

    2014-10-01

    This consensus statement was produced along with the gastric cancer discussions as stomach is the most common site for gastrointestinal stromal tumor (GIST). The recommendations apply to treatment of GIST.Evaluation of a patient with newly diagnosed GIST should include essential tests: A standard white light endoscopy with 6-8 biopsies (c-KIT testing on immunohistochemistry) from the tumor for confirmation of the diagnosis, a computed tomography (CT) scan (multi-detector or helical) of the abdomen and pelvis for staging with a CT chest or chest X-ray, and complete blood counts, renal function tests and liver function tests. Endoscopic ultrasonography (EUS)/magnetic resonance imaging (MRI)/positron emission tomography (PET)-CT are not recommended for all patients.For localized and resectable disease, surgery is recommended. The need for adjuvant treatment with imatinib would be guided by the risk stratification on the histopathological analysis of the resected specimen.For localized but borderline resectable tumors, upfront surgery may be considered only if complications due to the tumor are present such as major bleeding or gastric outlet obstruction. In all other patients, neoadjuvant imatinib should be considered to downstage the disease followed by surgery (with a curative intent, if feasible) in those with stable or partial response. This may be followed by adjuvant imatinib. In those patients with a poor response, further imatinib with dose escalation or sunitinib may be considered.Patients with metastatic disease must be assessed for treatment with imatinib as first-line therapy followed by sunitinib as second-line therapy versus best supportive care on an individual basis. PMID:25538399

  7. Solitary Fibrous Tumor of the Greater Omentum, Mimicking Gastrointestinal Stromal Tumor of the Small Intestine: A Case Report

    PubMed Central

    Urabe, Masayuki; Yamagata, Yukinori; Aikou, Susumu; Mori, Kazuhiko; Yamashita, Hiroharu; Nomura, Sachiyo; Shibahara, Junji; Fukayama, Masashi; Seto, Yasuyuki

    2015-01-01

    Solitary fibrous tumor (SFT) is one of the mesenchymal tumors, which rarely arises in the abdominal space. We report a very rare case of abdominal SFT, mimicking another mesenchymal tumor. A 52-year-old Japanese man was referred to our hospital for further evaluation and treatment of gallbladder polyp. Contrast-enhanced computed tomography (CT) showed an enhanced nodule within the gallbladder, and incidentally, also showed a well-circumscribed mass adjacent to the small intestine. The mass was depicted as slightly high density in plain CT, and with contrast-enhancement, the mass was partially stained in early phase and the stained area spread heterogeneously in delayed phase. Magnetic resonance imaging showed that the abdominal mass was depicted as slightly high intensity on T2-weighted imaging and low intensity on T1-weighted imaging. With double-balloon endoscopy and capsule endoscopy, we did not find any tumor inside the small intestine. These visual findings lead us to diagnose it as gastrointestinal stromal tumor of the small intestine with extraluminal growth. We planned to resect both the gallbladder polyp and the intraperitoneal tumor at the same time for pathologic diagnosis and treatment. When the operation was performed, we found a milk-white lobulated tumor on the greater omentum and the tumor was entirely resected. Microscopically, the gallbladder polyp was diagnosed as tubular adenoma, and the omental tumor was diagnosed as SFT. It is important to bear in mind that omental SFTs sometimes mimic other mesenchymal tumors and should be included in the differential diagnosis of abdominal tumor not revealed by endoscopy. PMID:26011203

  8. Tumor markers in colorectal cancer, gastric cancer and gastrointestinal stromal cancers: European group on tumor markers 2014 guidelines update

    PubMed Central

    Duffy, MJ; Lamerz, R; Haglund, C; Nicolini, A; Kalousová, M; Holubec, L; Sturgeon, C

    2014-01-01

    Biomarkers currently play an important role in the detection and management of patients with several different types of gastrointestinal cancer, especially colorectal, gastric, gastro-oesophageal junction (GOJ) adenocarcinomas and gastrointestinal stromal tumors (GISTs). The aim of this article is to provide updated and evidence-based guidelines for the use of biomarkers in the different gastrointestinal malignancies. Recommended biomarkers for colorectal cancer include an immunochemical-based fecal occult blood test in screening asymptomatic subjects ≥50 years of age for neoplasia, serial CEA levels in postoperative surveillance of stage II and III patients who may be candidates for surgical resection or systemic therapy in the event of distant metastasis occurring, K-RAS mutation status for identifying patients with advanced disease likely to benefit from anti-EGFR therapeutic antibodies and microsatellite instability testing as a first-line screen for subjects with Lynch syndrome. In advanced gastric or GOJ cancers, measurement of HER2 is recommended in selecting patients for treatment with trastuzumab. For patients with suspected GIST, determination of KIT protein should be used as a diagnostic aid, while KIT mutational analysis may be used for treatment planning in patients with diagnosed GISTs. PMID:23852704

  9. Gastrointestinal stromal tumors in a mouse model by targeted mutation of the Kit receptor tyrosine kinase

    PubMed Central

    Sommer, Gunhild; Agosti, Valter; Ehlers, Imke; Rossi, Ferdinand; Corbacioglu, Selim; Farkas, Judith; Moore, Malcolm; Manova, Katia; Antonescu, Cristina R.; Besmer, Peter

    2003-01-01

    Oncogenic Kit mutations are found in somatic gastrointestinal (GI) stromal tumors (GISTs) and mastocytosis. A mouse model for the study of constitutive activation of Kit in oncogenesis has been produced by a knock-in strategy introducing a Kit exon 11-activating mutation into the mouse genome based on a mutation found in a case of human familial GIST syndrome. Heterozygous mutant KitV558Δ/+ mice develop symptoms of disease and eventually die from pathology in the GI tract. Patchy hyperplasia of Kit-positive cells is evident within the myenteric plexus of the entire GI tract. Neoplastic lesions indistinguishable from human GISTs were observed in the cecum of the mutant mice with high penetrance. In addition, mast cell numbers in the dorsal skin were increased. Therefore KitV558Δ/+ mice reproduce human familial GISTs, and they may be used as a model for the study of the role and mechanisms of Kit in neoplasia. Importantly, these results demonstrate that constitutive Kit signaling is critical and sufficient for induction of GIST and hyperplasia of interstitial cells of Cajal. PMID:12754375

  10. The impact of additional malignancies in patients diagnosed with gastrointestinal stromal tumors.

    PubMed

    Smith, Myles J; Smith, Henry G; Mahar, Alyson L; Law, Calvin; Ko, Yoo-Joung

    2016-10-15

    A higher incidence of additional malignancies has been described in patients diagnosed with gastrointestinal stromal tumors (GIST). This study aimed to identify risk factors for developing additional malignancies in patients diagnosed with GIST and evaluate the impact on survival. Individuals diagnosed with GIST from 2001 to2009 were identified from the SEER database. Logistic regression was used to identify predictors of additional malignancies and Cox-proportional hazards regression used to identify predictors of survival. In the study period, 1705 cases of GIST were identified, with 181 (10.6%) patients developing additional malignancies. Colorectal cancer was the most common cancer developing within 6 months of GIST diagnosis (30%). The median time to diagnosis of a malignancy after 6 months of GIST diagnosis was 21.9 months. Older age (p < 0.0001) and extraoesophagogastric GIST (p = 0.0027) were significant prognostic factors associated with additional malignancies. The overall 5-year survival was 65%, with the presence of additional malignancies within 6 months of GIST diagnosis associated with poor overall survival (54%, HR 1.55 1.05-2.3 95% CI, p = 0.04). Predictive factors of additional malignancies in patients diagnosed with GIST are increasing age and the primary disease site. Developing additional malignancies within 6 months of GIST diagnosis is associated with poorer overall survival. Targeted surveillance may be warranted in patients diagnosed with GIST that are at high risk of developing additional malignancies. PMID:27299364

  11. Clinical Practice Guideline for Accurate Diagnosis and Effective Treatment of Gastrointestinal Stromal Tumor in Korea

    PubMed Central

    Kim, Kyoung-Mee; Sohn, Taesung; Choi, Dongil; Kang, Hye Jin; Ryu, Min-Hee; Kim, Woo Ho; Yang, Han-Kwang

    2010-01-01

    Despite the rarity in incidence and prevalence, gastrointestinal stromal tumor (GIST) has emerged as a distinct pathogenetic entity. And the clinical management of GIST has been evolving very rapidly due to the recent recognition of its oncogenic signal transduction pathway and the introduction of new molecular-targeted therapy. Successful management of GIST requires a multidisciplinary approach firmly based on accurate histopathologic diagnosis. However, there was no standardized guideline for the management of Korean GIST patients. In 2007, the Korean GIST study group (KGSG) published the first guideline for optimal diagnosis and treatment of GIST in Korea. As the second version of the guideline, we herein have updated recent clinical recommendations and reflected changes in diagnosis, surgical and medical treatments for more optimal clinical practice for GIST in Korea. We hope the guideline can be of help in enhancing the quality of diagnosis by members of the Korean associate of physicians involving in GIST patients's care and subsequently in achieving optimal efficacy of treatment. PMID:21060741

  12. The roles of serum CXCL16 in circulating Tregs and gastrointestinal stromal tumor cells

    PubMed Central

    Xing, Ya-Nan; Zhang, Jun-Yan; Xu, Hui-Mian

    2016-01-01

    Gastrointestinal stromal tumors (GIST) are the most common sarcomas of the digestive system. Abnormal expression of CXCL16 and its sole receptor, CXCR6, has been demonstrated in many cancers. However, no studies have shown the relationship between CXCL16 or CXCR6 expression and GIST. In this study, we detected CXCL16 and CXCR6 expression in GIST patient samples by using immunohistochemistry analysis and Western blot analysis. Serum CXCL16 level was determined by using enzyme-linked immunosorbent assay. Circulating Tregs were isolated by using flow cytometry. MTT assay, cell cycle assay, and transwell assay were used to test the effects of recombinant CXCL16 on Tregs and GIST cells in vitro. The levels of CXCL16 and CXCR6 protein were higher in cancer tissues than in normal tissues. Serum CXCL16 level and circulating Tregs were higher in GIST patients than that in the healthy volunteers. CXCL16, CXCR6, serum CXCL16, and circulating Tregs were significantly associated with a decreased survival time of patients. Relative to control cells, high concentration recombinant CXCL16 treated Tregs and GIST cells exhibited lower proliferation and mobility rates as assessed by MTT assay and transwell assay, respectively. Taken together, CXCL16 was observed to mediate the inhibitory effects in Tregs and GIST cells, and these involved suppression of the MEK/ERK signaling pathway. PMID:27418838

  13. Safety of Regular-Dose Imatinib Therapy in Patients with Gastrointestinal Stromal Tumors Undergoing Dialysis

    PubMed Central

    Niikura, Ryota; Serizawa, Takako; Yamada, Atsuo; Yoshida, Shuntaro; Tanaka, Mariko; Hirata, Yoshihiro; Koike, Kazuhiko

    2016-01-01

    The number of cancer patients undergoing dialysis has been increasing, and the number of these patients on chemotherapy is also increasing. Imatinib is an effective and safe therapy for KIT-positive gastrointestinal stromal tumors (GIST), but the efficacy and safety of imatinib in dialysis patients remain unclear. Because clinical trials have not been conducted in this population, more investigations are required. We report on a 75-year-old Japanese man undergoing dialysis who presented with massive tarry stool from a duodenal GIST. The duodenal GIST was 14 cm in diameter with multiple liver and bone metastases. The patient underwent an urgent pancreaticoduodenectomy to achieve hemostasis. After surgery, he was administered imatinib 400 mg/day. No severe adverse event including myelosuppression, congestive heart failure, liver functional impairment, intestinal pneumonia, or Steven-Johnson syndrome occurred, and the liver metastasis remained stable for 4 months. During chemotherapy, hemodialysis continued three times per week without adverse events. We suggest that regular-dose imatinib is an effective and safe treatment in patients with GIST undergoing dialysis. In addition, we present a literature review of the effectiveness and safety of imatinib treatment in dialysis patients. PMID:27403097

  14. Histopathological Features of Gastrointestinal Stromal Tumors and the Contribution of DOG1 Expression to the Diagnosis

    PubMed Central

    Güler, Beril; Özyılmaz, Filiz; Tokuç, Burcu; Can, Nuray; Taştekin, Ebru

    2015-01-01

    Background: Gastrointestinal stromal tumors (GIST) have KIT or platelet-derived growth factor receptor α (PDGFRα) mutations affecting receptor tyrosine kinase activity and do not benefit from classic treatment regimens. Aims: The aim of this study was to review the algorithm that may be followed for the diagnosis and differential diagnosis in GISTs by investigating the histomorphological parameters and expression characteristics of classical immunohistochemical antibodies used in routine tests in addition to DOG1 expression. Study Design: Diagnostic accuracy study. Methods: We reevaluated the histological and immunohistochemical parameters of 37 GISTs. The standard immunohistochemical diagnosis and differential diagnosis panel antibodies (CD117, PDGFRα, CD34, vimentin, desmin, SMA, S-100, and Ki67) were studied on the tumor sections. We also used the popular marker DOG1 antibody with accepted sensitivity for GISTs in recent years and the PDGFRα immune marker for which the benefit in routine practice is discussed. Results: Classification according to progressive disease risk groups of the 37 cases revealed that 54% were in the high risk, 19% in the moderate risk, 16% in the low risk, 8% in the very low risk and 8% in the no risk group. Cytological atypia, necrosis, mucosal invasion and the Ki67 index were found to be related to the progressive disease risk groups of the tumors (p<0.05). Positive immunoreaction was observed with CD117 and PDGFRα in all GISTs in the study (100%). Positivity with the DOG1 antibody was found in 33 (89%) cases. CD34 was positive in 62% (23) of the cases. Conclusion: The CD117 antibody still plays a key role in GIST diagnosis. However, the use of DOG1 and PDGFRα antibodies combined with CD117 as sensitive markers can be beneficial. PMID:26740899

  15. Concurrent gastrointestinal stromal tumor and digestive tract carcinoma: a single institution experience in China

    PubMed Central

    Zhang, Peng; Deng, Rui; Xia, Zefeng; Shuai, Xiaoming; Chang, Weilong; Gao, Jinbo; Wang, Guobin; Tao, Kaixiong

    2015-01-01

    The aim of this study was to review the clinicopathological characteristics and survival outcomes of patients with concurrent gastrointestinal stromal tumor (GIST) and digestive tract carcinoma. Among 585 patients diagnosed with GIST from January 2005 to July 2014, 32 (5.5%) had synchronous digestive tract carcinoma, including 19 (59.4%) men and 13 (40.6%) women. The median age was 64 years (range, 43-84). GIST was located in the stomach (n=24), small intestine (n=6), duodenum (n=1) and retroperitoneum (n=1). GISTs were intra- or postoperatively discovered (n=28) or preoperatively identified (n=4). The tumor size was less than 10 mm (microGIST) in 23 (71.9%) GIST patients. The preoperatively identified GIST subgroup showed a significantly larger tumor size, more mitotic figures and a higher risk grade than the intra- or postoperatively identified GIST subgroup. Concurrent digestive tract carcinomas were most frequently located in the stomach (24 cases, 75%). The other involved sites were the esophagus (n=5), duodenum (n=2) and colon (n=1). With a median follow-up of 32 months (range, 9-80), 24 patients were alive without evidence of disease, 6 patients had died of carcinoma progression, 1 patient had died from an accident, and 1 patient experienced GIST metastasis to the liver. In summary, we discovered that 5.5% of GIST patients also developed a concurrent digestive tract carcinoma in a series of 585 GIST cases. The majority of GISTs are incidentally identified microGISTs. The concurrent carcinoma seems to have a greater unfavorable effect on prognosis than the GIST. However, for a GIST that is identified preoperatively with a high risk of progression, adjuvant therapy is warranted. PMID:26885079

  16. Positive cyclin T expression as a favorable prognostic factor in treating gastric gastrointestinal stromal tumors

    PubMed Central

    LIN, LIEN-FU; JIN, JONG-SHIAW; CHEN, JUI-CHANG; HUANG, CHIA-CHI; SHEU, JENG-HORNG; CHEN, WENLUNG; TSAO, TANG-YI; HSU, CHIH-WEI

    2016-01-01

    Positive transcriptional elongation factor b (P-TEFb) contains the catalytic subunit cyclin-dependent kinase 9 (Cdk9) and the regulatory subunit cyclin T. Cyclin T1 and Cdk9 are the key factors of the PTEFb pathways and are overexpressed in the human head and neck carcinoma cell line. However, there have been limited studies regarding the role of cyclin T1 and Cdk9 in gastric gastrointestinal stromal tumors (GISTs). The aim of the present study was to assess the association between cyclin T1 and Cdk9 and their clinical significance in gastric GISTs. A total of 30 gastric GIST patients who underwent either laparoscopic or laparotomic partial gastrectomy were enrolled in the study. The surgical tissue slides were stained with Cdk9 and cyclin T1 antibodies, and the immunohistochemistry scores and disease-free survival (DFS) were analyzed. Ten patients were cyclin T1-positive, and 20 were negative. All 11 patients with recurrent tumors or distant metastases were cyclin T1-negative patients. Old age, large tumor size, a high Ki67 IHC staining score, high mitotic count and negative cyclin T1 staining revealed a worse clinical outcome in univariate analysis. By contrast, the Cdk9 score was not associated with clinical parameters. The Kaplan-Meier survival curve illustrated that the DFS rate of the patients with negative cyclin T1 staining was significantly lower than that of the patients with positive cyclin T1 staining. Positive expression of cyclin T1 was a good prognostic factor in patients with gastric GISTs. PMID:27284431

  17. Detection of Treatment-Induced Changes in Signaling Pathways in Gastrointestinal Stromal Tumors using Transcriptomic Data

    PubMed Central

    Ochs, Michael F.; Rink, Lori; Tarn, Chi; Mburu, Sarah; Taguchi, Takahiro; Eisenberg, Burton; Godwin, Andrew K.

    2009-01-01

    Cell signaling plays a central role in the etiology of cancer. Numerous therapeutics in use or under development target signaling proteins, however off-target effects often limit assignment of positive clinical response to the intended target. As direct measurements of signaling protein activity are not generally feasible during treatment, there is a need for more powerful methods to determine if therapeutics inhibit their targets and when off-target effects occur. We have used the Bayesian Decomposition algorithm and data on transcriptional regulation to create a novel methodology, DESIDE (Differential Expression for SIgnaling DEtermination), for inferring signaling activity from microarray measurements. We applied DESIDE to deduce signaling activity in gastrointestinal stromal tumor cell lines treated with the targeted therapeutic imatinib mesylate (Gleevec). We detected the expected reduced activity in the KIT pathway, as well as unexpected changes in the P53 pathway. Pursuing these findings, we have determined that imatinib-induced DNA damage is responsible for the increased activity of P53, identifying a novel off-target activity for this drug. We then used DESIDE on data from resected, post-imatinib treatment tumor samples and identified a pattern in these tumors similar to that at late time points in the cell lines, and this pattern correlated with initial clinical response. The pattern showed increased activity of ELK1 and STAT3 transcription factors, which are associated with the growth of side population cells. DESIDE infers the global reprogramming of signaling networks during treatment, permitting treatment modification that leverages ongoing drug development efforts, which is crucial for personalized medicine. PMID:19903850

  18. Gastrointestinal stromal tumour.

    PubMed

    Joensuu, Heikki; Hohenberger, Peter; Corless, Christopher L

    2013-09-14

    Gastrointestinal stromal tumours (GISTs) are mesenchymal neoplasms that arise in the gastrointestinal tract, usually in the stomach or the small intestine and rarely elsewhere in the abdomen. They can occur at any age, the median age being 60-65 years, and typically cause bleeding, anaemia, and pain. GISTs have variable malignant potential, ranging from small lesions with a benign behaviour to fatal sarcomas. Most tumours stain positively for the mast/stem cell growth factor receptor KIT and anoctamin 1 and harbour a kinase-activating mutation in either KIT or PDGFRA. Tumours without such mutations could have alterations in genes of the succinate dehydrogenase complex or in BRAF, or rarely RAS family genes. About 60% of patients are cured by surgery. Adjuvant treatment with imatinib is recommended for patients with a substantial risk of recurrence, if the tumour has an imatinib-sensitive mutation. Tyrosine kinase inhibitors substantially improve survival in advanced disease, but secondary drug resistance is common. PMID:23623056

  19. Molecular basis for primary and secondary tyrosine kinase inhibitor resistance in gastrointestinal stromal tumor

    PubMed Central

    Gounder, Mrinal M.

    2012-01-01

    Small molecule kinase inhibitors have irrevocably altered cancer treatment. March 2010 marks the 10th anniversary of using imatinib in gastrointestinal stromal tumors (GIST), a cardinal example of the utility of such targeted therapy in a solid tumor. Before imatinib, metastatic GIST was frustrating to treat due to its resistance to standard cytotoxic chemotherapy. Median survival for patients with metastatic GIST improved from 19 to 60 months with imatinib. In treating patients with GIST, two patterns of tyrosine kinase inhibitor resistance have been observed. In the first, ~9–14% of patients have progression within 3 months of starting imatinib. These patients are classified as having primary or early resistance. Median progression-free survival (PFS) on imatinib is approximately 24 months; patients with later progression are classified as having secondary or acquired resistance. Primary studies and a meta-analysis of studies of imatinib in GIST patients have identified prognostic features that contribute to treatment failure. One of the strongest predictors for success of therapy is KIT or PDGFRA mutational status. Patients with KIT exon 11 mutant GIST have better response rates, PFS, and overall survival compared to other mutations. A great deal has been learned in the last decade about sensitivity and resistance of GIST to imatinib; however, many unanswered questions remain about secondary resistance mechanisms and clinical management in the third- and fourth-line setting. This review will discuss the role of dose effects, and early and late resistance to imatinib and their clinical implications. Patients intolerant to imatinib (5%) and those who progress on imatinib are treated with sunitinib. The mechanism of resistance to sunitinib is unknown at this time but is also appears related to growth of clones with secondary mutations in KIT. Third- and fourth-line treatments of GIST and with future treatment strategies are also discussed. PMID:21116624

  20. Clinicopathological features and prognosis of small gastrointestinal stromal tumors outside the stomach

    PubMed Central

    WANG, YONG-PENG; LI, YI; SONG, CHUN

    2015-01-01

    The aim of the present study was to assess the clinicopathological features and prognostic factors of primary small gastrointestinal stromal tumors (GISTs) outside the stomach. The clinical data, clinicopathological features and prognostic factors of 20 patients with a pathologically-confirmed diagnosis of non-gastric GIST that were treated at Liaoning Cancer Hospital & Institute between July 2006 and December 2013 were retrospectively analyzed. In total, 15 patients were male and 5 were female, with a median age of 58 years (range, 44–82 years). A change in bowel habits was the original symptom of rectal small GISTs in 6 out of 8 patients, while patients with small GISTs in other locations demonstrated no overt symptoms and the lesions were detected by systematic examinations of other diseases or abdominal surgical procedures performed on other organs. In total, 19 patients out of the total 20 patients underwent surgery, and 1 patient with rectal GIST received continuous oral imatinib mesylate (400 mg once a day) instead of undergoing surgery. The mean diameter of tumors was 1.55±0.54 cm (range, 0.3–2.0 cm) and the median was 1.70 cm. The pathomorphology of the lesions was mainly spindle cell, and immunohistochemistry revealed the expression rate of cluster of differentiation (CD)117, CD34 and discovered on GIST-1 were 85, 80 and 70%. According to the mitosis index, small rectal GISTs were more frequent compared with other positions (P<0.05), while the frequency of small GISTs >1 cm in size was not significantly different from the frequency of small GISTs ≤1 cm in size (P=0.995). All 20 patients were followed up, with a median follow-up duration of 49.5 months (range, 10.5–94.4 months). At the end of the follow-up period, tumor recurrence occurred in 5 patients and 1 patient succumbed following progression. According to the analysis of the tumor sites, the RFS time of patients with small rectal GISTs was significantly different than the RFS time in

  1. Gastrointestinal stromal tumors of the duodenum: Surgical management and survival results

    PubMed Central

    Liang, Xiao; Yu, Hong; Zhu, Lin-Hua; Wang, Xian-Fa; Cai, Xiu-Jun

    2013-01-01

    AIM: To provide long-term survival results of operable duodenal gastrointestinal stromal tumors (DGISTs) in a tertiary center in China. METHODS: In this retrospective study, the pathological data of 28 patients with DGISTs who had been treated surgically at the Second Department of General Surgery, Sir Run Run Shaw Hospital (SRRSH) from June 1998 to December 2006 were reviewed. All pathological slides were examined by a single pathologist to confirm the diagnosis. In patients whose diagnosis was not confirmed by immunohistochemistry at the time of resection, representative paraffin blocks were reassembled, and sections were studied using antibodies against CD117 (c-kit), CD34, smooth muscle actin (SMA), vimentin, S-100, actin (HHF35), and desmin. Operative procedures were classified as wedge resection (WR, local resection with pure closure, without duodenal transection or anastomosis), segmental resection [SR, duodenal transection with Roux-Y or Billroth II gastrojejunostomy (G-J), end-to-end duodenoduodenostomy (D-D), end-to-end or end-to-side duodenojejunostomy (D-J)], and pancreaticoduodenectomy (PD, Whipple operation with pancreatojejunostomy). R0 resection was pursued in all cases, and at least R1 resection was achieved. Regional lymphadenectomy was not performed. Clinical manifestations, surgery, medical treatment and follow-up data were retrospectively analyzed. Related studies in the literature were reviewed. RESULTS: There were 12 males and 16 females patients, with a median age of 53 years (20-76 years). Their major complaints were “gastrointestinal bleeding” (57.2%) and “nonspecific discomfort” (32.1%). About 14.3%, 60.7%, 17.9%, and 7.1% of the tumors originated in the first to fourth portion, respectively, with a median size of 5.8 cm (1.6-20 cm). Treatment was by WR in 5 cases (17.9%), SR in 13 cases (46.4%), and by PD in 10 cases (35.7%). The morbidity and mortality rates were 35.7% and 3.6%, respectively. The median post-operative stay was

  2. Development of multiple myeloma in a patient with gastrointestinal stromal tumor treated with imatinib mesylate: A case report

    PubMed Central

    Tzilves, D; Gatopoulou, A; Zervas, K; Katodritou, E; Patakiouta, F; Tarpagos, A; Katsos, I

    2007-01-01

    Gastrointestinal stromal tumors (GISTs) are rare tumors, which represent approximately 1% of the neoplasms of the gastrointestinal tract. These tumors rarely give extra-abdominal metastases. However, their clinical outcome is potentially adverse. In some rare cases, co-existance of GISTs with other malignancies has been reported. Here we present a case of a 74-year old male with GIST, which was managed by surgical resection. Fourteen months later, the patient presented with liver metastases and imatinib mesylated was administered. During treatment, the patient reported skeletal pain and plane X-rays revealed osteolytic bone lesions. Further investigation revealed the presence of multiple myeloma. To the best of our knowledge, this is the first report of the co-existence of multiple myeloma (MM) with GIST. PMID:17461509

  3. Development of multiple myeloma in a patient with gastrointestinal stromal tumor treated with imatinib mesylate: a case report.

    PubMed

    Tzilves, D; Gatopoulou, A; Zervas, K; Katodritou, E; Patakiouta, F; Tarpagos, A; Katsos, I

    2007-04-01

    Gastrointestinal stromal tumors (GISTs) are rare tumors, which represent approximately 1% of the neoplasms of the gastrointestinal tract. These tumors rarely give extra-abdominal metastases. However, their clinical outcome is potentially adverse. In some rare cases, co-existance of GISTs with other malignancies has been reported. Here we present a case of a 74-year old male with GIST, which was managed by surgical resection. Fourteen months later, the patient presented with liver metastases and imatinib mesylated was administered. During treatment, the patient reported skeletal pain and plane X-rays revealed osteolytic bone lesions. Further investigation revealed the presence of multiple myeloma. To the best of our knowledge, this is the first report of the co-existence of multiple myeloma (MM) with GIST. PMID:17461509

  4. Pazopanib in metastatic multiply treated progressive gastrointestinal stromal tumors: feasible and efficacious

    PubMed Central

    Ramaswamy, Anant; Pande, Nikhil; Shetty, Omshree; Shetty, Nitin; Gupta, Sudeep

    2016-01-01

    Background A median progression free survival (PFS) of 18–20 months and median overall survival (OS) of 51–57 months can be achieved with the use of imatinib, in metastatic or advanced gastrointestinal stromal tumor (GIST). Sunitinib and regorafenib are approved options for patients progressing on imatinib, but with markedly decreased survival. pazopanib is a broad spectrum TKI targeting KIT, PDGFR and VEGFR receptors and has shown promising activity in phase 2 trials in GIST. Methods All patients who received pazopanib for GIST between March 2014 and September 2015 in our institution were reviewed. Patients were assessed for response with CT or PET CT scans. Patients continued pazopanib until progression or unacceptable toxicity. Survival was evaluated by Kaplan Meier product method. Results A total of 11 consecutive patients were included in our study. Median duration of follow up was seven months. The median lines of prior therapy was 2 [1-5]. Partial response (PR) was observed in seven patients and two had stable disease (SD). Two patients died within one month of start of pazopanib. Five of ten patients had progressed during the study with eight patients still alive. The median PFS was 11.9 months and the median OS was not reached. Common adverse events seen were hand-foot-syndrome (HFS) in four patients, anemia in four patients and fatigue in three patients. Grade 3/4 adverse events were uncommon. Three patients required dose modification of pazopanib. Conclusions Pazopanib is a reasonably efficacious well tolerated TKI and can be explored as a treatment option in advanced GIST that has progressed on imatinib. PMID:27563456

  5. Successful establishment of patient-derived tumor xenografts from gastrointestinal stromal tumor-a single center experience

    PubMed Central

    Jiang, Quan; Tong, Han-Xing; Zhang, Yong; Hou, Ying-Yong; Li, Jing-Lei; Wang, Jiong-Yuan; Zhou, Yu-Hong; Lu, Wei-Qi

    2016-01-01

    Patient-derived tumor xenografts (PDTX) generally represent a kind of more reliable model of human disease, by which a potential drugs’ preclinical efficacy could be evaluated. To date, no stable gastrointestinal stromal tumor (GIST) PDTX models have been reported. In this study, we aimed to establish stable GIST PDTX models and to evaluate whether these models accurately reflected the histological feature of the corresponding patient tumors and create a reliable GIST PDTX models for our future experiment. By engrafting fresh patient GIST tissues into immune-compromised mice (BALB/c athymic mice), 4 PDTX models were established. Histological features were assessed by a qualified pathologist based on H&E staining, CD117 and DOG-1. We also conduct whole exome sequencing(WES) for the 4 established GIST PDTX models to test if the model still harbored the same mutation detected in corresponding patient tumors and get a more intensive vision for the genetic profile of the models we have established, which will help a lot for our future experiment. To explore the tumorigenesis mechanism for GIST, we also have a statistical analysis for the genes detected as nonsynchronous-mutated simultaneously in 4 samples. All 4 GIST PDTX models retained the histological features of the corresponding human tumors, with original morphology type and positive stains for CD117 and DOG-1. Between the GIST PDTX models and their parental tumors, a same mutation site was detected, which confirmed the genetic consistency. The stability of molecular profiles observed within the GIST PDTX models provides confidence in the utility and translational significance of these models for in vivo testing of personalized therapies. To date, we conducted the first study to successfully establish a GIST PDTX model whose genetic profiles were revealed by whole exome sequencing. Our experience could be of great use. PMID:27186422

  6. Single-Incision Laparoscopic Surgery for a Small-Intestinal Gastrointestinal Stromal Tumor: Report of a Case

    PubMed Central

    Sakai, Makoto; Wada, Wataru; Kimura, Shintaro; Okada, Akiko; Hirakata, Tomoko; Onozato, Ryoichi; Saito, Kana; Morohara, Koji; Osawa, Hidenobu; Katayama, Kazuhisa; Yasuda, Naokuni; Tanaka, Shigebumi; Kuwano, Hiroyuki

    2014-01-01

    Our report concerns a 64-year-old man with a small-intestinal gastrointestinal stromal tumor (GIST), which was successfully treated with single-incision laparoscopic surgery (SILS). Small-bowel endoscopy detected a submucosal tumor located approximately 10 cm from the ligament of Treitz in the wall of the proximal jejunum. Contrast-enhanced computed tomography revealed a tumor (diameter, 4 cm) containing high- and low-density areas in the proximal jejunum. On 18F-fluorodeoxyglucose (FDG) positron-emission tomography (PET), the tumor demonstrated intense FDG uptake (maximum standard uptake value, 3.82), whereas it displayed high signal intensity on diffusion-weighted magnetic resonance images. No metastatic lesions were observed. The patient was diagnosed with a jejunal GIST. Wedge resection of the jejunum was performed using the SILS procedure. The tumor was histopathologically diagnosed as a low-grade malignant GIST. SILS is a useful resection technique for small-intestinal GIST. PMID:25058785

  7. Combination of PLR, MLR, MWR, and Tumor Size Could Significantly Increase the Prognostic Value for Gastrointestinal Stromal Tumors.

    PubMed

    Feng, Fan; Tian, Yangzi; Liu, Shushang; Zheng, Gaozan; Liu, Zhen; Xu, Guanghui; Guo, Man; Lian, Xiao; Fan, Daiming; Zhang, Hongwei

    2016-04-01

    Systemic inflammation and immune response were associated with prognosis of tumors. However, data was limited due to the relatively low incidence of gastrointestinal stromal tumors (GISTs). The aim of the present study was to investigate the predictive value of preoperative peripheral blood cells in prognosis of GISTs.From September 2008 to July 2015, a total of 274 GIST patients in our department were enrolled in the present study. Clinicopathological features of GISTs were recorded. The association between preoperative peripheral blood cells and prognosis of GISTs were analyzed.Tumor location, tumor size, mitotic index, intratumoral necrosis, and National Institutes of Health (NIH) risk category were associated with prognosis of GISTs. High neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), neutrophil-to-white blood cell ratio (NWR), monocyte-to-white blood cell ratio (MWR) and low lymphocyte-to-white blood cell ratio (LWR) was associated with poor prognosis of GISTs (76.2% vs 83.7%, P = 0.010. 70.5% vs 98.7%, P = 0.000. 65.7% vs 96.4%, P = 0.004. 78.5% vs 82.5%, P = 0.044. 73.5% vs 97.8%, P = 0.004. 76.6% vs 83.6%, P = 0.012, respectively). However, tumor size was the only independent risk factor for prognosis according to multivariate analysis (P = 0.006). Tumor location, tumor size, mitotic index, and NIH risk category were significantly correlated with the above-mentioned parameters (all P < 0.05). The prognosis of GISTs with tumor size >5 cm, high MLR, high PLR, and high MWR was significantly lower than the remnant patients (P = 0.010).The peripheral blood routine test is convenient, reproducible, and inexpensive. High NLR, MLR, PLR, NWR, MWR, and low LWR were associated with poor prognosis of GISTs. The association between the above parameters and prognosis of GISTs may be attributed to their correlation with tumor size, mitotic index, and NIH risk category. The

  8. Increased Risk of Additional Cancers Among Patients with Gastrointestinal Stromal Tumors: A Population-Based Study

    PubMed Central

    Murphy, James D.; Ma, Grace L.; Baumgartner, Joel M.; Madlensky, Lisa; Burgoyne, Adam M.; Tang, Chih-Min; Martinez, Maria Elena; Sicklick, Jason K.

    2015-01-01

    Purpose Most gastrointestinal stromal tumors (GIST) are considered non-hereditary or sporadic. However, single-institution studies suggest that GIST patients develop additional malignancies with increased frequencies. We hypothesized that we could gain greater insight into possible associations between GIST and other malignancies using a national cancer database inquiry. Methods Patients diagnosed with GIST (2001–2011) in the Surveillance, Epidemiology, and End Results database were included. Standardized prevalence ratios (SPRs) and standardized incidence ratios (SIRs) were used to quantify cancer risks incurred by GIST patients before and after GIST diagnoses, respectively, when compared with the general U.S. population. Results Of 6,112 GIST patients, 1,047 (17.1%) had additional cancers. There were significant increases in overall cancer rates: 44% (SPR=1.44) before diagnosis and 66% (SIR=1.66) after GIST diagnoses. Malignancies with significantly increased occurrence both before/after diagnoses included other sarcomas (SPR=5.24/SIR=4.02), neuroendocrine-carcinoid tumors (SPR=3.56/SIR=4.79), non-Hodgkin’s lymphoma (SPR=1.69/SIR=1.76), and colorectal adenocarcinoma (SPR=1.51/SIR=2.16). Esophageal adenocarcinoma (SPR=12.0), bladder adenocarcinoma (SPR=7.51), melanoma (SPR=1.46), and prostate adenocarcinoma (SPR=1.20) were significantly more common only before GIST. Ovarian carcinoma (SIR=8.72), small intestine adenocarcinoma (SIR=5.89), papillary thyroid cancer (SIR=5.16), renal cell carcinoma (SIR=4.46), hepatobiliary adenocarcinomas (SIR=3.10), gastric adenocarcinoma (SIR=2.70), pancreatic adenocarcinoma (SIR=2.03), uterine adenocarcinoma (SIR=1.96), non-small cell lung cancer (SIR=1.74), and transitional cell carcinoma of the bladder (SIR=1.65) were significantly more common only after GIST. Conclusion This is the first population-based study to characterize the associations and temporal relationships between GIST and other cancers, both by site and

  9. Analysis of mutation of the c-Kit gene and PDGFRA in gastrointestinal stromal tumors

    PubMed Central

    XU, CHUN-WEI; LIN, SHAN; WANG, WU-LONG; GAO, WEN-BIN; LV, JIN-YAN; GAO, JING-SHAN; ZHANG, LI-YING; LI, YANG; WANG, LIN; ZHANG, YU-PING; TIAN, YU-WANG

    2015-01-01

    The aim of the present study was to investigate mutation status of the c-Kit gene (KIT) and PDGFRA in patients with a gastrointestinal stromal tumor (GIST). In total, 93 patients with a GIST were included in the study, in which polymerase chain reaction amplification and gene sequencing were used to detect the sequences of exons 9, 11, 13 and 17 in KIT and exons 12 and 18 in PDGFRA. KIT mutations were detected in 64 cases (68.82%), of which exon 11 mutations were detected in 56 cases (60.22%), exon 13 mutations were detected in three cases (3.23%) and one case (1.08%) was shown to have a mutation in exon 17. The most common mutation in exon 11 was a deletion, which accounted for 55.36% (31/56) of the cases, followed by a point mutation observed in 26.79% (15/56) of the cases, while an insertion (tandem repeats) was identified in 14.29% (8/56) of the cases, and 3.57% (2/56) of the exon 11 mutations were deletions associated with a point mutation. The majority of the mutations were heterozygous, with only a few homozygous mutations. Mutational analysis revealed the mutations to be more concentrated in the classic hot zone at the 5′-end, followed by the tandem repeat frame at the 3′-end. In four cases, a mutation was detected in exon 18 of PDGFRA, of which one was associated with a mutation in KIT. The remaining three cases (10.34%, 3/29) were not associated with mutations in KIT and accounted for 37.5% (3/8) of the CD117-negative GIST cases. Therefore, the majority of the GIST cases were characterized by mutations in KIT or PDGFRA, which were directly associated with the disease. Pairs of different mutations in the same exon of KIT, or KIT mutations coupled with pairs of mutations in PDGFRA, were detected in a small number of patients. Imatinib is a small molecule tyrosine kinase inhibitor and is the first line targeted treatment for GIST, resulting in markedly improved survival rates. Thus, gene mutation genotyping may provide inspiration and guidance for

  10. Giant and high-risk gastrointestinal stromal tumor in the abdomino-pelvic cavity: A case report

    PubMed Central

    WANG, YUJIAO; PENG, JIE; HUANG, JINBAI

    2016-01-01

    Gastrointestinal stromal tumors (GISTs) are benign mesenchymal tumors of the gastrointestinal tract. The clinical presentations of patients with GIST are variable and may be non-specific. The current study reports the case of a 66-year-old man that presented with a gradual enlargement of the abdomen, emaciation, hyperhidrosis and frequent and urgent micturition. A computed tomography (CT) scan of the abdomen revealed a large, heterogeneous, low density mass that occupied the entire abdomino-pelvic cavity. Magnetic resonance imaging (MRI) identified a high signal intensity on the T2 weighted image and an intermediate signal intensity on the T1 weighted image. A contrast enhanced CT scan and MRI demonstrated the uptake of contrast material. A biopsy revealed that the tumor was composed of spindle cells, and immunohistochemical analysis identified the presence of mast/stem cell growth factor receptors. Together, these results lead to a diagnosis of GIST. The clinical findings, imaging modalities and pathological studies suggested that the GIST was a large and high-risk tumor located in the abdomino-pelvic cavity. The final surgical results confirmed these findings. Following conservative treatment with imatnib (400 mg, daily) for 6 months, the tumor became smaller and was suitable for surgery, which the patient received in December 2014. The final surgery confirmed the high-risk GIST. Subsequent to the surgery, the patient was recommended to continue the use of imatnib with regular CT or MRI reexaminations every 3 months, which are planned to continue for 3 years. PMID:26998117

  11. Dysphagia, melanosis, gastrointestinal stromal tumors and a germinal mutation of the KIT gene in an Argentine family.

    PubMed

    Adela Avila, Silvia; Peñaloza, José; González, Flavia; Abdo, Ivana; Rainville, Irene; Root, Elizabeth; Carrero Valenzuela, Roque Daniel; Garber, Judy

    2014-03-01

    Gastrointestinal stromal tumors (GIST) are the most common mesenchymatous neoplasms of the human digestive tract. They locate preferentially in stomach, duodenum or small bowel. Usually sporadic, familial cases unrelated to neurofibromatosis may be due to germline mutations in KIT or PDGFRA. We describe the first Argentine family with GIST in which we found, diffuse cutaneous melanosis, lentiginosis, and dysphagia. Dysphagia was not observed in the four families previously described with the same mutation. Histopathology resulted consistent with GIST, and tumor immunohistochemistry was likewise positive for DOG-1, CD117 (KIT) and CD34. The search for germline mutations identified the KIT c.1697T > C (p.559V > A) substitution in exon 11. Treatment with imatinib is furnishing positive results. PMID:24847623

  12. A Case of Gastrointestinal Stromal Tumor That Underwent Endoscopic Ultrasound-Guided Aspiration with a 25-Gauge Biopsy Needle

    PubMed Central

    Tomizawa, Minoru; Shinozaki, Fuminobu; Motoyoshi, Yasufumi; Sugiyama, Takao; Yamamoto, Shigenori; Ishige, Naoki

    2016-01-01

    Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is performed to obtain specimens for pathological analysis. For this procedure, 19-gauge (19G), 22-guage (22G), and 25-guage (25G) needles are available. The needles are classified into aspiration type and biopsy type. A 56-year-old woman underwent upper gastrointestinal endoscopy that showed a 38-mm-diameter submucosal tumor. The elevated lesion was diagnosed as a submucosal tumor of the stomach. Contrast-enhanced computed tomography showed a low-density area on the luminal surface of the gastric wall, which was covered with a thin layer of gastric mucosa. EUS showed a hypoechoic lesion in the submucosal layer. Color Doppler image showed a pulsating vascular signal extending into the center of the hypoechoic lesion from the periphery. EUS-FNA was performed with a 25G biopsy needle. The specimen tissue consisted of spindle-shaped cells. The cells were positive for CD117 and CD34. The submucosal tumor was diagnosed as a gastrointestinal stromal tumor.

  13. The emerging role of insulin-like growth factor 1 receptor (IGF1r) in gastrointestinal stromal tumors (GISTs)

    PubMed Central

    2010-01-01

    Recent years have seen a growing interest in insulin-like growth factor 1 receptor (IGF1R) in medical oncology. Interesting data have been reported also on IGF1r in gastrointestinal stromal tumors (GISTs) especially in children and in young adult patients whose disease does not harbour mutations on KIT and PDGFRA and are poorly responsive to conventional therapies. However, it is too early to reach conclusions on IGF1R as a novel therapeutic target in GIST because the receptor's biological role is still to be defined and the clinical significance in patients needs to be studied in larger studies. We update and comment the current literature on IGF1R in GISTs and discuss the future perspectives in this promising field. PMID:21078151

  14. The role of surgery in the management of gastrointestinal stromal tumors (GISTs) in the era of imatinib mesylate effectiveness.

    PubMed

    Kosmadakis, Nikolaos; Visvardis, Evangelos-Efstathios; Kartsaklis, Panagiotis; Tsimara, Maria; Chatziantoniou, Alexandros; Panopoulos, Ioannis; Erato, Palli; Capsambelis, Paul

    2005-08-01

    Surgical resection is the treatment of choice for the gastrointestinal stromal tumors (GISTs). In the literature, the 5-year patient survival after surgical resection, ranged from 48 to 80%, before the era of imatinib mesylate and the exploration of the prognostication criteria. Imatinib mesylate targets an intracellular signaling molecule of the natural history and malignant development of GISTs, and increased the 5-year survival rate, after the resection of primary low-risk GISTs, to similar values to the normal population. For high-risk GISTs, current knowledge which is still under expansion, show major improvement at the 1-year survival rate of more than 90% versus less than 50% before imatinib era. After surgical resection, for both low and high malignant potential GISTs, a closed control directed to the early identification of confined resectable recurrences, is required. This paper assesses the current knowledge of GIST management, motivated by a case of patient with intermediate risk GIST. PMID:15993051

  15. A Systematic Review and Meta-Analysis of Open vs. Laparoscopic Resection of Gastric Gastrointestinal Stromal Tumors.

    PubMed

    Pelletier, Jean-Sebastien; Gill, Richdeep S; Gazala, Sayf; Karmali, Shahzeer

    2015-05-01

    Gastric gastrointestinal stromal tumors (GISTs) are the most common sarcoma of the gastrointestinal tract, and surgical resection is the primary treatment of early disease. Limited data exist concerning laparoscopic resections of these neoplasms. This systematic review was designed to evaluate the literature comparing laparoscopic and open surgical resection of gastric GISTs and to assess the effectiveness and safety of this minimally invasive technique. We performed a systematic search of MEDLINE, the Cochrane Library, PubMed, Embase, Scopus, Web of Science, Google Scholar, the clinical trials database and ProQuest Dissertations and Theses as well as the past 3 years of conference abstracts from the Society of American Gastrointestinal and Endoscopic Surgeons Annual Meetings. Studies comparing the open and the laparoscopic approaches to the resection of gastric GISTs were included in this systematic review. Two reviewers independently performed the screen of titles and abstracts, the full manuscript review, the data extraction and the risk of bias assessment. A quantitative analysis was performed. Of the 189 studies identified, seven studies were included. The laparoscopic approach was associated with a significantly lower length of hospital stay (3.82 days (2.14 - 5.49)). There was no observed difference in operative time, adverse events, estimated blood loss, overall survival and recurrence rates. This study supports that laparoscopic resection is safe and effective for gastric GISTs and is associated with a significantly lower length of hospital stay. Further trials are needed for cost analysis and to rigorously assess oncologic outcomes. PMID:25780475

  16. The diagnostic value of endoscopic ultrasonography and contrast-enhanced harmonic endoscopic ultrasonography in gastrointestinal stromal tumors

    PubMed Central

    Zhao, Yanchao; Qian, Linxue; Li, Peng; Zhang, Shutian

    2016-01-01

    Objective: To evaluate the diagnostic value of endoscopic ultrasonography (EUS) and contrast-enhanced harmonic (CEH) EUS in patients with gastrointestinal stromal tumors (GISTs). Patients and Methods: About 19 patients with suspected GISTs underwent EUS and CEH-EUS before tumor resection. The malignant potential was assessed according to the modified Fletcher classification system. Patients were divided into lower (Group I) and higher (Group II) malignant potential group. The clinical characteristics and EUS/CEH-EUS features were compared between two groups. Results: The tumor size in Group II was significantly larger than that in Group I (14.6 ± 5.8 mm vs. 32.1 ± 8.4 mm, P < 0.05). Heterogeneous echogenicity was observed in 4 (4/8) cases in Group II and none in Group I (P < 0.05). Irregular intratumoral vessels were detected in 6 cases in Group II and none in Group I (P < 0.05). The sensitivity and specificity of irregular vessel detection for discriminating higher from lower malignant potential GISTs were 75% and 100%, respectively. The positive predictive value and negative predictive value of detection of irregular vessels to high malignant potential GISTs were 33% and 100%, respectively. Conclusion: Detection of irregular intratumoral vessels can predict higher malignant potential before tumor resection. The tumor size and echogenicity are assistant factors for malignant potential assessment. Endoscopic resection is an efficacious treatment with good security for appropriate patients. PMID:27080610

  17. Synchronous occurrence of gastrointestinal stromal tumor and acute myeloid leukemia: A case report and review of the literature

    PubMed Central

    GAO, NA; GUO, NONG-JIAN; YU, WEN-ZHENG; WANG, XUE-XIA; SUN, JIAN-RONG; YU, NING; LIU, REN-TONG; LIU, XIAO-DAN; LIU, ZENG-YAN; FENG, RUI

    2016-01-01

    Gastrointestinal stromal tumors (GISTs) originate from the mesenchymal tissue of the gastrointestinal tract. The pathogenesis of GIST is associated with the mutational activation of the receptor tyrosine kinase cluster of differentiation (CD)117 or platelet-derived growth factor receptor-α. Overall, ~60% of GISTs occur in the stomach. Clinically, GISTs may coexist with various types of cancer, including liver cancer, pancreatic tumors and lymphoma, either synchronously or metachronously. The present study reports the case of a patient with the synchronous occurrence of a CD117-positive GIST and acute myeloid leukemia. A 69-year-old man was hospitalized for heart palpitations and dizziness, and was diagnosed with acute myeloid leukemia (AML) by bone marrow aspiration and flow cytometry analysis. An abdominal computed tomograpy and gastroscopy revealed the presence of GIST. The patient received chemotherapy in combination with imatinib (400 mg/day), and the mass was removed 2 months later. To the best of our knowledge, the present study is the first reported case of the synchronous development of a CD117-positive GIST and AML. Additional studies are required in order to understand the association between GIST and hematological malignancies. PMID:27123049

  18. A novel germline mutation in SDHA identified in a rare case of gastrointestinal stromal tumor complicated with renal cell carcinoma.

    PubMed

    Jiang, Quan; Zhang, Yong; Zhou, Yu-Hong; Hou, Ying-Yong; Wang, Jiong-Yuan; Li, Jing-Lei; Li, Ming; Tong, Han-Xing; Lu, Wei-Qi

    2015-01-01

    Succinate dehydrogenase (SDH), which is located on the mitochondrial inner membrane, is essential to the Krebs cycle. Mutations of the SDH gene are associated with many tumors, such as renal cell carcinoma, wild type gastrointestinal stromal tumors (WT GISTs) and hereditary paragangliomas/pheochromocytomas. Herein we present a rare case diagnosed as a WT GIST complicated with a renal chromophobe cell tumor and detected a novel germline heterozygous mutation (c.2T>C: p.M1T) in the initiation codon of the SDHA gene. We also conduct a preliminary exploration for the mechanism of reduced expression of SDHB without mutation of SDHB gene. Our case enriches the mutation spectrum of the SDH gene. After reviewing previous studies, we found it to be the first case diagnosed as a WT GIST complicated with a synchronous renal chromophobe cell tumor and identified a novel germline heterozygous mutation. It was also the second reported case of a renal cell carcinoma associated with an SDHA mutation. PMID:26722403

  19. Intra-abdominal textiloma. A retained surgical sponge mimicking a gastric gastrointestinal stromal tumor: report of a case.

    PubMed

    Yamamura, Noriyuki; Nakajima, Kiyokazu; Takahashi, Tsuyoshi; Uemura, Mamoru; Nishitani, Akiko; Souma, Yoshihito; Nishida, Toshirou

    2008-01-01

    We describe a unique case of intra-abdominal textiloma (granuloma due to a retained foreign body), which mimicked a gastric tumor on preoperative imaging studies. A 78-year-old asymptomatic patient with a past history of a gastrectomy was referred for evaluation of an intra-abdominal mass lesion, which was incidentally observed on a computed tomography (CT) scan. Repeated CT with a higher resolution demonstrated a 5-cm heterogeneously enhanced mass with a distinct feeding artery. These findings were all compatible with a tumorous lesion originating in the gastric remnant, most likely gastric gastrointestinal stromal tumor. A diagnosis of textiloma was immediately made during surgery, and it was confirmed pathologically postoperatively. The feeding artery that appeared on CT images, which was a major reason for the false diagnosis, was considered to have resulted from a slow but continuous inflammation reaction around the retained surgical sponge. Surgeons should therefore always take the possibility of textilomas into consideration even with typical tumorous characteristics on preoperative imaging studies, especially in patients with a history of prior abdominal surgery. PMID:18516538

  20. Reversible sarcopenia in patients with gastrointestinal stromal tumor treated with imatinib

    PubMed Central

    Moryoussef, Frédérick; Dhooge, Marion; Volet, Julien; Barbe, Coralie; Brezault, Catherine; Hoeffel, Christine; Coriat, Romain; Bouché, Olivier

    2015-01-01

    Background Imatinib is a long-term, oral, targeted therapy for high-risk resected and advanced gastrointestinal stromal tumours (GIST). It is known that sarcopenia affects prognosis and treatment tolerance in patients with various solid cancers. We analysed lumbar skeletal muscle index changes in imatinib-treated GIST patients. Imatinib tolerance was also assessed to evaluate the influence of pre-treatment sarcopenia. Methods Thirty-one patients with advanced (n = 16) or high-risk resected (n = 15) GIST treated with imatinib (400 mg/day) were analysed retrospectively. Lumbar skeletal muscle indexes were evaluated on computed tomography images obtained before starting imatinib for all patients and at 6 months for those initially sarcopenic. Sarcopenia was defined using consensual cutoffs. Imatinib-induced toxicities were assessed after 3 months of administration. Results Twelve (38.7%) of the 31 patients were sarcopenic, including one unassessable at 6 months. Seven (63.6%) of the 11 assessable sarcopenic patients became non-sarcopenic after 6 months of imatinib. Pre-treatment sarcopenia was not associated with grades 3–4 toxicities, but the mean number of all-grade toxicities per sarcopenic patient was significantly higher for those non-sarcopenic (4.1 vs. 1.7, respectively, p < 0.01) after 3 months of treatment. Grades 1–2 anaemia and grades 1–2 fatigue were more frequent for sarcopenic than non-sarcopenic patients (83% vs. 26%, P < 0.01 and 42% vs. 5%, P = 0.02, respectively). Conclusions Sarcopenia is reversible in some GIST patients treated with imatinib. Pre-imatinib sarcopenia is predictive of non-severe toxicities, particularly anaemia and fatigue. PMID:26673372

  1. Laparoscopic en bloc excision of gastrointestinal stromal tumors of the rectum after neoadjuvant imatinib therapy: anteriorly extended intersphincteric resection combined with partial resection of the prostate.

    PubMed

    Ueki, T; Nagayoshi, K; Manabe, T; Maeyama, R; Yokomizo, A; Yamamoto, H; Oda, Y; Tanaka, M

    2015-04-01

    We herein present a novel technique for laparoscopic en bloc excision involving anteriorly extended intersphincteric resection with partial resection of the posterior lobe of the prostate for large rectal gastrointestinal stromal tumors (GISTs). The sequence of neoadjuvant imatinib therapy and this less invasive surgery for marginally resectable rectal GISTs has the potential to obviate the need for urinary reconstruction and permanent stomas without jeopardizing the tumor margin status. PMID:25550117

  2. Gastrointestinal stromal tumor with an unusual presentation as an enlarged prostate gland: a case report and review of the literature

    PubMed Central

    Deisch, Jeremy K.; Reinke, Dennis D.

    2016-01-01

    We report a case of a 78-year-old male who presented with urinary retention, constipation and an enlarged prostate gland. A transurethral resection of the prostate (TURP) was performed. Pathologic examination revealed a hypercellular-spindled neoplasm with frequent mitoses, nuclear pleomorphism, and multifocal geographic tumoral necrosis. A pathologic diagnosis of gastrointestinal stromal tumor (GIST) was made based on morphologic and immunohistochemical findings, and was later reinforced by molecular study results. This lesion was initially thought to represent a primary prostatic GIST. To the best of our knowledge, there have been only five cases of primary prostatic GISTs. Subsequent imaging studies revealed the mass to be contiguous with the anterior rectal wall, suggesting the possibility of a rectal primary with extension to the prostate gland. The patient was treated with imatinib mesylate, and after twelve months of follow up failed to demonstrate any evidence of progression or metastatic disease. GIST should be considered in cases of prostatic tumors with a spindled or epithelioid morphology, and immunohistochemistry and possible molecular studies are recommended to aid in diagnosis and guide treatment decisions. PMID:27034816

  3. Relationship between gene mutations and protein expressions of PDGFR α and C-kit in gastrointestinal stromal tumors

    PubMed Central

    He, Jun-Yi; Tong, HX; Zhang, Y; Wang, JY; Shao, YB; Zhu, J; Lu, Wei-Qi

    2015-01-01

    Objective: To investigate the relationship between gene mutations and protein expressions of PDGFR α and C-kit in gastrointestinal stromal tumors (GIST) and its significance in tumorigenesis. Methods: Single strand conformation polymorphism-polymerase chain reaction (PCR-SSCP), immunohistochemistry and Western blot were used to detect the gene mutations in PDGFR α and C-kit and their protein expressions in 105 cases of GIST specimens. Results: In 105 cases of GIST, PDGFR α gene mutation was found in 12 cases (11.4%), which was common in the stomach- derived spindle cell GIST. C-kit gene mutation was found in 58 cases (55.2%), which was common in the small intestine. Mutations of PDGFR α is in 12 cases of GIST were stronger than the C-kit mutations in GIST, normal gastrointestinal tissues and schwannomas. No significant correlation was found between mutations and C-kit protein expression (P>0.05), while the protein expression of PDGFR α was significantly correlated with mutations (P<0.0001). Conclusion: Mutations of PDGFR α and C-kit plays an important role in part of GIST tumorigenesis. Mutation sites were related with original sites and histological types. Most protein expressions were closely related to their gene mutations in GIST. PMID:26221304

  4. Immunostaining of phospho-histone H3 and Ki-67 improves reproducibility of recurrence risk assessment of gastrointestinal stromal tumors.

    PubMed

    Uguen, Arnaud; Conq, Gwenaël; Doucet, Laurent; Talagas, Matthieu; Costa, Sebastian; De Braekeleer, Marc; Marcorelles, Pascale

    2015-07-01

    Gastrointestinal stromal tumors (GISTs) are the most common non-epithelial tumors in the digestive tract. Beyond surgery, therapeutic management depends on risk of recurrence. Risk evaluation of GIST takes into account location and size of the tumor, whether or not the tumor was intact or ruptured and mitotic index. The mitotic index lacks in intra- and interobserver reproducibility. In this study, we evaluated on 61 GISTs, the reproducibility of mitotic counting using classical hematoxylin-eosin-saffron (HES) staining, and its correlation with the mitotic count obtained through immunohistochemical staining for phospho-histone H3 (PHH3) and the proliferation index based upon Ki-67 immunostaining. Mitotic counts by HES and PHH3 staining and Ki-67 proliferation index were evaluated twice by three independent observers taking into account interpretation times per tumor for each technique. HES-based and PHH3-based mitotic counts and Ki-67 proliferation index correlated well and presented good intra- and interobserver reproducibility. PHH3 staining resulted in a slight but statistically significant difference of about two more mitotic figures per 5 mm(2) than the HES-based count, which might have put some borderline tumors in a different risk category. Immunohistochemical staining for PHH3 and Ki-67 allowed more rapid interpretation than mitotic counts based upon HES staining, but only PHH3 staining allows counting of mitoses. Immunostaining using anti-PHH3 and anti-Ki-67 antibodies will eventually provide improved recurrence risk stratification of GIST and may become effective ancillary tools in deciding on optimal therapeutic management. PMID:25823616

  5. c-kit mutation-positive advanced thymic carcinoma successfully treated as a mediastinal gastrointestinal stromal tumor: A case report

    PubMed Central

    HIRAI, FUMIHIKO; EDAGAWA, MAKOTO; SHIMAMATSU, SHINICHIRO; TOYOZAWA, RYO; TOYOKAWA, GOUJI; NOSAKI, KANAME; YAMAGUCHI, MASAFUMI; SETO, TAKASHI; TWAKENOYAMA, MITSUHIRO; ICHINOSE, YUKITO

    2016-01-01

    Thymic carcinoma is an exceptionally rare tumor, which has a very poor prognosis, differing from thymoma. Although cytotoxic chemotherapy is commonly used to treat advanced thymic carcinoma, its effectiveness has not been found to be sufficient. There are several reports that thymic carcinoma also harbors an oncogenic driver mutation, similar to lung cancer. A patient with a c-kit mutation-positive thymic carcinoma received imatinib followed by sunitinib consecutively, which are both c-Kit inhibitors. Although the patient had achieved long-term disease control for 21 months, the primary lesion and pulmonary metastases had increased in size by November, 2014. Following failure of imatinib treatment, the patient received sunitinib, a multiple kinase inhibitor, initiated in December, 2014. Following administration of sunitinib, a computed tomography scan revealed a partial response and the disease was effectively controlled with continued sunitinib treatment for 6 months, up to June, 2015. The patient achieved long-term disease control (~27 months) with imatinib followed by sunitinib. The efficacy of consecutive molecular-targeted therapy for thymic carcinoma was demonstrated in this case. Therefore, thymic carcinoma with oncogenic driver mutations should be treated with molecular-targeted agents rather than with cytotoxic drugs, and it may be suitable to treat c-kit mutation-positive thymic carcinoma as a mediastinal gastrointestinal stromal tumor. PMID:27073655

  6. Adjuvant imatinib treatment in gastrointestinal stromal tumor: which risk stratification criteria and for how long? A case report.

    PubMed

    Blay, Jean-Yves; Levard, Alice

    2016-01-01

    Imatinib mesylate is approved for the adjuvant treatment of KIT-positive gastrointestinal stromal tumor (GIST) following surgical resection. However, uncertainty remains in terms of patient eligibility for adjuvant treatment and the optimal duration of treatment. Here, we present two challenging patient cases encountered in clinical practice that highlight the ambiguity in the current recommendations for adjuvant imatinib in GIST and discuss our approaches and rationales for treatment. The first case involves a 36-year-old man with a 7 cm duodenal GIST and possible tumor rupture during surgical resection. This patient's risk of GIST recurrence was either intermediate or high depending on which risk stratification criteria were used. The patient was treated with adjuvant imatinib for 3 years and experienced disease recurrence 14 months after the completion of treatment. Imatinib treatment was reintroduced, and the patient is in partial response 17 months later. The second case involves a 46-year-old woman at high risk of recurrence following surgical resection. Adjuvant treatment with imatinib was initiated. After considering the patient's initial high risk and good side-effect profile, the decision was made to continue adjuvant imatinib treatment for 5 years. As of May 2013, the patient has been receiving continuous imatinib treatment for 52 months, with no sign of progression. These reports exemplify the challenges faced in clinical practice because of uncertainties in optimal risk stratification criteria and duration of treatment. They stress the importance of individualized treatment and shared decision making between the physician and the patient. PMID:26457546

  7. Synchronous Large Gastrointestinal Stromal Tumor and Adenocarcinoma in the Stomach Treated with Imatinib Mesylate Followed by Total Gastrectomy.

    PubMed

    Namikawa, Tsutomu; Munekage, Eri; Munekage, Masaya; Maeda, Michihiro; Yatabe, Tomoaki; Kitagawa, Hiroyuki; Sakamoto, Kouichi; Obatake, Masayuki; Kobayashi, Michiya; Hanazaki, Kazuhiro

    2016-04-01

    Herein we report on a case of synchronous large gastrointestinal stromal tumor (GIST) and adenocarcinoma of the stomach treated with radical surgery following neoadjuvant therapy with imatinib mesylate. A 58-year-old man was referred to our hospital with a large mass in the peritoneal cavity. Abdominal computed tomography showed a large mass measuring 21×20×14 cm in the left upper peritoneal cavity. Esophagogastroduodenoscopy revealed a large elevated lesion in the upper body and a depressed lesion in the lower gastric body near the lesser curvature. Biopsy specimens revealed GIST in the large elevated lesion and signet-ring cell carcinoma in the depressed lesion. Because of the large size of the GIST, the patient was treated with neoadjuvant therapy with imatinib mesylate (400 mg/day) for 5 months. After confirmation of a marked decrease in tumor size following imatinib mesylate therapy, the patient underwent total gastrectomy and regional lymph-node dissection with distal pancreatectomy and splenectomy. Pathological examination confirmed the diagnosis of high-risk GIST and signet-ring cell carcinoma invading the muscularis propria with one lymph-node metastasis. At the time of writing, the patient was receiving postoperative chemotherapy using oral fluoropyrimidine (S-1) without evidence of disease recurrence for 4 months after surgery. In addition to the present case, we provide a retrospective review of another 15 patients who were diagnosed with synchronous GIST in the stomach and primary gastric adenocarcinoma. PMID:27069170

  8. Clinicopathological significance of c-KIT mutation in gastrointestinal stromal tumors: a systematic review and meta-analysis

    PubMed Central

    Yan, Lin; Zou, Lei; Zhao, Wenhua; Wang, Yansen; Liu, Bo; Yao, Hongliang; Yu, Haihua

    2015-01-01

    Many types of KIT mutations have been observed in gastrointestinal stromal tumors (GISTs), but their prognostic and predictive significance are still unclear. A meta-analysis and literature review were conducted to estimate the contribution of KIT mutations in prognostic parameters and clinic-pathological significance of GISTs. A total of 18 relevant articles from PubMed, EMBASE and Web of Science databases were included in this study. The frequency of KIT mutation was significantly increased in the GIST patients with higher mitosis (≥5/50 high-power fields (HPFs) and larger size (≥5 cm) of tumors than in those with lower MI (≤5/50HPFs) and smaller size (≤5 cm) of GISTs respectively. The rate of KIT mutation was not significantly changed between GISTs in stomachs and in small intestines. KIT mutational status has prognostic significance for patients’ outcome. GIST patients with KIT exon 9 mutations have higher risk of progression than those with exon 11 mutations. 5 year relapse-free survival (RFS) rate was significantly higher in patients with KIT exon 11 deletion than in those with other type of KIT exon 11 mutations. The deletion involving KIT exon 11, particularly codons 557–558, is a valuable predictor of prognosis for patients with GISTs. PMID:26349547

  9. Expression of L1 protein correlates with cluster of differentiation 24 and integrin β1 expression in gastrointestinal stromal tumors

    PubMed Central

    DU, YUE; ZHANG, HAIHONG; JIANG, ZHONGMIN; HUANG, GUOWEI; LU, WENLI; WANG, HESHENG

    2015-01-01

    The present study examined 66 cases of gastrointestinal stromal tumors (GISTs), 20 cases of smooth muscle tumors, 20 cases of schwannomas and 20 cases of normal gastric tissues in order to analyze the expression of L1, cluster of differentiation (CD)24 and integrin β1 by immunohistochemical staining. Patients were subjected to follow-up, and survival data were evaluated. L1 expression was detected in 57.6% of GIST cases; this was a significantly higher percentage compared with that found in the smooth muscle tumor cases or the normal control group. CD24 and integrin β1 were also expressed at significantly higher levels in the GIST cases than in the normal control group, although no significant difference was found in the expression levels of these proteins in smooth muscle tumor or schwannoma cases. These higher levels of L1 and integrin β1 expression were associated with an increased risk of invasive GIST, and were significantly positively correlated with Ki-67 expression. CD24 expression was not associated with the risk of GIST invasion or Ki-67 expression. There were positive correlations between L1, CD24 and integrin β1 expression; however, these had no significant association with patient survival. Therefore, L1 alone or in conjunction with CD24 (L1 + CD24), or integrin β1 (L1 + integrin β1) can be considered a valuable indicator for the differential diagnosis of GIST. Furthermore, L1 and integrin β1 can be used alone or in combination to evaluate the biological behavior of GISTs. Future studies are required to evaluate the prognostic value of these markers. PMID:26137113

  10. STRONG EXPRESSION OF IGF1R IN PEDIATRIC GASTROINTESTINAL STROMAL TUMORS WITHOUT IGF1R GENOMIC AMPLIFICATION

    PubMed Central

    Janeway, Katherine A.; Zhu, Mei-Jun; Barretina, Jordi; Perez-Atayde, Antonio; Demetri, George D.; Fletcher, Jonathan A.

    2010-01-01

    Wildtype (WT) gastrointestinal stromal tumors (GISTs), lacking mutations in KIT or PDGFRA, represent 85% of GISTs in pediatric patients. Treatment options for pediatric WT GIST are limited. Recently, expression profiling of a limited number of pediatric and adult WT GISTs and more in depth study of a single pediatric WT GIST implicated the insulin like growth factor 1 receptor (IGF1R) as a potential therapeutic target in pediatric WT GIST. We performed immunoblotting, SNP and FISH studies to determine the extent of expression, biochemical activation and genomic amplification of IGF1R in a larger number of pediatric WT GISTs. Pediatric WT GISTs expressed IGF1R strongly, whereas typical adult KIT mutant GISTs did not. IGF1R gene amplification was not detected in pediatric WT GISTs, and some KIT-mutant GISTs had IGF1R gene deletion due to monosomy 15. Despite the absence of apparent genomic activation mechanisms accounting for overexpression, clinical study of IGF1R-directed therapies in pediatric WT GIST is warranted. PMID:20162573

  11. Molecular alterations and expression of succinate dehydrogenase complex in wild-type KIT/PDGFRA/BRAF gastrointestinal stromal tumors.

    PubMed

    Celestino, Ricardo; Lima, Jorge; Faustino, Alexandra; Vinagre, João; Máximo, Valdemar; Gouveia, António; Soares, Paula; Lopes, José Manuel

    2013-05-01

    Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract, disclosing somatic KIT, PDGFRA and BRAF mutations. Loss of function of succinate dehydrogenase (SDH) complex is an alternative molecular mechanism in GISTs, namely in carriers of germline mutations of the SDH complex that develop Carney-Stratakis dyad characterized by multifocal GISTs and multicentric paragangliomas (PGLs). We studied a series of 25 apparently sporadic primary wild-type (WT) KIT/PDGFRA/BRAF GISTs occurring in patients without personal or familial history of PGLs, re-evaluated clinicopathological features and analyzed molecular alterations and immunohistochemistry expression of SDH complex. As control, we used a series of well characterized 49 KIT/PDGFRA/BRAF-mutated GISTs. SDHB expression was absent in 20% and SDHB germline mutations were detected in 12% of WT GISTs. Germline SDHB mutations were significantly associated to younger age at diagnosis. A significant reduction in SDHB expression in WT GISTs was found when compared with KIT/PDGFRA/BRAF-mutated GISTs. No significant differences were found when comparing DOG-1 and c-KIT expression in WT, SDHB-mutated and KIT/PDGFRA/BRAF-mutated GISTs. Our results confirm the occurrence of germline SDH genes mutations in isolated, apparently sporadic WT GISTs. WT KIT/PDGFRA/BRAF GISTs without SDHB or SDHA/SDHB expression may correspond to Carney-Stratakis dyad or Carney triad. Most importantly, the possibility of PGLs (Carney-Stratakis dyad) and/or pulmonary chondroma (Carney triad) should be addressed in these patients and their kindred. PMID:22948025

  12. Genetic alteration and mutation profiling of circulating cell-free tumor DNA (cfDNA) for diagnosis and targeted therapy of gastrointestinal stromal tumors.

    PubMed

    Yan, Weixin; Zhang, Aiguo; Powell, Michael J

    2016-01-01

    Gastrointestinal stromal tumors (GISTs) have been recognized as a biologically distinctive type of tumor, different from smooth muscle and neural tumors of the gastrointestinal tract. The identification of genetic aberrations in proto-oncogenes that drive the growth of GISTs is critical for improving the efficacy of cancer therapy by matching targeted drugs to specific mutations. Research into the oncogenic mechanisms of GISTs has found that these tumors frequently contain activating gene mutations in either platelet-derived growth factor receptor A (PDGFRA) or a receptor tyrosine protein associated with a mast cell growth factor receptor encoded by the KIT gene. Mutant cancer subpopulations have the potential to disrupt durable patient responses to molecularly targeted therapy for GISTs, yet the prevalence and size of subpopulations remain largely unexplored. Detection of the cancer subpopulations that harbor low-frequency mutant alleles of target proto-oncogenes through the use of molecular genetic methods, such as polymerase chain reaction (PCR) target amplification technology, is hampered by the high abundance of wild-type alleles, which limit the sensitivity of detection of these minor mutant alleles. This is especially true in the case of mutant tumor DNA derived "driver" and "drug-resistant" alleles that are present in the circulating cell-free tumor DNA (cfDNA) in the peripheral blood circulation of GIST patients. So-called "liquid biopsy" allows for the dynamic monitoring of the patients' tumor status during treatment using minimally invasive sampling. New methodologies, such as a technology that employs a xenonucleic acid (XNA) clamping probe to block the PCR amplification of wild-type templates, have allowed improved molecular detection of these low-frequency alleles both in tissue biopsy samples and in cfDNA. These new methodologies could be widely applied for minimally invasive molecular testing in the therapeutic management of GISTs. PMID:27443349

  13. GSTT1 Copy Number Gain and ZNF Overexpression Are Predictors of Poor Response to Imatinib in Gastrointestinal Stromal Tumors

    PubMed Central

    Kang, Shin Woo; Jang, Kee-Taek; Lee, Jeeyun; Park, Joon Oh; Park, Cheol Keun; Sohn, Tae Sung; Kim, Sung; Kim, Kyoung-Mee

    2013-01-01

    Oncogenic mutations in gastrointestinal stromal tumors (GISTs) predict prognosis and therapeutic responses to imatinib. In wild-type GISTs, the tumor-initiating events are still unknown, and wild-type GISTs are resistant to imatinib therapy. We performed an association study between copy number alterations (CNAs) identified from array CGH and gene expression analyses results for four wild-type GISTs and an imatinib-resistant PDGFRA D842V mutant GIST, and compared the results to those obtained from 27 GISTs with KIT mutations. All wild-type GISTs had multiple CNAs, and CNAs in 1p and 22q that harbor the SDHB and GSTT1 genes, respectively, correlated well with expression levels of these genes. mRNA expression levels of all SDH gene subunits were significantly lower (P≤0.041), whereas mRNA expression levels of VEGF (P=0.025), IGF1R (P=0.026), and ZNFs (P<0.05) were significantly higher in GISTs with wild-type/PDGFRA D842V mutations than GISTs with KIT mutations. qRT-PCR validation of the GSTT1 results in this cohort and 11 additional malignant GISTs showed a significant increase in the frequency of GSTT1 CN gain and increased mRNA expression of GSTT1 in wild-type/PDGFRA D842V GISTs than KIT-mutant GISTs (P=0.033). Surprisingly, all four malignant GISTs with KIT exon 11 deletion mutations with primary resistance to imatinib had an increased GSTT1 CN and mRNA expression level of GSTT1. Increased mRNA expression of GSTT1 and ZNF could be predictors of a poor response to imatinib. Our integrative approach reveals that for patients with wild-type (or imatinib-resistant) GISTs, attempts to target VEGFRs and IGF1R may be reasonable options. PMID:24124608

  14. [New challenges in the diagnosis and treatment of gastrointestinal stromal tumor: thinking and practice from evidence-based medicine to precision medicine].

    PubMed

    Cao, Hui; Wang, Ming

    2016-01-01

    With the development of tumor molecular diagnosis and the administration of targeted drugs, cancer treatment has gradually entered a new era of precision medicine. The diagnosis and treatment of gastrointestinal stromal tumor (GIST) is a full embodiment of the concept of precision medicine, but there are still many problems needed to be solved in the clinical diagnosis and treatment of GIST (such as the correlation between the gene mutation and prognosis, the treatment strategy of wild type GIST and the drug resistance phenomenon). PMID:26797831

  15. Hypoglycemia Associated with a Gastrointestinal Stromal Tumor Producing High-molecular-weight Insulin Growth Factor II: A Case Report and Literature Review.

    PubMed

    Hirai, Hiroyuki; Ogata, Emi; Ohki, Shinji; Fukuda, Izumi; Tanaka, Mizuko; Watanabe, Tsuyoshi; Satoh, Hiroaki

    2016-01-01

    A 61-year-old woman with multiple metastatic and unresectable gastrointestinal stromal tumors (GISTs) was referred for investigation of refractory hypoglycemia that developed four months before this hospitalization. On admission, her fasting plasma glucose was 38 mg/dL despite 10% glucose infusion. Investigations revealed that her serum C-peptide, insulin and growth hormone levels were suppressed, and big insulin-like growth factor II was observed. She was diagnosed with non-islet cell tumor hypoglycemia, which resolved after glucocorticoid treatment. Clinicians should thus be vigilant to identify hypoglycemia in patients with large metastatic GISTs because glucocorticoid therapy is useful even if the GIST is inoperable. PMID:27181538

  16. Beginning of personalized medicine in Panama: Molecular and pathological characteristics of gastrointestinal stromal tumors from archival paraffin-embedded tissue

    PubMed Central

    Mendoza, Yaxelis; Singh, Carlos; Castillo Mewa, Juan; Fonseca, Evelise; Smith, Rebecca; Pascale, Juan M.

    2011-01-01

    This is the first study from Central America to analyze genetic mutations and histopathological features associated with gastrointestinal stromal tumors (GIST). Mutations found in the tyrosine kinase membrane receptors c-kit and pdgfra are associated with clinical and pathological characteristics of GIST. New drugs that inhibit the expression of these oncogenes at the molecular level substantially improve the quality of life for patients with this tumor. It is therefore essential for patient care in Panama that genetic analysis of GIST tumors continues to develop from the pilot study presented herein into routine clinical use. This study evaluated 39 cases of GIST in Panama, using samples archived at the Instituto Oncológico Nacional from 1994 to 2004. DNA from paraffin‑embedded tumor tissues was isolated and amplified for the exons of c-kit and pdgfra associated with a high frequency of mutations. Direct PCR sequencing of specific exons was performed, and those with different alleles were cloned and re-sequenced. Amino acid sequences were inferred from DNA and aligned to Genbank reference sequences to determine the position and type of mutation. The highest frequency of mutations was found in exon 11 of the c-kit gene (70%). Mutations found in this exon were heterogeneous, while only one type of mutation (p.A502_Y503dup) was observed in c-kit exon 9. Mutations in the pdgfra gene constituted several substitutions, with the deletion p.D842V being observed most frequently. The observed GIST-associated mutations were previously described. Four patients with mutations associated with familial GIST were also found. The majority (66%) of patients with mutations in exon 11 (residues 550-591) were considered to be at high risk and 75% of patients with mutations specifically within residues 556-560 (exon 11) were considered to have high-risk GIST. This is the first molecular study of GIST in Central America. It was performed to gain a better understanding of the cancer

  17. A duodenal gastrointestinal stromal tumor with a large central area of fluid and gas due to fistulization into the duodenal lumen, mimicking a large duodenal diverticulum.

    PubMed

    Okasha, Hussein Hassan; Amin, Hoda Mahmoud; Al-Shazli, Mostafa; Nabil, Ahmed; Hussein, Hossam; Ezzat, Reem

    2015-01-01

    Gastrointestinal stromal tumors (GISTs) can occur anywhere along the gastrointestinal tract especially the stomach and upper small bowel. They are usually solid, but cystic degeneration, necrosis, and focal hemorrhage have been described in larger tumors leading to central necrotic cavitation. The most sensitive marker of GIST is CD117 (c-kit). In computed tomography (CT) scan, it is often difficult to decide the origin of the primary tumor, especially in large GISTs. We report an incidental case of a large duodenal GIST fistulizing into the second part of the duodenum with a large amount of fluid and gas inside, mistaken for a cystic pancreatic neoplasm by CT and mistaken for a duodenal diverticulum by endoscopic ultrasound. PMID:26374586

  18. ¹⁸F-FDG PET/CT and contrast enhanced CT in differential diagnosis between leiomyoma and gastrointestinal stromal tumor.

    PubMed

    Hirose, Yasumitus; Kaida, Hayato; Kawahara, Akihiko; Kurata, Seiji; Ishibashi, Masatoshi; Abe, Toshi

    2015-01-01

    In a 49 years old woman a large abdominal tumor was diagnosed by abdominal ultrasound. Dynamic contrast-enhanced computed tomography (CECT) showed a large tumor with minute calcification and poor contrast enhancement in the left abdominal cavity. The fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) scan showed low ¹⁸F-FDG uptake in the tumor. The SUV max (early image) was 1.90, and that of the delayed image was 2.86. A gastrointestinal stromal tumor (GIST) was suspected. Tumor resection revealed that it was a leiomyoma originating in the major curvature of the stomach. In conclusion, the findings of low ¹⁸F-FDG uptake on ¹⁸F-FDG PET and poor contrast enhancement on CECT in a gastric submucosal tumor suggested of a gastric leiomyoma rather than GIST. PMID:26574696

  19. Antitumor Effect of the Tyrosine Kinase Inhibitor Nilotinib on Gastrointestinal Stromal Tumor (GIST) and Imatinib-Resistant GIST Cells

    PubMed Central

    Sako, Hiroyuki; Fukuda, Kazumasa; Saikawa, Yoshiro; Nakamura, Rieko; Takahashi, Tsunehiro; Wada, Norihito; Kawakubo, Hirohumi; Takeuchi, Hiroya; Ohmori, Tai; Kitagawa, Yuko

    2014-01-01

    Despite the benefits of imatinib for treating gastrointestinal stromal tumors (GIST), the prognosis for high risk GIST and imatinib-resistant (IR) GIST remains poor. The mechanisms of imatinib resistance have not yet been fully clarified. The aim of the study was to establish imatinib-resistant cell lines and investigate nilotinib, a second generation tyrosine kinase inhibitor (TKI), in preclinical models of GIST and imatinib-resistant GIST. For a model of imatinib-resistant GIST, we generated resistant cells from GK1C and GK3C cell lines by exposing them to imatinib for 6 months. The parent cell lines GK1C and GK3C showed imatinib sensitivity with IC50 of 4.59±0.97 µM and 11.15±1.48 µM, respectively. The imatinib-resistant cell lines GK1C-IR and GK3C-IR showed imatinib resistance with IC50 values of 11.74±0.17 µM (P<0.001) and 41.37±1.07 µM (P<0.001), respectively. The phosphorylation status of key cell signaling pathways, receptor tyrosine kinase KIT (CD117), platelet-derived growth factor receptor alpha (PDGFRA) and downstream signaling kinases: serine-threonine kinase Akt (AKT) and extracellular signal-regulated kinase 1/2 (ERK1/2) or the non-receptor tyrosine kinase: proto-oncogene tyrosine-protein kinase Src (SRC), was analyzed in established cell lines and ERK1/2 phosphorylation was found to be increased compared to the parental cells. Nilotinib demonstrated significant antitumor efficacy against GIST xenograft lines and imatinib-resistant GIST cell lines. Thus, nilotinib may have clinical potential for patients with GIST or imatinib-resistant GIST. PMID:25221952

  20. Elevated preoperative neutrophil-to-lymphocyte ratio is associated with poor prognosis in gastrointestinal stromal tumor patients

    PubMed Central

    Jiang, Chang; Hu, Wan-Ming; Liao, Fang-Xin; Yang, Qiong; Chen, Ping; Rong, Yu-Ming; Guo, Gui-Fang; Yin, Chen-Xi; Zhang, Bei; He, Wen-Zhuo; Xia, Liang-Ping

    2016-01-01

    Purpose To investigate the prognostic relevance of preoperative peripheral neutrophil- to-lymphocyte ratio (NLR) in gastrointestinal stromal tumor (GIST) patients. Materials and methods We enrolled 129 consecutive GIST patients who underwent initial curative surgical resection with or without adjuvant/palliative imatinib treatment in our study. Blood NLR was calculated as neutrophil count (number of neutrophils ×109/L) divided by lymphocyte count (number of lymphocytes ×109/L). Survival curves were constructed by using the Kaplan–Meier method. Univariate and multivariate Cox proportional hazard regression models were performed to identify associations with outcome variable. All tests were two-sided, and P<0.05 was considered statistically significant. Results The optimal cut-off value of NLR was 2.07 in the receiver operating characteristic curve analysis. The median overall survival (OS) of high NLR group was 113.0 months, whereas that of the low NLR group had not reached the median OS both in the general (P<0.001) and subgroup analyses. The elevated NLR suggested shorter OS in the high malignant potential groups (P=0.01) and the combined low and moderate groups (P=0.02). Increased NLR indicated poor OS in patients regardless of whether if received imatinib treatment or not (P=0.005, and P=0.032, respectively). High NLR indicated poor OS of patients in stage I and II disease (P=0.005) and a clear tendency that increased level of NLR is inimical to OS. Conclusion Elevated NLR was detected as an independent adverse prognostic factor. Elevated preoperative NLR predicts poor clinical outcome in GIST patients and may serve as a cost-effective and broadly available independent prognostic biomarker. PMID:26966375

  1. Fluid Retention Associated with Imatinib Treatment in Patients with Gastrointestinal Stromal Tumor: Quantitative Radiologic Assessment and Implications for Management

    PubMed Central

    Shinagare, Atul B.; Krajewski, Katherine M.; Pyo, Junhee; Tirumani, Sree Harsha; Jagannathan, Jyothi P.; Ramaiya, Nikhil H.

    2015-01-01

    Objective We aimed to describe radiologic signs and time-course of imatinib-associated fluid retention (FR) in patients with gastrointestinal stromal tumor (GIST), and its implications for management. Materials and Methods In this Institutional Review Board-approved, retrospective study of 403 patients with GIST treated with imatinib, 15 patients with imaging findings of FR were identified by screening radiology reports, followed by manual confirmation. Subcutaneous edema, ascites, pleural effusion, and pericardial effusion were graded on a four-point scale on CT scans; total score was the sum of these four scores. Results The most common radiologic sign of FR was subcutaneous edema (15/15, 100%), followed by ascites (12/15, 80%), pleural effusion (11/15, 73%), and pericardial effusion (6/15, 40%) at the time of maximum FR. Two distinct types of FR were observed: 1) acute/progressive FR, characterized by acute aggravation of FR and rapid improvement after management, 2) intermittent/steady FR, characterized by occasional or persistent mild FR. Acute/progressive FR always occurred early after drug initiation/dose escalation (median 1.9 month, range 0.3-4.0 months), while intermittent/steady FR occurred at any time. Compared to intermittent/steady FR, acute/progressive FR was severe (median score, 5 vs. 2.5, p = 0.002), and often required drug-cessation/dose-reduction. Conclusion Two distinct types (acute/progressive and intermittent/steady FR) of imatinib-associated FR are observed and each type requires different management. PMID:25741192

  2. Involvement of c-KIT mutation in the development of gastrointestinal stromal tumors through proliferation promotion and apoptosis inhibition

    PubMed Central

    Ma, Ying-Yu; Yu, Sheng; He, Xu-Jun; Xu, Yuan; Wu, Fang; Xia, Ying-Jie; Guo, Kun; Wang, Hui-Ju; Ye, Zai-Yuan; Zhang, Wei; Tao, Hou-Quan

    2014-01-01

    The aim of this study was to discuss the role of c-KIT mutation in the pathogenesis of gastrointestinal stromal tumors (GISTs) and analyze its correlation with proliferation and apoptosis. c-KIT and PDGFRA genotypes were examined by deoxyribonucleic acid sequencing. Immunohistochemistry was performed to determine the expression levels of Kit, Ki-67 (proliferation marker), and apoptotic protease-activating factor (APAF)-1 (apoptosis marker) and the relationship between their three genes. In the 68 cases examined, 44 cases (64.7%) showed mutations in one of the four exons of c-KIT. The mutations were most frequently found in exon 11 (30 cases [44.1%]), followed by exon 9 (ten cases [14.7%]) and exon 13 (four cases [5.9%]). c-KIT mutation showed no association with prognostic factors using the classification of risk of aggressive behavior in GIST proposed by Fletcher et al. No cases had mutated exon 17 of c-KIT, and neither did exon 12, 14, or 18 of PDGFRA in our present study. There was a positive correlation between the expression level of Kit and Ki-67 (R=0.282, P=0.020). Conversely, a negative correlation was found between the expression levels of Kit and APAF1 (R=−0.243, P=0.046). In conclusion, most GISTs with Kit expression showed c-KIT mutation. Kit expression has a positive correlation with Ki-67 and a negative correlation with APAF1, showing that c-KIT is involved in GIST occurrence and development through proliferation promotion and apoptosis inhibition. PMID:24833907

  3. Feasibility and Timing of Cytoreduction Surgery in Advanced (Metastatic or Recurrent) Gastrointestinal Stromal Tumors During the Era of Imatinib

    PubMed Central

    Chang, Shih-Chun; Liao, Chien-Hung; Wang, Shang-Yu; Tsai, Chun-Yi; Chiang, Kun-Chun; Cheng, Chi-Tung; Yeh, Ta-Sen; Chen, Yen-Yang; MA, Ming-Chun; Liu, Chien-Ting; Yeh, Chun-Nan

    2015-01-01

    Abstract The prognosis of advanced gastrointestinal stromal tumors (GISTs) was dramatically improved in the era of imatinib. Cytoreduction surgery was advocated as an additional treatment for advanced GISTs, especially when patients having poor response to imatinib or developing resistance to it. However, the efficacy and benefit of cytoreduction were still controversial. Likewise, the sequence between cytoreduction surgery and imatinib still need evaluation. In this study, we tried to assess the feasibility and efficiency of cytoreduction in advanced GISTs. Furthermore, we analyzed the impact of timing of the cytoreduction surgery on the prognosis of advanced GISTs. We conducted a prospective collecting retrospective review of patients with advanced GISTs (metastatic, unresectable, and recurrent GISTs) treated in Chang Gung memorial hospital (CGMH) since 2001 to 2013. We analyzed the impact of cytoreduction surgery to response to imatinib, progression-free survival (PFS), and overall survival (OS) in patients with advanced GISTs. Moreover, by the timing of cytoreduction to imatinib, we divided the surgical patients who had surgery before imatinib use into early group and those who had surgery after imatinib into late. We compared the clinical response to imatinib, PFS and OS between early and late cytoreduction surgical groups. Totally, 182 patients were enrolled into this study. Seventy-six patients underwent cytoreduction surgery. The demographic characteristics and tumor presentation were similar between surgical and non-surgical groups. The surgical group showed better complete response rate (P < 0.001) and partial response rate (P = 0.008) than non-surgical group. The 1-year, 3-year, and 5-year PFS were significantly superior in surgical group (P = 0.003). The 1-year, 3-year, and 5-year OS were superior in surgical group, but without statistical significance (P = 0.088). Dividing by cytoreduction surgical timing, the demographic

  4. Gene expression of the IGF pathway family distinguishes subsets of gastrointestinal stromal tumors wild type for KIT and PDGFRA

    PubMed Central

    Beadling, Carol; Patterson, Janice; Justusson, Emily; Nelson, Dylan; Pantaleo, Maria A.; Hornick, Jason L.; Chacón, Matias; Corless, Christopher L.; Heinrich, Michael C.

    2013-01-01

    Gastrointestinal stromal tumors (GISTs) arise from the interstitial cells of Cajal (ICCs) and are the most common mesenchymal neoplasm of the gastrointestinal tract. While the majority of GISTs harbor activating mutations in either the v-kit Hardy-Zuckerman feline sarcoma viral oncogene homolog (KIT) or platelet-derived growth factor receptor alpha (PDGFRA) tyrosine kinases, approximately 10–15% of adult GISTs and 85% of pediatric GISTs lack such mutations. These “wild-type” GISTs have been reported to express high levels of the insulin-like growth factor 1 receptor (IGF1R), and IGF1R-targeted therapy of wild-type GISTs is being evaluated in clinical trials. However, it is not clear that all wild-type GISTs express IGF1R, because studies to date have predominantly focused on a particular subtype of gastric wild-type GIST that is deficient in the mitochondrial succinate dehydrogenase (SDH) complex. This study of a series of 136 GISTs, including 72 wild-type specimens, was therefore undertaken to further characterize wild-type GIST subtypes based on the relative expression of transcripts encoding IGF1R. Additional transcripts relevant to GIST biology were also evaluated, including members of the IGF-signaling pathway (IGF1, IGF2, and insulin receptor [INSR]), neural markers (CDH2[CDH: Cadherin], neurofilament, light polypeptide, LHX2 [LHX: LIM homeobox], and KIRREL3 [KIRREL: kin of IRRE like]), KIT, PDGFRA, CD34, and HIF1A. Succinate dehydrogenase complex, subunit B protein expression was also assessed as a measure of SDH complex integrity. In addition to the previously described SDH-deficient, IGF1Rhigh wild-type GISTs, other SDH-intact wild-type subpopulations were defined by high relative expression of IGF1R, neural markers, IGF1 and INSR, or low IGF1R coupled with high IGF2. These results underscore the complexity and heterogeneity of wild-type GISTs that will need to be factored into molecularly-targeted therapeutic strategies. PMID:24133624

  5. Gene expression of the IGF pathway family distinguishes subsets of gastrointestinal stromal tumors wild type for KIT and PDGFRA.

    PubMed

    Beadling, Carol; Patterson, Janice; Justusson, Emily; Nelson, Dylan; Pantaleo, Maria A; Hornick, Jason L; Chacón, Matias; Corless, Christopher L; Heinrich, Michael C

    2013-02-01

    Gastrointestinal stromal tumors (GISTs) arise from the interstitial cells of Cajal (ICCs) and are the most common mesenchymal neoplasm of the gastrointestinal tract. While the majority of GISTs harbor activating mutations in either the v-kit Hardy-Zuckerman feline sarcoma viral oncogene homolog (KIT) or platelet-derived growth factor receptor alpha (PDGFRA) tyrosine kinases, approximately 10-15% of adult GISTs and 85% of pediatric GISTs lack such mutations. These "wild-type" GISTs have been reported to express high levels of the insulin-like growth factor 1 receptor (IGF1R), and IGF1R-targeted therapy of wild-type GISTs is being evaluated in clinical trials. However, it is not clear that all wild-type GISTs express IGF1R, because studies to date have predominantly focused on a particular subtype of gastric wild-type GIST that is deficient in the mitochondrial succinate dehydrogenase (SDH) complex. This study of a series of 136 GISTs, including 72 wild-type specimens, was therefore undertaken to further characterize wild-type GIST subtypes based on the relative expression of transcripts encoding IGF1R. Additional transcripts relevant to GIST biology were also evaluated, including members of the IGF-signaling pathway (IGF1, IGF2, and insulin receptor [INSR]), neural markers (CDH2[CDH: Cadherin], neurofilament, light polypeptide, LHX2 [LHX: LIM homeobox], and KIRREL3 [KIRREL: kin of IRRE like]), KIT, PDGFRA, CD34, and HIF1A. Succinate dehydrogenase complex, subunit B protein expression was also assessed as a measure of SDH complex integrity. In addition to the previously described SDH-deficient, IGF1R(high) wild-type GISTs, other SDH-intact wild-type subpopulations were defined by high relative expression of IGF1R, neural markers, IGF1 and INSR, or low IGF1R coupled with high IGF2. These results underscore the complexity and heterogeneity of wild-type GISTs that will need to be factored into molecularly-targeted therapeutic strategies. PMID:24133624

  6. Laparoscopic versus open gastric resections for primary gastrointestinal stromal tumors (GISTs): a size-matched comparison

    PubMed Central

    Karakousis, Giorgos C.; Singer, Samuel; Zheng, Junting; Gonen, Mithat; Coit, Daniel; DeMatteo, Ronald P.; Strong, Vivian E.

    2016-01-01

    Background Laparoscopic resection of gastric GISTs appears technically feasible and associated with favorable outcomes. Tumor size however frequently plays a role in surgical approach with larger tumors tending towards laparotomy, raising concern that favorable outcomes reported for the laparoscopic approach may reflect this selection bias. Methods From a prospectively collected sarcoma database, 155 primary gastric GIST resections were identified (1998–2009); 40 patients underwent successful laparoscopic resection for non-GE junction GIST and were randomly matched (1:1) by tumor size (+/− 2.0 cm) to patients with open resection. Clinical, pathologic variables and surgical outcomes were associated with surgery type using conditional logistic regression analyses. Results The two surgical approaches were comparable for clinical and pathologic variables. Median operating room (OR) time was similar, although median length of stay post-surgery was lower in the laparoscopic versus open group (4 vs. 7 d, p=0.002), as was estimated blood loss (EBL) (25 vs. 100 mL, p=0.006). There was no operative mortality, and 30 d morbidity was similar. Oncologic outcomes were also similar with no positive microscopic margins, and 1 recurrence in each group with a median follow-up of 34 months. There were 13 conversions overall, 5 secondary to tumor location at the GE junction or lesser curve. Conclusions When matched for tumor size, laparoscopic resection of primary gastric GISTs ≤ 8 cm results in shorter hospital stays with similar OR time while maintaining sound oncologic outcomes compared to open resection. PMID:21207158

  7. PK-PD modeling of individual lesion FDG-PET response to predict overall survival in patients with sunitinib-treated gastrointestinal stromal tumor.

    PubMed

    Schindler, E; Amantea, M A; Karlsson, M O; Friberg, L E

    2016-04-01

    Pharmacometric models were developed to characterize the relationships between lesion-level tumor metabolic activity, as assessed by the maximum standardized uptake value (SUVmax) obtained on [(18)F]-fluorodeoxyglucose (FDG) positron emission tomography (PET), tumor size, and overall survival (OS) in 66 patients with gastrointestinal stromal tumor (GIST) treated with intermittent sunitinib. An indirect response model in which sunitinib stimulates tumor loss best described the typically rapid decrease in SUVmax during on-treatment periods and the recovery during off-treatment periods. Substantial interindividual and interlesion variability were identified in SUVmax baseline and drug sensitivity. A parametric time-to-event model identified the relative change in SUVmax at one week for the lesion with the most pronounced response as a better predictor of OS than tumor size. Based on the proposed modeling framework, early changes in FDG-PET response may serve as predictor for long-term outcome in sunitinib-treated GIST. PMID:27299707

  8. Clinicopathological features and prognosis of omental gastrointestinal stromal tumor: evaluation of a pooled case series

    PubMed Central

    Feng, Fan; Tian, Yangzi; Liu, Zhen; Liu, Shushang; Xu, Guanghui; Guo, Man; Lian, Xiao; Fan, Daiming; Zhang, Hongwei

    2016-01-01

    Clinicopathological features and prognosis of omental GISTs are limited due to the extremely rare incidence. Therefore, the aim of the present study was to investigate the clinicopathological features and prognosis of omental GISTs. Omental GISTs cases were obtained from our center and from case reports and clinical studies extracted from MEDLINE. Clinicopathological features and survivals were analyzed. A total of 99 cases of omental GISTs were enrolled in the present study. Omental GISTs occurred predominantly in greater omentum (78/99, 78.8%). The majority of tumors exceeded 10 cm in diameter (67/98, 68.3%) and were high risk (88/96, 91.7%). Histological type was correlated with tumor location and mutational status. The five year DFS and DSS was 86.3% and 80.6%, respectively. Mitotic index was risk factor for prognosis of omental GISTs. Prognosis of omental GISTs was worse than that of gastric GISTs by Kaplan-Meier analysis. However, multivariate analysis showed that the prognosis was comparable between the two groups. The majority of omental GISTs were large and high risk. Mitotic index was risk factor for prognosis of omental GISTs. The prognosis was comparable between omental and gastric GISTs. PMID:27471066

  9. [A case of a gastrointestinal stromal tumor of the rectum effectively treated with continuously-administered regorafenib after failure of imatinib and sunitinib].

    PubMed

    Kajiura, Shinya; Hosokawa, Ayumu; Nanjyo, Sohachi; Nakada, Naokatsu; Ando, Takayuki; Sugiyama, Toshiro

    2016-04-01

    Regorafenib is recommended as a third-line treatment for unresectable gastrointestinal stromal tumors (GIST). It is usually administered in a repeating cycle of three-weeks on and one-week off. We describe a patient with an unresectable GIST in the pelvic cavity who complained of pelvic pain while taking the one-week break from regorafenib administration. Subsequently, we reduced the dosage to one level and regorafenib was continuously administered. As a result, the adverse events were improved and the antitumor effect against the GIST was retained. The continuous administration of reduced-dose regorafenib could be considered a viable dosage adjustment in specific situations. PMID:27052395

  10. Crosstalk between KIT and FGFR3 Promotes Gastrointestinal Stromal Tumor Cell Growth and Drug Resistance

    PubMed Central

    Javidi-Sharifi, Nathalie; Traer, Elie; Martinez, Jacqueline; Gupta, Anu; Taguchi, Takehiro; Dunlap, Jennifer; Heinrich, Michael C.; Corless, Christopher L.; Rubin, Brian P.; Druker, Brian J.; Tyner, Jeffrey W.

    2014-01-01

    Kinase inhibitors such as imatinib have dramatically improved outcomes for GIST patients, but many patients develop resistance to these treatments. While in some patients this event corresponds with mutations in the GIST driver oncogenic kinase KIT, other patients development resistance without KIT mutations. In this study, we address this patient subset in reporting a functional dependence of GIST on the FGF receptor FGFR3 and its crosstalk with KIT in GIST cells. Addition of the FGFR3 ligand FGF2 to GIST cells restored KIT phosphorylation during imatinib treatment, allowing sensitive cells to proliferate in the presence of the drug. FGF2 expression was increased in imatinib-resistant GIST cells, the growth of which was blocked by RNAi-mediated silencing of FGFR3. Moreover, combining KIT and FGFR3 inhibitors synergized to block the growth of imatinib-resistant cells. Signaling crosstalk between KIT and FGFR3 activated the MAPK pathway to promote resistance to imatinib. Clinically, an immunohistochemical analysis of tumor specimens from imatinib-resistant GIST patients revealed a relative increase in FGF2 levels, with a trend towards increased expression in imatinib-naïve samples consistent with possible involvement in drug resistance. Our findings provide a mechanistic rationale to evaluate existing FGFR inhibitors and multi-kinase inhibitors that target FGFR3 as promising strategies to improve treatment of GIST patients with de novo or acquired resistance to imatinib. PMID:25432174

  11. An innovative procedure of laparoscope combined with endoscopy for gastrointestinal stromal tumor resection and cholecystectomy: A case report and literature review

    PubMed Central

    YAN, YE; LI, FENG; GAI, YONG-HAO; LIU, QING-WEI

    2016-01-01

    The present study reports a novel approach to laparoscopic and endoscopic cooperative surgery for gastric gastrointestinal stromal tumor (GIST) resection and cholecystectomy, and conducts a review of the associated literature. The novel surgical procedure was performed on one patient who was diagnosed with a GIST and cholecystic polypus. The GIST was resected using an insulation-tipped diathermic electrosurgical knife under the guide of an endoscope. Subsequently, a cholecystectomy was performed by inserting two more 5-mm trocars and instruments transumbilically, guided using an endoscope. The tumor and the gallbladder were exteriorized using a peroral approach and the incision lining of the stomach was sutured laparoscopically. The procedure was successfully performed and the patient experienced no discomfort during the 5-year follow-up. In conclusion, the present study demonstrates that laparoscopic and endoscopic cooperative surgery is feasible and would be an ideal choice for invisible abdominal scar surgery, in particular for multi-visceral resection. PMID:27073455

  12. Capsule endoscopy in the diagnosis of an exophytic gastrointestinal stromal tumor in the small intestine of a young adult woman: A case report

    PubMed Central

    XU, XIAOLING; CAO, ZHENGLONG; ZHU, HAIHANG

    2016-01-01

    Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors that mainly arise in the gastrointestinal tract. They are usually asymptomatic and are incidentally discovered during endoscopy or surgery. Diagnosis is confirmed by histological examination of the specimen. This is the case report of an asymptomatic GIST of the small intestine diagnosed by wireless capsule endoscopy. The tumor was initially suspected to be a leiomyoma, as GISTs in young adults are rare and are mainly discovered incidentally during colorectal cancer screening. The patient was a 35-year-old woman with occult gastrointestinal bleeding, with a normal medical history. An endoscopic assessment of the upper and lower GI tract (gastroscopy and colonoscopy) was performed, but did not reveal any abnormalities. Subsequently, an exophytic tumor initially suspected as leiomyoma or external pressure was detected in the small intestine by capsule endoscopy. A computed tomography scan was suggestive of a soft tissue tumor arising from the small intestine. A surgical specimen was obtained and the immunohistochemical examination revealed that the tumor was positive for CD117 and discovered on GIST-1 markers, while the markers of carcinoma, melanoma and lymphoma were negative, which was consistent with a diagnosis of a low-risk GIST with a mitotic count of <5/50 high-power fields. In this study, we aimed to present in detail the capsule endoscopic and radiological characteristics, as well as the findings of the histological examination of the surgical specimen. In conclusion, when occult blood is detected in the stool, even when gastroscopy and colonoscopy reveal no abnormal findings, small intestinal lesions should be suspected. Exophytic small intestinal GISTs, although rare, particularly in younger patients, they should be considered by physicians in the differential diagnosis of obscure GI bleeding of unknown origin, in order to reduce morbidity and mortality. Capsule endoscopy may be considered to

  13. Fibromatosis of the Sigmoid Colon With CTNNB1 (β-Catenin) Gene Mutation, Arising at the Site of Ileocolic Anastomosis for Resection of Gastrointestinal Stromal Tumor.

    PubMed

    Thway, Khin; Abou Sherif, Sara; Riddell, Angela M; Mudan, Satvinder

    2016-05-01

    We describe a case of intra-abdominal fibromatosis, which occurred in a 44-year-old woman who had a previous history of gastrointestinal stromal tumor (GIST) of the sigmoid mesocolon, which was treated with imatinib and resection. A mass was detected at the site of ileocolic anastomosis of the previous small bowel resection and sigmoid colectomy, nearly 3 years later. Clinically, this was suspected to represent recurrent GIST and was excised, but histology and mutational analysis showed desmoid-type fibromatosis with a mutation in codon 41 of exon 3 of the CTNNB1 (β-catenin) gene. The occurrence of fibromatosis at the site of excision of GIST is very rare, but its recognition is important as the treatment of the two neoplasms differs significantly. As imaging cannot reliably distinguish between these 2 entities, histological diagnosis is crucial for correct clinical management. PMID:26721303

  14. Skull metastasis from rectal gastrointestinal stromal tumours.

    PubMed

    Gil-Arnaiz, Irene; Martínez-Trufero, Javier; Pazo-Cid, Roberto Antonio; Felipo, Francesc; Lecumberri, María José; Calderero, Verónica

    2009-09-01

    Gastrointestinal stromal tumours (GIST) are the most common mesenchymal neoplasm of the gastrointestinal tract. Rectum localisation is infrequent for these neoplasms, accounting for about 5% of all cases. Distant metastases of GIST are also rare. We present a patient with special features: the tumour is localised in rectum and it has an uncommon metastatic site, the skull, implying a complex differential diagnosis approach. PMID:19776004

  15. CTHRC1 Acts as a Prognostic Factor and Promotes Invasiveness of Gastrointestinal Stromal Tumors by Activating Wnt/PCP-Rho Signaling1

    PubMed Central

    Ma, Ming-Ze; Zhuang, Chun; Yang, Xiao-Mei; Zhang, Zi-Zhen; Ma, Hong; Zhang, Wen-Ming; You, Haiyan; Qin, Wenxin; Gu, Jianren; Yang, Shengli; Cao, Hui; Zhang, Zhi-Gang

    2014-01-01

    Gastrointestinal stromal tumors (GISTs) are the major gastrointestinal mesenchymal tumors with a variable malignancy ranging from a curable disorder to highly malignant sarcomas. Metastasis and recurrence are the main causes of death in GIST patients. To further explore the mechanism of metastasis and to more accurately estimate the recurrence risk of GISTs after surgery, the clinical significance and functional role of collagen triple helix repeat containing-1 (CTHRC1) in GIST were investigated. We found that CTHRC1 expression was gradually elevated as the risk grade of NIH classification increased, and was closely correlated with disease-free survival and overall survival in 412 GIST patients. In vitro experiments showed that recombinant CTHRC1 protein promoted the migration and invasion capacities of primary GIST cells. A luciferase reporter assay and pull down assay demonstrated that recombinant CTHRC1 protein activated noncanonical Wnt/PCP-Rho signaling but inhibited canonical Wnt signaling. The pro-motility effect of CTHRC1 on GIST cells was reversed by using a Wnt5a neutralizing antibody and inhibitors of Rac1 or ROCK. Taken together, these data indicate that CTHRC1 may serve as a new predictor of recurrence risk and prognosis in post-operative GIST patients and may play an important role in facilitating GIST progression. Furthermore, CTHRC1 promotes GIST cell migration and invasion by activating Wnt/PCP-Rho signaling, suggesting that the CTHRC1-Wnt/PCP-Rho axis may be a new therapeutic target for interventions against GIST invasion and metastasis. PMID:24726140

  16. Laparoscopic resection of a gastrointestinal stromal tumor of the lower rectum in a patient with coronary artery disease following long-term neoadjuvant imatinib treatment and anticoagulation therapy

    PubMed Central

    2014-01-01

    Surgery is the mainstay of treatment for gastrointestinal stromal tumors (GISTs). However, complete resection of rectal GISTs is sometimes difficult because of bulkiness and/or anatomical reasons. Neoadjuvant imatinib therapy has gained attention as an alternative treatment to increase the chance of en bloc resection of rectal GISTs, although it usually takes several months. In this case report, we first demonstrated that neoadjuvant imatinib therapy can be performed safely not only to downsize tumors, but also to allow adequate time for the effective treatment of major comorbid illnesses. A 74-year-old man was diagnosed with a 45 mm GIST of the lower rectum. He also had severe stenosis in the proximal segment of the left anterior descending coronary artery. Following the implantation of a drug-eluting stent, the patient received imatinib together with dual anti-platelet therapy for 12 months without obvious side effects. Follow-up image studies revealed tumor shrinkage as well as stent patency. En bloc resection of the GIST was performed laparoscopically, which preserved the anus. The patient is currently alive without any evidence of relapse for 12 months after surgery. PMID:25022862

  17. Tumor suppression by stromal TIMPs.

    PubMed

    Shimoda, Masayuki; Jackson, Hartland W; Khokha, Rama

    2016-05-01

    The tumor stroma has the capacity to drive cancer progression, although the mechanisms governing these effects are incompletely understood. Recently, we reported that deletion of tissue inhibitor of metalloproteinases (Timps) in fibroblasts unleashes the function of cancer-associated fibroblasts and identifies a novel mode of stromal-tumor communication that activates key oncogenic pathways invoving Notch and ras homolog gene family, member A (RhoA) via stromal exosomes. PMID:27314104

  18. Chemical modifications in the seed region of miRNAs 221/222 increase the silencing performances in gastrointestinal stromal tumor cells.

    PubMed

    Durso, Montano; Gaglione, Maria; Piras, Linda; Mercurio, Maria Emilia; Terreri, Sara; Olivieri, Michele; Marinelli, Luciana; Novellino, Ettore; Incoronato, Mariarosaria; Grieco, Paolo; Orsini, Gaetano; Tonon, Giancarlo; Messere, Anna; Cimmino, Amelia

    2016-03-23

    Most GastroIntestinal Stromal Tumors (GISTs) are characterized by KIT gene overexpression, which in turn is regulated by levels of microRNA 221 and microRNA 222. GISTs can also be distinguished by their miRNAs expression profile in which miRNAs 221/222 result reduced in comparison with GI normal tissues. In this paper, to restore normal miRNAs levels and to improve the silencing performances of miRNAs 221/222, new miRNA mimics in which guide strands are modified by Phosphorothioate (PS) and/or 2'-O-methyl RNA (2'-OMe) inside and outside the seed region, were synthesized and tested in GIST48 cells. We evaluated the positional effect of the chemical modifications on the miRNAs silencing activity, compared to natural and several commercial miRNA mimics. Our results show that chemically modified miRNAs 221/222 with alternating 2'-OMe-PS and natural nucleotides in the seed region are effective inhibitors of KIT gene expression and exhibit increased stability in rat plasma. Besides, their transfection in GIST 48 cells showed significant effects on different cellular processes in which KIT plays a functional role for tumor development (such as migration, cell proliferation, and apoptosis). Therefore, modified miRNAs 221/222 may provide an alternative therapeutic option for GIST treatment also aimed to overcome drug resistance concerns. PMID:26854374

  19. Treatment of non-resectable and metastatic gastrointestinal stromal tumors: experience with the use of tyrosine kinase inhibitors in a third level hospital in Mexico

    PubMed Central

    Pimentel Renteria, Alberto; Pluma Jiménez, Miguel; Pérez Martínez, Mario; Martínez Martínez, Gloria; Rivera Rivera, Samuel; Grajales Álvarez, Rocío; Bautista Aragón, Yolanda; Quintana Quintana, Miguel; Alejandro Silva, Juan

    2016-01-01

    Background Stromal tumors of the digestive tract are uncommon malignant diseases, are subclassified as leiomyosarcomas and Gastrointestinal Stromal Tumors (GIST) depending on the molecular expression of tyrosine kinase receptor KIT (CD117). GISTs represent 1% of malignant tumors affecting this anatomical site. Localized tumours diseases are reasonably well controlled by surgical resection and several criteria define the need for adjuvant therapy. In the case of metastatic disease a poor prognosis has been reported with systemic treatment based on chemotherapy. Recently, significant advances have been shown since tyrosine kinase inhibitors (TKIs) were introduced, with median overall survival close to 5 years. Unfortunately in Mexico, even though the therapy has been long used there are no published data of the experience in the treatment of these tumors. Methods We used an electronic data base to obtain clinical, radiological and histological data of patients diagnosed with GIST and treated in the oncological center of the Mexican Institute of Social Security, patients were subclassified by stage, symptoms at diagnosis as well as the initial and subsequent systemic treatment. Finally we made an analysis for progression free survival and overall survival identifying prognostic factors. Results We obtained information of 71 patients with metastatic, non-resectable or recurrent GIST, treated with a TKI, we observed a predominant relation for women (60.4%) with median age of 58 years. Stage at diagnosis was predominantly metastatic (46.5%), most frequently affected sites were lung, liver and retroperitoneum. Median progression free survival was 30.6 months and overall survival was 81.3 months. All patients were initially treated with imatinib at a dose of 400 mg per day. Treatment was well-tolerated in most cases. Conclusions Metastatic GIST evaluated in our center shows a different affection in gender and age, and our population shows a different response to TKIs

  20. Clinical Outcomes of Patients with Advanced Gastrointestinal Stromal Tumors: Safety and Efficacy in a Worldwide Treatment-use Trial of Sunitinib

    PubMed Central

    Reichardt, Peter; Kang, Yoon-Koo; Rutkowski, Piotr; Schuette, Jochen; Rosen, Lee S; Seddon, Beatrice; Yalcin, Suayib; Gelderblom, Hans; Williams, Charles C; Fumagalli, Elena; Biasco, Guido; Hurwitz, Herbert I; Kaiser, Pamela E; Fly, Kolette; Matczak, Ewa; Chen, Liang; Lechuga, Maria José; Demetri, George D

    2015-01-01

    BACKGROUND To provide sunitinib to patients with gastrointestinal stromal tumor (GIST) who were otherwise unable to obtain sunitinib; to obtain broad safety and efficacy data from a large population of patients with advanced GIST after imatinib failure. METHODS Imatinib-resistant/intolerant patients with advanced GIST received sunitinib on an initial dosing schedule (IDS) of 50 mg/day in 6-week cycles (4 weeks on treatment, 2 weeks off). Tumor assessment frequency was per local practice, with response assessed by investigators per Response Evaluation Criteria in Solid Tumors version 1.0. Overall survival (OS) and safety were assessed regularly. Post-hoc analyses evaluated different patterns of treatment management. RESULTS At final data cutoff, 1124 patients comprised the intent-to-treat population; 15% had a baseline Eastern Cooperative Oncology Group performance status ≥2. Median treatment duration was 7.0 months. Median time to tumor progression was 8.3 months (95% confidence interval [CI], 8.0–9.4), and median OS was 16.6 months (95% CI, 14.9–18.0) with 36% of patients alive at the time of analysis. Patients in whom the IDS was modified exhibited longer median OS (23.5 months) than those treated strictly per the IDS (11.1 months). The most common treatment-related grade 3/4 adverse events (AEs) were hand-foot syndrome (11%), fatigue (9%), neutropenia (8%), hypertension (7%), and thrombocytopenia (6%). Treatment-related AEs associated with cardiac function (eg, congestive heart failure and myocardial infarction) were reported at frequencies of ≤1% each. CONCLUSIONS This treatment-use study confirms the long-term safety and efficacy of sunitinib in a large international population of patients with advanced GIST after imatinib failure. PMID:25641662

  1. Long-term results of adjuvant imatinib mesylate in localized, high-risk, primary gastrointestinal stromal tumor (GIST): ACOSOG Z9000 (Alliance) intergroup phase 2 trial

    PubMed Central

    DeMatteo, Ronald P.; Ballman, Karla V.; Antonescu, Cristina R.; Corless, Christopher; Kolesnikova, Violetta; von Mehren, Margaret; McCarter, Martin D.; Norton, Jeffrey; Maki, Robert G.; Pisters, Peter W.T.; Demetri, George D.; Brennan, Murray F.; Owzar, Kouros

    2014-01-01

    Objective To conduct the first adjuvant trial of imatinib mesylate for treatment of gastrointestinal stromal tumor (GIST). Summary Background Data GIST is the most common sarcoma. While surgical resection has been the mainstay of therapy for localized, primary GIST, postoperative tumor recurrence is common. The KIT proto-oncogene or, less frequently, platelet-derived growth factor receptor alpha (PDGFRA) is mutated in GIST; the gene products of both are inhibited by imatinib mesylate. Methods This was a phase II, intergroup trial led by the American College of Surgeons Oncology Group (ACOSOG), registered at ClinicalTrials.gov as NCT00025246. From 09/2001 to 09/2003, we accrued 106 patients who had undergone complete gross tumor removal but were deemed at high risk for recurrence. Patients were prescribed imatinib 400 mg/day for 1 year and followed with serial radiologic evaluation. The primary endpoint was overall survival (OS). Results After a median follow-up of 7.7 years, the 1-, 3-, and 5-year OS rate was 99, 97, and 83%, which compared favorably with a historical 5 year OS rate of 35%. The 1-, 3-, and 5-year RFS rate was 96, 60, and 40%. On univariable analysis, age and mitotic rate were associated with OS. On multivariable analysis, the RFS rate was lower with increasing tumor size, small bowel site, KIT exon 9 mutation, high mitotic rate, and older age. Conclusion Adjuvant imatinib in patients with primary GIST who are at high risk of recurrence prolongs OS compared to that of historical controls. Optimal duration of adjuvant therapy remains undefined. (NCT00025246) PMID:23860199

  2. S0502: A SWOG Phase III Randomized Study of Imatinib, With or Without Bevacizumab, in Patients With Untreated Metastatic or Unresectable Gastrointestinal Stromal Tumors

    PubMed Central

    Rankin, Cathy; Corless, Christopher; Eary, Janet F.; Mulder, Karen; Okuno, Scott H.; George, Suzanne; Heinrich, Michael

    2015-01-01

    Lessons Learned Despite having significant rationale, S0502 failed to accrue for a number of reasons. Vetting a trial first, with scientific experts and funding agencies, does not guarantee success, especially when dealing with a rare tumor and/or one with an existing highly effective therapy. In the present case, adding an intravenous drug to an oral medication as part of a regimen expected to be continued for many years likely decreased patient (and physician) convenience and, thus, interest in the study. Background. Imatinib mesylate, a potent inhibitor of the KIT and PDGFR tyrosine kinases, is highly effective in the treatment of advanced gastrointestinal stromal tumors (GISTs). However, most imatinib-treated tumors eventually become resistant, accounting for a median progression-free survival of 19–23 months. Expression of vascular endothelial growth factor (VEGF) correlates with poor prognosis in GIST; bevacizumab, a monoclonal antibody against VEGF, is effective in a variety of solid tumors. We postulated combination therapy with imatinib plus bevacizumab would benefit patients with advanced GIST, particularly those reliant on VEGFA-dependent angiogenesis. Methods. Patients with metastatic or surgically unresectable GIST were eligible for this phase III open-label clinical trial, S0502. At registration, patients were randomly assigned to either imatinib 400 mg (standard) or 800 mg (patients with exon 9 KIT mutations), or imatinib plus bevacizumab, 7.5 mg/kg i.v. every 3 weeks. Patients were treated to progression, symptomatic deterioration, unacceptable toxicity, treatment delay greater than 4 weeks, or patient choice to withdraw from the study. The primary objective was to determine whether the addition of bevacizumab to imatinib would improve progression-free survival (PFS) in first-line treatment of incurable GIST. Results. S0502 opened on April 15, 2008. As of fall 2009, only 12 patients from at least 178 eligible SWOG centers plus those participating

  3. Epidemiology and molecular biology of gastrointestinal stromal tumors (GISTs): a population-based study in the South of Switzerland, 1999-2005.

    PubMed

    Mazzola, Paola; Spitale, Alessandra; Banfi, Sara; Mazzucchelli, Luca; Frattini, Milo; Bordoni, Andrea

    2008-11-01

    Introduction. Gastrointestinal stromal tumors (GISTs) are characterized at the molecular level by c-kit or PDGFRA oncogene mutations. Although GISTs raised major interest in past decades, population-based studies are still rare. Materials and Methods. All GISTs diagnosed in Southern Switzerland (1999-2005) were identified using Ticino Cancer Registry and analysed for c-kit and PDGFRA mutations. Clinical and molecular features were studied. Results. Annual incidence of GISTs was 1.47 cases/100,000 inhabitants (median age: 64 years; median size: 6.0 cm). Most GISTs arose in the stomach (60.5%). The malignancy risk was very-low/low in 47% of patients. DNA sequences showed a gene alteration in either c-kit or PDGFRA genes in 72.5% of patients. Mutations occurred mostly in c-kit exon 11 (60%). No mutations in c-kit exons 13 or 17 were found. An equal number of alterations in exons 12 and 18, and no mutations in exon 14 were observed in the PDGFRA gene. Discussion. This is the first comprehensive population-based study of GISTs incidence and molecular biology characterization in Central Europe. Our incidence data showed higher age-standardized rates compared to other European countries. The gene mutation spectrum differed when compared to the literature. This is relevant to improve the molecular profile knowledge based on Cancer Registry data. PMID:18785120

  4. Functional role of the Ca{sup 2+}-activated Cl{sup −} channel DOG1/TMEM16A in gastrointestinal stromal tumor cells

    SciTech Connect

    Berglund, Erik; Akcakaya, Pinar; Berglund, David; Karlsson, Fredrik; Vukojević, Vladana; Lee, Linkiat; Bogdanović, Darko; Lui, Weng-Onn; Larsson, Catharina; Zedenius, Jan; Fröbom, Robin; Bränström, Robert

    2014-08-15

    DOG1, a Ca{sup 2+}-activated Cl{sup −} channel (CaCC), was identified in 2004 to be robustly expressed in gastrointestinal stromal tumors (GIST). It was rapidly included as a tumor marker in routine diagnostics, but the functional role remained unknown. CaCCs are important regulators of normal physiological functions, but also implicated in tumorigenesis, cancer progression, metastasis, cell migration, apoptosis, proliferation and viability in several malignancies. We therefore investigated whether DOG1 plays a role in the three latter in GIST by utilizing in vitro cell model systems. Confocal microscopy identified different subcellular localizations of DOG1 in imatinib-sensitive and imatinib-resistant cells. Electrophysiological studies confirmed that DOG1-specific pharmacological agents possess potent activating and inhibiting properties. Proliferation assays showed small effects up to 72 h, and flow cytometric analysis of adherent cells with 7-AAD/Annexin V detected no pharmacological effects on viable GIST cells. However, inhibition of DOG1 conveyed pro-apoptotic effects among early apoptotic imatinib-resistant cells. In conclusion, DOG1 generates Cl{sup −} currents in GIST that can be regulated pharmacologically, with small effects on cell viability and proliferation in vitro. Inhibition of DOG1 might act pro-apoptotic on some early apoptotic GIST cell populations. Further studies are warranted to fully illuminate the function of DOG1 and its potential as therapeutic target. - Highlights: • Subcellular DOG1 localization varies between GIST cells. • DOG1 in GIST is voltage- and Ca{sup 2+}-activated. • Known TMEM16A modulators, like A01 and Eact, modulate DOG1. • DOG1 has small effects on cell viability and proliferation in vitro. • DOG1 impact early apoptotic GIST cells to undergo late apoptosis.

  5. Safety, efficacy and prognostic analyses of sunitinib in the post-marketing surveillance study of Japanese patients with gastrointestinal stromal tumor

    PubMed Central

    Komatsu, Yoshito; Ohki, Emiko; Ueno, Naomi; Yoshida, Ai; Toyoshima, Yasuharu; Ueda, Eiji; Houzawa, Hiroyuki; Togo, Kanae; Nishida, Toshirou

    2015-01-01

    Objective This study was conducted to expand the sunitinib safety database in Japanese imatinib-resistant/-intolerant gastrointestinal stromal tumor patients. Retrospective analyses investigated common adverse events as potential prognostic markers. Methods Four hundred and seventy patients who received sunitinib between June 2008 and November 2009 were analyzed for safety, progression-free survival and overall survival; 386 for objective response rate; 88% received sunitinib on Schedule 4/2 starting at 50 mg/day. Results No unexpected safety issues occurred. Grade ≥ 3 adverse events occurred in 70%, most commonly thrombocytopenia (33%), neutropenia (22%) and leukopenia (15%). Objective response rate was 20% (95% confidence interval 16–24). Median progression-free survival was 22.4 weeks (95% confidence interval, 21.7–24.0). The overall survival rate at 24 weeks was 91% (95% confidence interval, 88–94). Higher relative dose intensity (≥70 vs. <70%) during the first 6 weeks and better Eastern Cooperative Oncology Group performance status (0 vs. ≥1) were associated with longer progression-free survival (24.0 vs. 20.1 weeks; P = 0.011; and 24.1 vs. 16.9 weeks; P < 0.001) and higher 24-week overall survival rate (94 vs. 83%; P < 0.001; and 96 vs. 83%; P < 0.001). Increased progression-free survival and overall survival rates were associated with specific adverse events. Cox proportional hazard modeling adjusted for relative dose intensity and performance status established hand–foot syndrome (hazard ratio = 0.636; 95% confidence interval, 0.456–0.888) and leukopenia (hazard ratio = 0.683; 95% confidence interval, 0.492–0.948) occurring within 12 weeks were significantly correlated with increased progression-free survival. Conclusion Sunitinib showed good efficacy and tolerable safety. Factors associated with greater efficacy were relative dose intensity, performance status and specific early adverse events. PMID:26373318

  6. Imatinib treatment for gastrointestinal stromal tumour (GIST)

    PubMed Central

    Lopes, Lisandro F; Bacchi, Carlos E

    2010-01-01

    Abstract Gastrointestinal stromal tumour (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. GISTs are believed to originate from intersticial cells of Cajal (the pacemaker cells of the gastrointestinal tract) or related stem cells, and are characterized by KIT or platelet-derived growth factor receptor alpha (PDGFRA) activating mutations. The use of imatinib has revolutionized the management of GIST and altered its natural history, substantially improving survival time and delaying disease progression in many patients. The success of imatinib in controlling advanced GIST led to interest in the neoadjuvant and adjuvant use of the drug. The neoadjuvant (preoperative) use of imatinib is recommended to facilitate resection and avoid mutilating surgery by decreasing tumour size, and adjuvant therapy is indicated for patients at high risk of recurrence. The molecular characterization (genotyping) of GISTs has become an essential part of the routine management of the disease as KIT and PDGFRA mutation status predicts the likelihood of achieving response to imatinib. However, the vast majority of patients who initially responded to imatinib will develop tumour progression (secondary resistance). Secondary resistance is often related to secondary KIT or PDGFRA mutations that interfere with drug binding. Multiple novel tyrosine kinase inhibitors may be potentially useful for the treatment of imatinib-resistant GISTs as they interfere with KIT and PDGFRA receptors or with the downstream-signalling proteins. PMID:19968734

  7. Preoperative Imatinib Treatment in Patients With Advanced Gastrointestinal Stromal Tumors: Patient Experiences and Systematic Review of 563 Patients

    PubMed Central

    Xu, Jia; Ling, Tian-Long; Wang, Ming; Zhao, Wen-Yi; Cao, Hui

    2015-01-01

    Preoperative IM therapy for GIST is now a research focus. Due to the low incidence of the disease, there are few RCTs on the preoperative treatment for advanced GIST, let alone relevant meta-analysis. Efficacy of this therapy and targeting population are still undetermined. Therefore, the first part of this article is composed of a controlled retrospective study and demonstrates that preoperative therapy with IM can significantly improve the outcome of advanced GIST. In the second part of the paper, we further investigated what portion of advanced GIST patients benefit more from the therapy, based on a meta-analysis. As the disease is relatively rare, we involved 563 cases in the meta-analysis, much higher than in the controlled clinical studies (51 cases). The objective of this paper is to investigate effects of surgical resection on imatinib-treated advanced GIST. Twenty-two consecutive advanced GIST patients (Group A) with preoperative IM treatment were compared to 29 patients (Group B) who underwent initial tumor resection during the same period. Subsequently, a systematic review of 563 patients was applied to identify the benefit of the advanced GIST patients receiving imatinib before surgery. Compared with Group B, less patients in Group A underwent multivisceral resection (18.2% versus 48.3%, P = 0.026) or suffered tumor rupture at time of surgery (0% versus 17.2%, P = 0.04). The 3-year estimated progression-free survival of Group A (94.4%) was also superior to that of Group B (61.4%; P = 0.045). Subsequent meta-analysis indicated that primarily unresectable patients had higher complete resection and 2-year PFS rates than recurrent/metastasis patients (P = 0.005 and 0.20, respectively); (b) stable disease (SD) patients had better outcome in resection including resectability rate (P < 0.0001), PFS (P < 0.00001) and OS (P = 0.0008) than progressive disease (PD) patients; (c) in recurrent/metastatic PD patients, surgery played a minor role, because they had a

  8. Gastrointestinal stromal tumor of the stomach in a child with a 3-year follow-up period-Case report.

    PubMed

    Miranda, Marcelo Eller; Alberti, Luiz Ronaldo; Tatsuo, Edson Samesima; Piçarro, Clécio; Rausch, Marcelo

    2011-01-01

    We report a case of a nine-year-old boy with a 4-week history of general fatigue, loss of appetite, vomits and hematemesis. Laboratory evaluation revealed a hemoglobin level of 4.4 g/dl. After a transfusion of packed red blood cells the patient underwent an esophagogastroduodenoscopy, which showed a smooth, rounded 6-8 cm submucosal lesion with a central depression with ulceration and active bleeding in the cardia extending to the fundus.Computed tomography (CT) of the chest, abdomen and pelvis showed a large mass originating from the gastric wall but not infiltrating surrounding organs, approximately 8.0 cm × 7.0 cm × 5 cm. Despite the tumor size, no metastases were diagnosed. The patient underwent a total gastrectomy in an en-bloc resection including the distal part of the esophagus (3 cm) and omentum with oncologic margins. Reconstruction was performed with a mediastinal end-to-side esophago-jejunal anastomosis. Immunehistochemic confirmed GIST. He remains well without evidence of disease after 36 months of follow-up with a multiprofessional team. PMID:22096700

  9. Gastrointestinal stromal tumor of the stomach in a child with a 3-year follow-up period—Case report

    PubMed Central

    Miranda, Marcelo Eller; Alberti, Luiz Ronaldo; Tatsuo, Edson Samesima; Piçarro, Clécio; Rausch, Marcelo

    2011-01-01

    We report a case of a nine-year-old boy with a 4-week history of general fatigue, loss of appetite, vomits and hematemesis. Laboratory evaluation revealed a hemoglobin level of 4.4 g/dl. After a transfusion of packed red blood cells the patient underwent an esophagogastroduodenoscopy, which showed a smooth, rounded 6–8 cm submucosal lesion with a central depression with ulceration and active bleeding in the cardia extending to the fundus. Computed tomography (CT) of the chest, abdomen and pelvis showed a large mass originating from the gastric wall but not infiltrating surrounding organs, approximately 8.0 cm × 7.0 cm × 5 cm. Despite the tumor size, no metastases were diagnosed. The patient underwent a total gastrectomy in an en-bloc resection including the distal part of the esophagus (3 cm) and omentum with oncologic margins. Reconstruction was performed with a mediastinal end-to-side esophago-jejunal anastomosis. Immunehistochemic confirmed GIST. He remains well without evidence of disease after 36 months of follow-up with a multiprofessional team. PMID:22096700

  10. Targeted therapy of gastrointestinal stromal tumours

    PubMed Central

    Jakhetiya, Ashish; Garg, Pankaj Kumar; Prakash, Gaurav; Sharma, Jyoti; Pandey, Rambha; Pandey, Durgatosh

    2016-01-01

    Gastrointestinal stromal tumours (GISTs) are mesenchymal neoplasms originating in the gastrointestinal tract, usually in the stomach or the small intestine, and rarely elsewhere in the abdomen. The malignant potential of GISTs is variable ranging from small lesions with a benign behaviour to fatal sarcomas. The majority of the tumours stain positively for the CD-117 (KIT) and discovered on GIST-1 (DOG-1 or anoctamin 1) expression, and they are characterized by the presence of a driver kinase-activating mutation in either KIT or platelet-derived growth factor receptor α. Although surgery is the primary modality of treatment, almost half of the patients have disease recurrence following surgery, which highlights the need for an effective adjuvant therapy. Traditionally, GISTs are considered chemotherapy and radiotherapy resistant. With the advent of targeted therapy (tyrosine kinase inhibitors), there has been a paradigm shift in the management of GISTs in the last decade. We present a comprehensive review of targeted therapy in the management of GISTs. PMID:27231512

  11. Targeted therapy of gastrointestinal stromal tumours.

    PubMed

    Jakhetiya, Ashish; Garg, Pankaj Kumar; Prakash, Gaurav; Sharma, Jyoti; Pandey, Rambha; Pandey, Durgatosh

    2016-05-27

    Gastrointestinal stromal tumours (GISTs) are mesenchymal neoplasms originating in the gastrointestinal tract, usually in the stomach or the small intestine, and rarely elsewhere in the abdomen. The malignant potential of GISTs is variable ranging from small lesions with a benign behaviour to fatal sarcomas. The majority of the tumours stain positively for the CD-117 (KIT) and discovered on GIST-1 (DOG-1 or anoctamin 1) expression, and they are characterized by the presence of a driver kinase-activating mutation in either KIT or platelet-derived growth factor receptor α. Although surgery is the primary modality of treatment, almost half of the patients have disease recurrence following surgery, which highlights the need for an effective adjuvant therapy. Traditionally, GISTs are considered chemotherapy and radiotherapy resistant. With the advent of targeted therapy (tyrosine kinase inhibitors), there has been a paradigm shift in the management of GISTs in the last decade. We present a comprehensive review of targeted therapy in the management of GISTs. PMID:27231512

  12. Characterization of various types of mast cells derived from model mice of familial gastrointestinal stromal tumors with KIT-Asp818Tyr mutation

    PubMed Central

    Kajimoto, Noriko; Nakai, Norihiro; Ohkouchi, Mizuka; Hashikura, Yuka; Liu-Kimura, Ning-Ning; Isozaki, Koji; Hirota, Seiichi

    2015-01-01

    Sporadic mast cell neoplasms and gastrointestinal stromal tumors (GISTs) often have various types of somatic gain-of-function mutations of the c-kit gene which encodes a receptor tyrosine kinase, KIT. Several types of germline gain-of-function mutations of the c-kit gene have been detected in families with multiple GISTs. All three types of model mice for the familial GISTs with germline c-kit gene mutations at exon 11, 13 or 17 show development of GIST, while they are different from each other in skin mast cell number. Skin mast cell number in the model mice with exon 17 mutation was unchanged compared to the corresponding wild-type mice. In the present study, we characterized various types of mast cells derived from the model mice with exon 17 mutation (KIT-Asp818Tyr) corresponding to human familial GIST case with human KIT-Asp820Tyr to clarify the role of the c-kit gene mutation in mast cells. Bone marrow-derived cultured mast cells (BMMCs) derived from wild-type mice, heterozygotes and homozygotes were used for the experiments. Immortalized BMMCs, designated as IMC-G4 cells, derived from BMMCs of a homozygote during long-term culture were also used. Ultrastructure, histamine contents, proliferation profiles and phosphorylation of various signaling molecules in those cells were examined. In IMC-G4 cells, presence of additional mutation(s) of the c-kit gene and effect of KIT inhibitors on both KIT autophosphorylation and cell proliferation were also analyzed. We demonstrated that KIT-Asp818Tyr did not affect ultrastructure and proliferation profiles but did histamine contents in BMMCs. IMC-G4 cells had an additional novel c-kit gene mutation of KIT-Tyr421Cys which is considered to induce neoplastic transformation of mouse mast cells and the mutation appeared to be resistant to a KIT inhibitor of imatinib but sensitive to another KIT inhibitor of nilotinib. IMC-G4 cells might be a useful mast cell line to investigate mast cell biology. PMID:26722383

  13. Clinical efficacy of second-generation tyrosine kinase inhibitors in imatinib-resistant gastrointestinal stromal tumors: a meta-analysis of recent clinical trials

    PubMed Central

    Wu, Lile; Zhang, Zhongqiang; Yao, Hongliang; Liu, Kuijie; Wen, Yu; Xiong, Li

    2014-01-01

    Background Primary and secondary resistance to imatinib, a selective receptor tyrosine kinase inhibitor (TKI), is a serious clinical problem in the control of advanced gastrointestinal stromal tumors (GIST). Here we report on a meta-analysis we performed to evaluate the efficacy of second-generation TKIs in the treatment of patients with imatinib-resistant GIST. Methods Randomized controlled trials evaluating the clinical efficacy of second-generation TKIs were identified by searching PubMed and EMBASE from 2000 to February 2014. Outcomes subjected to analysis were progression-free survival and overall survival. Statistical analyses were performed using Review Manager version 5.1.0 (Cochrane Collaboration, Oxford, UK). Weighted hazard ratios (HR) with 95% confidence intervals (CIs) were calculated for the outcomes. Fixed-effects or random-effects models were used, depending on the degree of heterogeneity across the selected studies. Results Three randomized controlled trials were selected for meta-analysis. Among imatinib-resistant or imatinib-intolerant patients, 541 received second-generation TKIs (sunitinib, nilotinib, or regorafenib) and 267 controls received placebo or best supportive care. Progression-free survival was significantly improved in the TKI-treated group (HR 0.38; 95% CI 0.24–0.59; P<0.0001). No statistically significant difference was detected in overall survival between the treatment group and the control group (HR 0.85; 95% CI 0.71–1.03; P=0.09). In the subgroup of patients who were resistant or intolerant to both imatinib and sunitinib, TKI therapy (nilotinib or regorafenib) improved progression-free survival (HR 0.40; 95% CI 0.19–0.84; P=0.02) but not overall survival (HR 0.83; 95% CI 0.63–1.08; P=0.17). Regorafenib was shown to be effective in terms of progression-free survival across different subpopulations of patients who were resistant to both imatinib and sunitinib. Conclusion Second-generation TKIs (sunitinib, nilotinib, and

  14. Insulin-like growth factor binding protein-3 has dual effects on gastrointestinal stromal tumor cell viability and sensitivity to the anti-tumor effects of imatinib mesylate in vitro

    PubMed Central

    2009-01-01

    Background Imatinib mesylate has significantly improved survival and quality of life of patients with gastrointestinal stromal tumors (GISTs). However, the molecular mechanism through which imatinib exerts its anti-tumor effects is not clear. Previously, we found up-regulation of insulin-like growth factor binding protein-3 (IGFBP3) expression in imatinib-responsive GIST cells and tumor samples. Because IGFBP3 regulates cell proliferation and survival and mediates the anti-tumor effects of a number of anti-cancer agents through both IGF-dependent and IGF-independent mechanisms, we hypothesized that IGFBP3 mediates GIST cell response to imatinib. To test this hypothesis, we manipulated IGFBP3 levels in two imatinib-responsive GIST cell lines and observed cell viability after drug treatment. Results In the GIST882 cell line, imatinib treatment induced endogenous IGFBP3 expression, and IGFBP3 down-modulation by neutralization or RNA interference resulted in partial resistance to imatinib. In contrast, IGFBP3 overexpression in GIST-T1, which had no detectable endogenous IGFBP3 expression after imatinib, had no effect on imatinib-induced loss of viability. Furthermore, both the loss of IGFBP3 in GIST882 cells and the overexpression of IGFBP3 in GIST-T1 cells was cytotoxic, demonstrating that IGFBP3 has opposing effects on GIST cell viability. Conclusion This data demonstrates that IGFBP3 has dual, opposing roles in modulating GIST cell viability and response to imatinib in vitro. These preliminary findings suggest that there may be some clinical benefits to IGFBP3 therapy in GIST patients, but further studies are needed to better characterize the functions of IGFBP3 in GIST. PMID:19903356

  15. [Regression grading in gastrointestinal tumors].

    PubMed

    Tischoff, I; Tannapfel, A

    2012-02-01

    Preoperative neoadjuvant chemoradiation therapy is a well-established and essential part of the interdisciplinary treatment of gastrointestinal tumors. Neoadjuvant treatment leads to regressive changes in tumors. To evaluate the histological tumor response different scoring systems describing regressive changes are used and known as tumor regression grading. Tumor regression grading is usually based on the presence of residual vital tumor cells in proportion to the total tumor size. Currently, no nationally or internationally accepted grading systems exist. In general, common guidelines should be used in the pathohistological diagnostics of tumors after neoadjuvant therapy. In particularly, the standard tumor grading will be replaced by tumor regression grading. Furthermore, tumors after neoadjuvant treatment are marked with the prefix "y" in the TNM classification. PMID:22293790

  16. Discovery of N-(3-((1-Isonicotinoylpiperidin-4-yl)oxy)-4-methylphenyl)-3-(trifluoromethyl)benzamide (CHMFL-KIT-110) as a Selective, Potent, and Orally Available Type II c-KIT Kinase Inhibitor for Gastrointestinal Stromal Tumors (GISTs).

    PubMed

    Wang, Qiang; Liu, Feiyang; Wang, Beilei; Zou, Fengming; Chen, Cheng; Liu, Xiaochuan; Wang, Aoli; Qi, Shuang; Wang, Wenchao; Qi, Ziping; Zhao, Zheng; Hu, Zhenquan; Wang, Wei; Wang, Li; Zhang, Shanchun; Wang, Yuexiang; Liu, Jing; Liu, Qingsong

    2016-04-28

    c-KIT kinase is a validated drug discovery target for gastrointestinal stromal tumors (GISTs). Clinically used c-KIT kinase inhibitors, i.e., Imatinib and Sunitinib, bear other important targets such as ABL or FLT3 kinases. Here we report our discovery of a more selective c-KIT inhibitor, compound 13 (CHMFL-KIT-110), which completely abolished ABL and FLT3 kinase activity. KinomeScan selectivity profiling (468 kinases) of 13 exhibited a high selectivity (S score (1) = 0.01). 13 displayed great antiproliferative efficacy against GISTs cell lines GIST-T1 and GIST-882 (GI50: 0.021 and 0.043 μM, respectively). In the cellular context, it effectively affected c-KIT-mediated signaling pathways and induced apoptosis as well as cell cycle arrest. In addition, 13 possessed acceptable bioavailability (36%) and effectively suppressed the tumor growth in GIST-T1 cell inoculated xenograft model without apparent toxicity. 13 currently is undergoing extensive preclinical evaluation and might be a potential drug candidate for GISTs. PMID:27077705

  17. Synchronous occurrence of a primary colon adenocarcinoma and a gastric stromal tumor. A case report.

    PubMed

    Tzilves, D; Moschos, J; Paikos, D; Tagarakis, G; Pilpilidis, I; Soufleris, K; Kadis, S; Tarpagos, A; Katsos, I

    2008-03-01

    Gastrointestinal stromal tumors are currently the object of a great clinical and experimental interest. We are presenting the case of a 69-year-old patient, who was presented with lower gastrointestinal bleeding and dyspeptic symptoms over the last six months. The colonoscopy showed a large tumor of the sigmoid and the gastroscopy a large gastric tumor of the antrum, which were histologically diagnosed as colonic adenocarcinoma and gastric stromal tumor respectively. The patient underwent a sigmoidectomy and a partial gastrectomy. Six months after surgery were the clinical condition, abdominal CT, gastroscopy and colonoscopy without pathological findings. To our best knowledge, this is the second report of a synchronous gastric stromal tumor and a colonic adenocarcinoma in medical literature. PMID:18299673

  18. Treatment for Stromal Tumors of the Ovary

    MedlinePlus

    ... Get Involved Find Local ACS Learn About Cancer » Ovarian Cancer » Detailed Guide » Treatment for stromal tumors of the ... saved articles window. My Saved Articles » My ACS » Ovarian Cancer + - Text Size Download Printable Version [PDF] » Treating Ovarian ...

  19. What Should You Ask Your Doctor about Gastrointestinal Carcinoid Tumors?

    MedlinePlus

    ... gastrointestinal carcinoid tumors? What should you ask your doctor about gastrointestinal carcinoid tumors? It is important to ... Staging Treating Gastrointestinal Carcinoid Tumors Talking With Your Doctor After Treatment What`s New in Gastrointestinal Carcinoid Tumors ...

  20. Can Gastrointestinal Carcinoid Tumors Be Found Early?

    MedlinePlus

    ... problems. Carcinoid tumors often are found incidentally (by accident). These tumors aren’t causing any symptoms but ... Carcinoid Tumors? Causes, Risk Factors, and Prevention Early Detection, Diagnosis, and Staging Treating Gastrointestinal Carcinoid Tumors Talking ...

  1. Endometriosis mimicking colonic stromal tumor

    PubMed Central

    Wadhwa, Vaibhav; Slattery, Eoin; Garud, Sagar; Sethi, Saurabh; Wang, Helen; Poylin, Vitaliy Y.; Berzin, Tyler M.

    2016-01-01

    Endometriosis is defined as the presence of endometrial glands and stroma at extra-uterine sites; it is a common disease affecting women of reproductive age. Endometrial tissue can implant itself to various organs, including the gastrointestinal tract, and can cause significant gastrointestinal symptoms. These ectopic endometrial tissue implants are usually located in the pelvis but can be present almost anywhere in the body. Endometriosis seems to be the most frequent cause of chronic pelvic pain in women of reproductive age and may cause prolonged suffering and disability that negatively affect health-related quality of life. We report a case in a generally healthy young female patient who presented for evaluation of diarrhea. PMID:25725039

  2. Characteristics of gastrointestinal stromal tumours, diagnostic procedure and therapeutic management and main directions of nursing practice in gastrointestinal stromal tumours

    PubMed Central

    Głuszek, Stanisław; Kozieł, Dorota

    2014-01-01

    Gastrointestinal stromal tumours (GIST) constitute a separate group of mesenchymal neoplasms of the gastrointestinal tract. They have been commonly recognized for a few years, they have created a new problem in medical practice. GIST are more often centred in the stomach. They equally affect female and male patients and occur mainly in patients older than 50 years of age. The clinical picture of the tumour is non-specific. Radical surgical treatment and molecularly targeted therapy with tyrosine kinase inhibitors are used in GIST treatment. Nursing practice with reference to GIST danger is connected with biopsychosocial interventions of perioperative, oncological and palliative procedures and involves the area of health education mainly oriented towards shaping preventive procedures which favour early disease detection and support therapy and recovery. PMID:25784835

  3. Rare recurrence of a rare ovarian stromal tumor with luteinized cells: a case report

    PubMed Central

    2011-01-01

    Introduction Sex cord-stromal tumors of the ovary are uncommon. They behave unpredictably and often have a late recurrence, making counseling, management, and prediction of prognosis challenging. Case presentation A 52-year-old Moroccan woman with an sex cord-stromal tumors underwent a bilateral oophorectomy. The histology was unusual but was likely to be a luteinized thecoma with suspicious features for invasion. Seven years later, after a gastrointestinal bleed, a metastasis within the small bowel mucosa was detected. This represents probable isolated hematogenous or lymphatic spread, which is highly unusual, especially in the absence of concurrent peritoneal disease. Conclusions To the best of our knowledge, this is the second reported case of an sex cord-stromal tumors recurring in small bowel mucosa and mimicking a primary colorectal tumor. This highlights the diverse nature and behavior of these tumors. PMID:21816048

  4. Molecular characterization of metastatic exon 11 mutant gastrointestinal stromal tumors (GIST) beyond KIT/PDGFRα genotype evaluated by next generation sequencing (NGS).

    PubMed

    Saponara, Maristella; Urbini, Milena; Astolfi, Annalisa; Indio, Valentina; Ercolani, Giorgio; Del Gaudio, Massimo; Santini, Donatella; Pirini, Maria Giulia; Fiorentino, Michelangelo; Nannini, Margherita; Lolli, Cristian; Mandrioli, Anna; Gatto, Lidia; Brandi, Giovanni; Biasco, Guido; Pinna, Antonio Daniele; Pantaleo, Maria Abbondanza

    2015-12-01

    About 85% of GISTs are associated with KIT and PDGFRα gene mutations, which predict response to tyrosine kinase inhibitors. Although the outcomes in patients affected by GIST have dramatically improved, tumor progression control still remains a challenge. The aim of this study is the genomic characterization of individual metastatic KIT-exon 11-mutant GIST to identify additional aberrations and simultaneous molecular events representing potential therapeutic targets.Seven patients with metastatic GIST were studied with whole transcriptome sequencing and copy number analysis. Somatic single nucleotide variations were called; however, no shared mutated genes were detected except KIT. Almost all patients showed loss of genomic regions containing tumor suppressor genes, sometimes coupled with single nucleotide mutation of the other allele. Additionally, six fusion transcripts were found and three patients showed amplifications involving known oncogenes.Evaluating the concordance between CN status and mRNA expression levels, we detected overexpression of CCND2 and EGFR and silencing of CDKN2A, CDKN2C, SMARCB1, PTEN and DMD. Altered expression of these genes could be responsible for aberrant activation of signaling pathways that support tumor growth. In this work, we assessed the effect of Hedgehog pathway inhibition in GIST882 cells, which causes decrement of cell viability associated with reduction of KIT expression.Additional genomic alterations not previously reported in GIST were found even if not shared by all samples. This contributes to a more detailed molecular understanding of this disease, useful for identification of new targets and novel therapeutics and representing a possible point of departure for a truly individualized clinical approach. PMID:26544626

  5. Molecular characterization of metastatic exon 11 mutant gastrointestinal stromal tumors (GIST) beyond KIT/PDGFRα genotype evaluated by next generation sequencing (NGS)

    PubMed Central

    Astolfi, Annalisa; Indio, Valentina; Ercolani, Giorgio; Del Gaudio, Massimo; Santini, Donatella; Pirini, Maria Giulia; Fiorentino, Michelangelo; Nannini, Margherita; Lolli, Cristian; Mandrioli, Anna; Gatto, Lidia; Brandi, Giovanni; Biasco, Guido; Pinna, Antonio Daniele; Pantaleo, Maria Abbondanza

    2015-01-01

    About 85% of GISTs are associated with KIT and PDGFRα gene mutations, which predict response to tyrosine kinase inhibitors. Although the outcomes in patients affected by GIST have dramatically improved, tumor progression control still remains a challenge. The aim of this study is the genomic characterization of individual metastatic KIT-exon 11-mutant GIST to identify additional aberrations and simultaneous molecular events representing potential therapeutic targets. Seven patients with metastatic GIST were studied with whole transcriptome sequencing and copy number analysis. Somatic single nucleotide variations were called; however, no shared mutated genes were detected except KIT. Almost all patients showed loss of genomic regions containing tumor suppressor genes, sometimes coupled with single nucleotide mutation of the other allele. Additionally, six fusion transcripts were found and three patients showed amplifications involving known oncogenes. Evaluating the concordance between CN status and mRNA expression levels, we detected overexpression of CCND2 and EGFR and silencing of CDKN2A, CDKN2C, SMARCB1, PTEN and DMD. Altered expression of these genes could be responsible for aberrant activation of signaling pathways that support tumor growth. In this work, we assessed the effect of Hedgehog pathway inhibition in GIST882 cells, which causes decrement of cell viability associated with reduction of KIT expression. Additional genomic alterations not previously reported in GIST were found even if not shared by all samples. This contributes to a more detailed molecular understanding of this disease, useful for identification of new targets and novel therapeutics and representing a possible point of departure for a truly individualized clinical approach. PMID:26544626

  6. Immunohistochemical features of the gastrointestinal tract tumors

    PubMed Central

    Wong, Hannah H.

    2012-01-01

    Gastrointestinal tract tumors include a wide variety of vastly different tumors and on a whole are one of the most common malignancies in western countries. These tumors often present at late stages as distant metastases which are then biopsied and may be difficult to differentiate without the aid of immunohistochemical stains. With the exception of pancreatic and biliary tumors where there are no distinct immunohistochemical patterns, most gastrointestinal tumors can be differentiated by their unique immunohistochemical profile. As the size of biopsies decrease, the role of immunohistochemical stains will become even more important in determining the origin and differentiation of gastrointestinal tract tumors. PMID:22943017

  7. An update on molecular genetics of gastrointestinal stromal tumours

    PubMed Central

    Tornillo, L; Terracciano, L M

    2006-01-01

    Gastrointestinal stromal tumours (GISTs) are the most common primary mesenchymal tumours of the gastrointestinal tract. Most of them show activating mutations of the genes coding for KIT or platelet‐derived growth factor receptor α (PDGFRα), two receptor tyrosine kinases (RTKs). The RTK inhibitor Imatinib (Gleevec®, Novartis, Switzerland), induces regression of the tumour. The level of response to treatment, together with other clinicopathological parameters is related to the type and site of the activating mutation, thus suggesting that these tumours should be classified according to the molecular context. This is confirmed also by the phenomenon of the resistance to treatment, which arises because of different mechanisms (second mutation, amplification, activation of other RTKs) and can be fought only by specific RTK inhibitors, that are at present under development. RTK activation involves an homogeneous transduction pathway whose components (MAPK, AKT, PI3K, mTOR and RAS) are possible targets of new molecular treatment. A new paradigm of classification integrating the classic pathological criteria with the molecular changes will permit personalised prognosis and treatment. PMID:16731599

  8. How Are Gastrointestinal Stromal Tumors Diagnosed?

    MedlinePlus

    ... can’t be biopsied during the test. Double balloon enteroscopy (endoscopy) This is another way to look ... at the lining of the intestine. Then a balloon on the end of the endoscope is inflated ...

  9. Primary pericardial extragastrointestinal stromal tumor: A case report and literature review

    PubMed Central

    ARPACI, TANER; TOKAT, FATMA; ARPACI, RABIA BOZDOGAN; AKBAS, TUGANA; UGURLUER, GAMZE; YAVUZ, SINAN

    2015-01-01

    Gastrointestinal stromal tumors (GISTs) are the most prevalent mesenchymal tumors of the gastrointestinal tract. GISTs are considered to originate from the interstitial cells of Cajal, the pacemakers of the peristaltic activity of the gastrointestinal tract. More than 95% of GISTs express KIT protein and discovered on GIST-1. GISTs may also be encountered in locations outside the gastrointestinal tract, in which case they are referred to as extra-GISTs (EGISTs) and often behave more aggressively. This is the case report of a primary pericardial EGIST in a 53-year-old male patient, confirmed by immunohistochemistry. To the best of our knowledge, this is the third case of EGIST diagnosed above the diaphragm, without being associated with the esophageal wall. Two cases of primary EGIST arising from the pleura were reported previously. In addition, this is the first reported case of an EGIST originating from the pericardium. PMID:26137136

  10. Tumoral pseudoangiomatous stromal hyperplasia of the breast.

    PubMed

    Wieman, Stephanie M; Landercasper, Jeffrey; Johnson, Jeanne M; Ellis, Richard L; Wester, Susan M; Lambert, Pamela J; Ross, Lauren A

    2008-12-01

    Tumoral pseudoangiomatous stromal hyperplasia (PASH) is a rare benign proliferative disease of the breast. The majority of the literature reports of PASH have not contained detailed descriptions of the imaging characteristics of PASH. A 10-year retrospective study of patients with tumoral PASH and a 20-year Ovid MEDLINE search were performed to determine whether specific imaging and needle biopsy results could characterize PASH preoperatively. We identified 22 patients with tumoral PASH. Seventeen (77%) of 22 women had a palpable lump and 14 (72%) of 21 had a density on mammography. Ultrasound (US) findings included mixed or hypoechoic echogenicity in 83 per cent and ill-defined borders in 62 per cent. Eight (36%) patients had lesions with a Breast Imaging Reporting and Data System (BI-RADS) classification of 4 or 5. The sensitivity of preoperative core needle biopsy (CNB) to identify PASH was 83 per cent. A review of the literature revealed that 90 per cent of patients with PASH had some malignant imaging characteristics and 95 per cent had a mass on mammography. The imaging characteristics of PASH exhibited marked variability. Excision of PASH after CNB may be considered for patients with symptoms, enlarging lesions, or lesions classified as BI-RADS 4 or 5. PASH diagnosed by CNB allows selected patients to avoid excision. PMID:19097540

  11. Current Guidelines in the Management of Upper Gastrointestinal Subepithelial Tumors

    PubMed Central

    Cho, Jin Woong

    2016-01-01

    Subepithelial tumors are frequently found in asymptomatic patients in Japan and Korea where cancer screening tests routinely include endoscopy. Most lesions are asymptomatic and clinically insignificant. However, carcinoid tumors, lymphomas, glomus tumor and gastrointestinal stromal tumors (GISTs) are malignant or have the potential to become malignant. Inflammation due to parasitic infestation by Anisakis and poorly differentiated adenocarcinomas in the stomach rarely present as subepithelial lesions. In contrast to the frequency of gastric GIST in the gastrointestinal system, they are uncommon in the duodenum and very rare in the esophagus. The prognosis of patients with GISTs in the stomach is relatively good compared with GISTs in other organs. Along with the location of the tumor, its size and mitotic count are major factors that determine the malignant potential of GIST. Small (<2 cm) asymptomatic GISTs usually have benign clinical course. GIST is the most common subepithelial tumor to occur in the stomach. Although various methods are employed to diagnose GISTs, the risk of GIST metastasis cannot be accurately predicted before lesions are completely resected. Recently, new endoscopic diagnostic methods and treatment techniques have been developed that allow the diagnosis and resection of lesions located in the muscularis propria, without any complications. These endoscopic methods have different indications depending on regions where they are performed. PMID:26898512

  12. Ovarian signet-ring stromal tumor: a potential diagnostic pitfall.

    PubMed

    Shaco-Levy, Ruthy; Kachko, Leonid; Mazor, Moshe; Piura, Benjamin

    2008-04-01

    Signet-ring stromal tumor is a rare ovarian neoplasm with only 10 reported cases in the literature. We report an unusual case of ovarian signet-ring stromal tumor in a 69-year-old woman who presented with right adnexal mass and underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. The diagnosis was based on histological, histochemical, immunohistochemical, and electron microscopy characteristics. The main significance is to differentiate this benign tumor from the highly malignant Krukenberg tumor, and this differential diagnosis is discussed. PMID:18417676

  13. Heme oxygenase-1 system and gastrointestinal tumors

    PubMed Central

    Zhu, Xiao; Fan, Wen-Guo; Li, Dong-Pei; Lin, Marie CM; Kung, Hsiangfu

    2010-01-01

    Heme oxygenase-1 (HO-1) system catabolizes heme into three products: carbon monoxide, biliverdin/bilirubin and free iron. It is involved in many physiological and pathophysiological processes. A great deal of data has demonstrated the roles of HO-1 in the formation, growth and metastasis of tumors. The interest in this system by investigators involved in gastrointestinal tumors is fairly recent, and few papers on HO-1 have touched upon this subject. This review focuses on the current understanding of the physiological significance of HO-1 induction and its possible roles in the gastrointestinal tumors studied to date. The implications for possible therapeutic manipulation of HO-1 in gastrointestinal tumors are also discussed. PMID:20518085

  14. What's New in Gastrointestinal Carcinoid Tumors Research and Treatment?

    MedlinePlus

    ... Topic Additional resources for gastrointestinal carcinoid tumors What’s new in gastrointestinal carcinoid tumor research and treatment? There ... for the causes of , ways to prevent , and new approaches to diagnose and treat GI carcinoid tumors. ...

  15. Extragastrointestinal stromal tumors: Computed tomography and magnetic resonance imaging findings

    PubMed Central

    ZHU, JINGQI; YANG, ZHANGWEI; TANG, GUANGYU; WANG, ZHONGQIU

    2015-01-01

    Extragastrointestinal stromal tumors (EGISTs) are rare mesenchymal tumors that originate outside the gastrointestinal tract. The aim of the present study was to investigate the computed tomography (CT) and magnetic resonance imaging (MRI) features of EGISTs and analyze the correlations between radiological findings and pathological features. CT and MRI images of 24 patients with EGISTs were reviewed retrospectively. Patient demographics and tumor characteristics, including localization, size, contours, borders, cystic-necrotic components, calcification, hemorrhage, tumor vessels, attenuation and intensity, degree and pattern of enhancement, ascites, tumor invasion, lymphadenopathy and distant metastasis were recorded. Statistical analyses to compare the radiological characteristics of low- and high-grade EGISTs were performed with χ2 or Fisher’s exact tests. The mean patient age at the time of presentation was 53 years. A total of 24 EGISTs were detected, originating in the omentum (n=4), mesentery (n=19) and retroperitoneum (n=1), respectively. The EGISTs displayed a predominantly spindle cell subtype (87.5%; 21/24). The majority of the EGISTs appeared as large (>10 cm; 70.8%; 17/24), round or oval (66.7%; 16/24), cystic-solid (87.5%; 21/24) and ill-defined (66.7%; 16/24) soft-tissue masses. The EGISTs were hypodense (69.6%; 16/23) or isodense (30.4%; 7/23) on CT images, hypointense (50%; 3/6), isointense (33.3%; 2/6) or hyperintense (16.7%; 1/6) on T1-weighted imaging (T1WI), and hyperintense on T2WI (100%; 6/6) and diffusion-WI (DWI; 100%; 6/6). A total of 54.2% (13/24) of the EGISTs displayed tumor vessels. Overall, 95.8% (23/24) of the masses showed marked enhancement and 87.5% (21/24) demonstrated heterogeneous enhancement. Calcification, hemorrhage, ascites and lymphadenopathy were rare characteristics in the EGISTs. Distant metastases were present in 10 patients (41.7%). The size, borders, tumor vessels and distant metastasis correlated with high

  16. A rare combination between familial multiple lipomatosis and extragastrointestinal stromal tumor

    PubMed Central

    Arabadzhieva, Elena; Yonkov, Atanas; Bonev, Sasho; Bulanov, Dimitar; Taneva, Ivanka; Ivanova, Vesela; Dimitrova, Violeta

    2015-01-01

    Introduction Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Rarely, GISTs can be located in mesentery, retroperitoneal space, omentum or pancreas. In these cases, the neoplasm is defined as “extra-gastrointestinal stromal tumors” (EGISTs). Presentation of case We reported a case of a 63-year-old male patient diagnosed by computer tomography with large intraabdominal tumor with vague origin, postoperatively determined as an EGIST. The diagnosis was confirmed by immunohistochemical study. The patient had multiple, subcutaneous, painless lipomas localized in the arms, forearms, thighs, abdomen and thorax. Because of the family history and the clinical presentation the disease was determined as familial multiple lipomatosis (FML). We performed radical tumor resection with distal pancreatectomy and splenectomy, and abdominoplasty, removing redundant skin and underlying subcutaneous fat tissue with multiple lipomas. Discussion FML is a rare hereditary benign disease. On the other hand, only few cases with familial GIST have been reported. In cases with extensive abdominal involvement, the primary origin of EGIST may be impossible to determine so the differential diagnosis is very difficult. Conclusion Although we could not prove correlation between the observed diseases, they are extremely rare and their combination is unusual which makes the presented case valuable and interesting. PMID:26263450

  17. Stages of Gastrointestinal Carcinoid Tumors

    MedlinePlus

    ... symptoms of GI carcinoid tumors in the jejunum (middle part of the small intestine) and ileum (last part ... Treatment of GI carcinoid tumors in the jejunum (middle part of the small intestine) and ileum (last part ...

  18. Pten in Stromal Fibroblasts Suppresses Mammary Epithelial Tumors

    PubMed Central

    Trimboli, Anthony J.; Cantemir-Stone, Carmen Z.; Li, Fu; Wallace, Julie A.; Merchant, Anand; Creasap, Nicholas; Thompson, John C.; Caserta, Enrico; Wang, Hui; Chong, Jean-Leon; Naidu, Shan; Wei, Guo; Sharma, Sudarshana M.; Stephens, Julie A.; Fernandez, Soledad A.; Gurcan, Metin N.; Weinstein, Michael B.; Barsky, Sanford H.; Yee, Lisa; Rosol, Thomas J.; Stromberg, Paul C.; Robinson, Michael L.; Pepin, Francois; Hallett, Michael; Park, Morag; Ostrowski, Michael C.; Leone, Gustavo

    2009-01-01

    SUMMARY The tumor stroma is believed to contribute to some of the most malignant characteristics of epithelial tumors. However, signaling between stromal and tumor cells is complex and remains poorly understood. Here we show that the genetic inactivation of Pten in stromal fibroblasts of mouse mammary glands accelerated the initiation, progression and malignant transformation of mammary epithelial tumors. This was associated with the massive remodeling of the extra-cellular matrix (ECM), innate immune cell infiltration and increased angiogenesis. Loss of Pten in stromal fibroblasts led to increased expression, phosphorylation (T72) and recruitment of Ets2 to target promoters known to be involved in these processes. Remarkably, Ets2 inactivation in Pten stroma-deleted tumors ameliorated disruption of the tumor microenvironment and was sufficient to decrease tumor growth and progression. Global gene expression profiling of mammary stromal cells identified a Pten-specific signature that was highly represented in the tumor stroma of breast cancer patients. These findings identify the Pten-Ets2 axis as a critical stroma-specific signaling pathway that suppresses mammary epithelial tumors. PMID:19847259

  19. Sex cord-gonadal stromal tumor of the rete testis.

    PubMed

    Sajadi, Kamran P; Dalton, Rory R; Brown, James A

    2009-01-01

    A 34-year-old tetraplegic patient with suppurative epididymitis was found on follow-up examination and ultrasonography to have a testicular mass. The radical orchiectomy specimen contained an undifferentiated spindled sex cord-stromal tumor arising in the rete testis. Testicular sex cord-stromal tumors are far less common than germ cell neoplasms and are usually benign. The close relationship between sex cords and ductules of the rete testis during development provides the opportunity for these uncommon tumors to arise anatomically within the rete tesis. This undifferentiated sex cord-stromal tumor, occurring in a previously unreported location, is an example of an unusual lesion mimicking an intratesticular malignant neoplasm. PMID:19125206

  20. Sex Cord-Gonadal Stromal Tumor of the Rete Testis

    PubMed Central

    Sajadi, Kamran P.; Dalton, Rory R.; Brown, James A.

    2009-01-01

    A 34-year-old tetraplegic patient with suppurative epididymitis was found on follow-up examination and ultrasonography to have a testicular mass. The radical orchiectomy specimen contained an undifferentiated spindled sex cord-stromal tumor arising in the rete testis. Testicular sex cord-stromal tumors are far less common than germ cell neoplasms and are usually benign. The close relationship between sex cords and ductules of the rete testis during development provides the opportunity for these uncommon tumors to arise anatomically within the rete tesis. This undifferentiated sex cord-stromal tumor, occurring in a previously unreported location, is an example of an unusual lesion mimicking an intratesticular malignant neoplasm. PMID:19125206

  1. Gastrointestinal stromal tumours (GISTs) with a thousand faces: atypical manifestations and causes of misdiagnosis on imaging.

    PubMed

    Kim, S W; Kim, H C; Yang, D M; Won, K Y

    2016-02-01

    Gastrointestinal stromal tumours (GISTs) can lead to emergency situations, such as gastrointestinal bleeding, intestinal obstruction, and tumoural rupture with haemoperitoneum or peritonitis. In addition, if a GIST grows exophytically to a large size, it is often misdiagnosed as a tumour arising from adjacent organs. Sometimes, the atypical appearance of GISTs on imaging causes diagnostic confusion. In this article, we illustrate a variety of GISTs with atypical presentations and also discuss the important diagnostic clues for differentiating GISTs from other lesions. PMID:26646370

  2. Mucinous cyst exhibiting severe dysplasia in gastric heterotopic pancreas associated with gastrointestinal stromal tumour.

    PubMed

    Kaufman, Antony; Storey, David; Lee, Cheok Soon; Murali, Rajmohan

    2007-11-21

    Heterotopic pancreatic tissue within the stomach is rare and dysplasia within heterotopic pancreatic tissue is very rare. We present the first report of a patient with concurrent occurrence of heterotopic pancreas in the stomach with a gastrointestinal stromal tumour. PMID:17963310

  3. Tumor-associated stromal cells as key contributors to the tumor microenvironment.

    PubMed

    Bussard, Karen M; Mutkus, Lysette; Stumpf, Kristina; Gomez-Manzano, Candelaria; Marini, Frank C

    2016-01-01

    The tumor microenvironment is a heterogeneous population of cells consisting of the tumor bulk plus supporting cells. It is becoming increasingly evident that these supporting cells are recruited by cancer cells from nearby endogenous host stroma and promote events such as tumor angiogenesis, proliferation, invasion, and metastasis, as well as mediate mechanisms of therapeutic resistance. In addition, recruited stromal cells range in type and include vascular endothelial cells, pericytes, adipocytes, fibroblasts, and bone-marrow mesenchymal stromal cells. During normal wound healing and inflammatory processes, local stromal cells change their phenotype to become that of reactive stroma. Under certain conditions, however, tumor cells can co-opt these reactive stromal cells and further transition them into tumor-associated stromal cells (TASCs). These TASCs express higher levels of proteins, including alpha-smooth muscle actin, fibroblast activating protein, and matrix metalloproteinases, compared with their normal, non-reactive counterparts. TASCs are also known to secrete many pro-tumorigenic factors, including IL-6, IL-8, stromal-derived factor-1 alpha, vascular endothelial growth factor, tenascin-C, and matrix metalloproteinases, among others, which recruit additional tumor and pro-tumorigenic cells to the developing microenvironment. Here, we review the current literature pertaining to the origins of recruited host stroma, contributions toward tumor progression, tumor-associated stromal cells, and mechanisms of crosstalk between endogenous host stroma and tumor cells. PMID:27515302

  4. [Synchronous tumors of the gastrointestinal tract].

    PubMed

    Pătraşcu, Tr; Doran, H; Catrina, E; Mihalache, O; Degeratu, D; Predescu, G

    2010-01-01

    The term "synchronous tumors" is reserved for simultaneous evolution of two or more tumors with distinct sites, in which the possibility that one tumor is a metastasis of the other has been excluded. In medical practice, the involvement of two different cavitary organs of the gastrointestinal tract is very rare. We present two clinical cases of synchronous tumors: one of a malignant degeneration of a colonic polyp, associated to a jejunal tumor; the other of a patient with a gastric adenocarcinoma, who also had a bulky rectal villous tumor. We tried to find out the etiology of the tumors and the frequency of these associations, mentioned in medical literature. Immunohistochemistry investigations, genetic analysis and familial screening must complete an individualized medical approach in which the surgical technique must be adequate for each case. PMID:20405687

  5. What Are the Key Statistics about Gastrointestinal Carcinoid Tumors?

    MedlinePlus

    ... for gastrointestinal carcinoid tumors? What are the key statistics about gastrointestinal carcinoid tumors? Although the exact number ... Symptoms of Cancer Treatments & Side Effects Cancer Facts & Statistics News About Cancer Expert Voices Blog Programs & Services ...

  6. Do We Know What Causes Gastrointestinal Carcinoid Tumors?

    MedlinePlus

    ... Topic Can gastrointestinal carcinoid tumors be prevented? Do we know what causes gastrointestinal carcinoid tumors? Researchers have ... our genes, which control how our cells function. We look like our parents because they are the ...

  7. Pathological analysis of collision (double primary) cancer in the upper digestive tract concomitant with gastric stromal tumor: a case report

    PubMed Central

    Sun, Xun; Zou, Yabin; Hao, Yueming; Cheng, Hongjing; Zhou, Changli; Meng, Xiangwei

    2015-01-01

    Carcinoma of the esophagus and cardiac cancer are common malignancies, while multiple primary cancers in the esophagus and cardia is rarely encountered and easily misdiagnosed. Multiple primary cancers mean the same organs (tissues) or different organs (tissues) have two or more than two primary malignant tumors at the same time or in sequence in the same individual. The case below of two independent primary lesions is double primary carcinoma which meets the diagnosis standard of multiple primary cancers. Gastrointestinal stromal tumor is the most common stromal tumor, which is usually considered as originating from Cajal cells in the gastrointestinal tract or mesenchymal stem cells with the mutation of KIT or PDGFRA gene. Study on stromal tumor with digestive tract cancer is less both at home and abroad, while double primary carcinoma with stromal tumor is rare, which has not been reported at present. Although scholars have different viewpoints on the prognosis, but the full understanding of this disease can be as a warning for the future work and to avoid misdiagnosis. PMID:26722567

  8. Targeted Proapoptotic Peptides Depleting Adipose Stromal Cells Inhibit Tumor Growth.

    PubMed

    Daquinag, Alexes C; Tseng, Chieh; Zhang, Yan; Amaya-Manzanares, Felipe; Florez, Fernando; Dadbin, Ali; Zhang, Tao; Kolonin, Mikhail G

    2016-02-01

    Progression of many cancers is associated with tumor infiltration by mesenchymal stromal cells (MSC). Adipose stromal cells (ASC) are MSC that serve as adipocyte progenitors and endothelium-supporting cells in white adipose tissue (WAT). Clinical and animal model studies indicate that ASC mobilized from WAT are recruited by tumors. Direct evidence for ASC function in tumor microenvironment has been lacking due to unavailability of approaches to specifically inactivate these cells. Here, we investigate the effects of a proteolysis-resistant targeted hunter-killer peptide D-WAT composed of a cyclic domain CSWKYWFGEC homing to ASC and of a proapoptotic domain KLAKLAK2. Using mouse bone marrow transplantation models, we show that D-WAT treatment specifically depletes tumor stromal and perivascular cells without directly killing malignant cells or tumor-infiltrating leukocytes. In several mouse carcinoma models, targeted ASC cytoablation reduced tumor vascularity and cell proliferation resulting in hemorrhaging, necrosis, and suppressed tumor growth. We also validated a D-WAT derivative with a proapoptotic domain KFAKFAK2 that was found to have an improved cytoablative activity. Our results for the first time demonstrate that ASC, recruited as a component of tumor microenvironment, support cancer progression. We propose that drugs targeting ASC can be developed as a combination therapy complementing conventional cancer treatments. PMID:26316391

  9. Laparoscopic wedge resection of synchronous gastric intraepithelial neoplasia and stromal tumor: a case report.

    PubMed

    Mou, Yi-Ping; Xu, Xiao-Wu; Xie, Kun; Zhou, Wei; Zhou, Yu-Cheng; Chen, Ke

    2010-10-21

    Synchronous occurrence of epithelial neoplasia and gastrointestinal stromal tumor (GIST) in the stomach is uncommon. Only rare cases have been reported in the literature. We present here a 60-year-old female case of synchronous occurrence of gastric high-level intraepithelial neoplasia and GIST with the features of 22 similar cases and detailed information reported in the English-language literature summarized. In the present patient, epithelial neoplasia and GIST were removed en bloc by laparoscopic wedge resection. To the best of our knowledge, this is the first reported case treated by laparoscopic wedge resection. PMID:20954290

  10. Treatment for Gastrointestinal Stromal Tumors (GISTs) Based on Tumor Spread

    MedlinePlus

    ... treatment are (whether it is to try to cure the cancer, to help you live longer, or to prevent ... in the liver, but are not expected to cure the cancer. Cancers that are no longer responding to the ...

  11. Synchronous Appearance of Adenocarcinoma and Gastrointestinal Stromal Tumour (GIST) of the Stomach: A Case Report

    PubMed Central

    Pushparaj, Magesh; Masih, Dipti; Pulimood, Anna

    2016-01-01

    Adenocarcinoma is the most common histological type of gastric tumour, accounting for approximately 95% of all gastric carcinomas. Gastrointestinal stromal tumours (GISTs) are rare mesenchymal neoplasms of the digestive tract. Synchronous adenocarcinoma and gastrointestinal stromal tumour (GIST) occurring in the stomach is rare and very few cases have been reported in literature. Synchronous tumours in the stomach are rarely diagnosed preoperatively. A 63-year-old gentleman was diagnosed with a gastric adenocarcinoma on endoscopic biopsy and underwent surgery. Postoperative histopathologic examination revealed 2 synchronous tumours with both adenocarcinoma and GIST. The adenocarcinoma was determined to be the aggressive tumour based on histologic features. GIST was categorized as a very low risk of malignancy, based on its size and mitosis. The patient underwent chemotherapy for adenocarcinoma. He is under follow up and is currently disease free. Careful histopathologic evaluation is required to detect co-existing rare synchronous tumours. Presence of the second tumour may require additional procedures or protocols. PMID:27042477

  12. Synchronous Appearance of Adenocarcinoma and Gastrointestinal Stromal Tumour (GIST) of the Stomach: A Case Report.

    PubMed

    Telugu, Ramesh Babu; Pushparaj, Magesh; Masih, Dipti; Pulimood, Anna

    2016-02-01

    Adenocarcinoma is the most common histological type of gastric tumour, accounting for approximately 95% of all gastric carcinomas. Gastrointestinal stromal tumours (GISTs) are rare mesenchymal neoplasms of the digestive tract. Synchronous adenocarcinoma and gastrointestinal stromal tumour (GIST) occurring in the stomach is rare and very few cases have been reported in literature. Synchronous tumours in the stomach are rarely diagnosed preoperatively. A 63-year-old gentleman was diagnosed with a gastric adenocarcinoma on endoscopic biopsy and underwent surgery. Postoperative histopathologic examination revealed 2 synchronous tumours with both adenocarcinoma and GIST. The adenocarcinoma was determined to be the aggressive tumour based on histologic features. GIST was categorized as a very low risk of malignancy, based on its size and mitosis. The patient underwent chemotherapy for adenocarcinoma. He is under follow up and is currently disease free. Careful histopathologic evaluation is required to detect co-existing rare synchronous tumours. Presence of the second tumour may require additional procedures or protocols. PMID:27042477

  13. Carcinoid Tumors of the Gastrointestinal Tract

    PubMed Central

    Morgan, John G.; Marks, Charles; Hearn, David

    1974-01-01

    The charts of 135 patients with gastrointestinal carcinoid tumors diagnosed over a 22-year period at 2 hospitals are reviewed and the clinical and pathological aspects discussed. Carcinoids occur most commonly in the appendix, jejunoileum, and rectum. Those smaller than 1 cm in diameter provide evidence of malignant potential only occasionally; lesions in the 1-1.9 cm range do this quite variably, and tumors 2 cm and larger are almost always invasive or metastatic or both. All gastrointestinal carcinoids except those of the appendix enlarge, invade, and metastasize predictably if given sufficient time. Most carcinoids except those of the rectum have already been adequately treated surgically when diagnosed by the pathologist. Local excision is effective treatment for noninvasive rectal carcinoids smaller than 2 cm in diameter, but those that have invaded or grown to 2 cm should undergo more radical resection. In general, gastrointestinal carcinoids carry better prognoses than do adenocarcinomata, and even in the presence of distant metastases long-term survival occurs in a significant number of patients. The frequent concomitance of associated malignant diseases accounts for as many or more deaths in these patients than the carcinoids themselves. ImagesFig. 1.Fig. 2.Fig. 3.Fig. 4. PMID:4421375

  14. Updates in Tumor Profiling in Gastrointestinal Cancers.

    PubMed

    Perez, Kimberly; Safran, Howard P

    2015-10-01

    In the last decade there has been a focus on biomarkers that play a critical role in understanding molecular and cellular mechanisms which drive tumor initiation, maintenance and progression of cancers. Characterization of genomes by next-generation sequencing (NGS) has permitted significant advances in gastrointestinal cancer care. These discoveries have fueled the development of novel therapeutics and have laid the groundwork for the development of new treatment strategies. Work in colorectal cancer (CRC) has been in the forefront of these advances. With the continued development of NGS technology and the positive clinical experience in CRC, genome work has begun in esophagogastric, pancreatic, and hepatocellular carcinomas as well. PMID:26422541

  15. Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation

    PubMed Central

    Tape, Christopher J.; Ling, Stephanie; Dimitriadi, Maria; McMahon, Kelly M.; Worboys, Jonathan D.; Leong, Hui Sun; Norrie, Ida C.; Miller, Crispin J.; Poulogiannis, George; Lauffenburger, Douglas A.; Jørgensen, Claus

    2016-01-01

    Summary Oncogenic mutations regulate signaling within both tumor cells and adjacent stromal cells. Here, we show that oncogenic KRAS (KRASG12D) also regulates tumor cell signaling via stromal cells. By combining cell-specific proteome labeling with multivariate phosphoproteomics, we analyzed heterocellular KRASG12D signaling in pancreatic ductal adenocarcinoma (PDA) cells. Tumor cell KRASG12D engages heterotypic fibroblasts, which subsequently instigate reciprocal signaling in the tumor cells. Reciprocal signaling employs additional kinases and doubles the number of regulated signaling nodes from cell-autonomous KRASG12D. Consequently, reciprocal KRASG12D produces a tumor cell phosphoproteome and total proteome that is distinct from cell-autonomous KRASG12D alone. Reciprocal signaling regulates tumor cell proliferation and apoptosis and increases mitochondrial capacity via an IGF1R/AXL-AKT axis. These results demonstrate that oncogene signaling should be viewed as a heterocellular process and that our existing cell-autonomous perspective underrepresents the extent of oncogene signaling in cancer. Video Abstract PMID:27087446

  16. Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation.

    PubMed

    Tape, Christopher J; Ling, Stephanie; Dimitriadi, Maria; McMahon, Kelly M; Worboys, Jonathan D; Leong, Hui Sun; Norrie, Ida C; Miller, Crispin J; Poulogiannis, George; Lauffenburger, Douglas A; Jørgensen, Claus

    2016-05-01

    Oncogenic mutations regulate signaling within both tumor cells and adjacent stromal cells. Here, we show that oncogenic KRAS (KRAS(G12D)) also regulates tumor cell signaling via stromal cells. By combining cell-specific proteome labeling with multivariate phosphoproteomics, we analyzed heterocellular KRAS(G12D) signaling in pancreatic ductal adenocarcinoma (PDA) cells. Tumor cell KRAS(G12D) engages heterotypic fibroblasts, which subsequently instigate reciprocal signaling in the tumor cells. Reciprocal signaling employs additional kinases and doubles the number of regulated signaling nodes from cell-autonomous KRAS(G12D). Consequently, reciprocal KRAS(G12D) produces a tumor cell phosphoproteome and total proteome that is distinct from cell-autonomous KRAS(G12D) alone. Reciprocal signaling regulates tumor cell proliferation and apoptosis and increases mitochondrial capacity via an IGF1R/AXL-AKT axis. These results demonstrate that oncogene signaling should be viewed as a heterocellular process and that our existing cell-autonomous perspective underrepresents the extent of oncogene signaling in cancer. VIDEO ABSTRACT. PMID:27087446

  17. Influence of Cancer-Associated Endometrial Stromal Cells on Hormone-Driven Endometrial Tumor Growth

    PubMed Central

    Pineda, M. J.; Lu, Z.; Cao, D.

    2016-01-01

    Cancer-associated fibroblasts have been shown to inhibit or stimulate tumor growth depending on stage, grade, and tumor type. It remains unclear, however, the effect of endometrial-cancer-associated fibroblasts on hormone-driven responses in endometrial cancer. In this study, we investigated the effect of normal and cancer-associated stromal cells from patients with and without endometrial cancer on endometrial tumor growth in response to estradiol (E2) and progesterone (P4). Compared to benign endometrial stromal cells, the low-grade and high-grade cancer-associated stromal cells exhibited a blunted hormone response for proliferation as well as IGFBP1 secretion. Additional analysis of the influence of stromal cells on hormone-driven tumor growth was done by mixing stromal cells from benign, low-grade, or high-grade tumors, with Ishikawa cells for subcutaneous tumor formation. The presence of both benign and high-grade cancer-associated stromal cells increased estradiol-driven xenografted tumor growth compared to Ishikawa cells alone. Low-grade cancer-associated stromal cells did not significantly influence hormone-regulated tumor growth. Addition of P4 attenuated tumor growth in Ishikawa + benign or high-grade stromal cells, but not in Ishikawa cells alone or with low-grade stromal cells. Using an angiogenesis focused real-time array TGFA, TGFB2 and TGFBR1 and VEGFC were identified as potential candidates for hormone-influenced growth regulation of tumors in the presence of benign and high-grade stromal cells. In summary, endometrial-cancer-associated cells responded differently to in vitro hormone treatment compared to benign endometrial stromal cells. Additionally, presence of stromal cells differentially influenced hormone-driven xenograft growth in vivo depending on the disease status of the stromal cells. PMID:25976290

  18. Dissecting Tumor-Stromal Interactions in Breast Cancer Bone Metastasis.

    PubMed

    Kang, Yibin

    2016-06-01

    Bone metastasis is a frequent occurrence in breast cancer, affecting more than 70% of late stage cancer patients with severe complications such as fracture, bone pain, and hypercalcemia. The pathogenesis of osteolytic bone metastasis depends on cross-communications between tumor cells and various stromal cells residing in the bone microenvironment. Several growth factor signaling pathways, secreted micro RNAs (miRNAs) and exosomes are functional mediators of tumor-stromal interactions in bone metastasis. We developed a functional genomic approach to systemically identified molecular pathways utilized by breast cancer cells to engage the bone stroma in order to generate osteolytic bone metastasis. We showed that elevated expression of vascular cell adhesion molecule 1 (VCAM1) in disseminated breast tumor cells mediates the recruitment of pre-osteoclasts and promotes their differentiation to mature osteoclasts during the bone metastasis formation. Transforming growth factor β (TGF-β) is released from bone matrix upon bone destruction, and signals to breast cancer to further enhance their malignancy in developing bone metastasis. We furthered identified Jagged1 as a TGF-β target genes in tumor cells that engaged bone stromal cells through the activation of Notch signaling to provide a positive feedback to promote tumor growth and to activate osteoclast differentiation. Substantially change in miRNA expression was observed in osteoclasts during their differentiation and maturation, which can be exploited as circulating biomarkers of emerging bone metastasis and therapeutic targets for the treatment of bone metastasis. Further research in this direction may lead to improved diagnosis and treatment strategies for bone metastasis. PMID:27184014

  19. Dissecting Tumor-Stromal Interactions in Breast Cancer Bone Metastasis

    PubMed Central

    2016-01-01

    Bone metastasis is a frequent occurrence in breast cancer, affecting more than 70% of late stage cancer patients with severe complications such as fracture, bone pain, and hypercalcemia. The pathogenesis of osteolytic bone metastasis depends on cross-communications between tumor cells and various stromal cells residing in the bone microenvironment. Several growth factor signaling pathways, secreted micro RNAs (miRNAs) and exosomes are functional mediators of tumor-stromal interactions in bone metastasis. We developed a functional genomic approach to systemically identified molecular pathways utilized by breast cancer cells to engage the bone stroma in order to generate osteolytic bone metastasis. We showed that elevated expression of vascular cell adhesion molecule 1 (VCAM1) in disseminated breast tumor cells mediates the recruitment of pre-osteoclasts and promotes their differentiation to mature osteoclasts during the bone metastasis formation. Transforming growth factor β (TGF-β) is released from bone matrix upon bone destruction, and signals to breast cancer to further enhance their malignancy in developing bone metastasis. We furthered identified Jagged1 as a TGF-β target genes in tumor cells that engaged bone stromal cells through the activation of Notch signaling to provide a positive feedback to promote tumor growth and to activate osteoclast differentiation. Substantially change in miRNA expression was observed in osteoclasts during their differentiation and maturation, which can be exploited as circulating biomarkers of emerging bone metastasis and therapeutic targets for the treatment of bone metastasis. Further research in this direction may lead to improved diagnosis and treatment strategies for bone metastasis. PMID:27184014

  20. Multipotent Mesenchymal Stromal Cells: Possible Culprits in Solid Tumors?

    PubMed Central

    Johann, Pascal David; Müller, Ingo

    2015-01-01

    The clinical use of bone marrow derived multipotent mesenchymal stromal cells (BM-MSCs) in different settings ranging from tissue engineering to immunotherapies has prompted investigations on the properties of these cells in a variety of other tissues. Particularly the role of MSCs in solid tumors has been the subject of many experimental approaches. While a clear phenotypical distinction of tumor associated fibroblasts (TAFs) and MSCs within the tumor microenvironment is still missing, the homing of bone marrow MSCs in tumor sites has been extensively studied. Both, tumor-promoting and tumor-inhibiting effects of BM-MSCs have been described in this context. This ambiguity requires a reappraisal of the different studies and experimental methods employed. Here, we review the current literature on tumor-promoting and tumor-inhibiting effects of BM-MSCs with a particular emphasis on their interplay with components of the immune system and also highlight a potential role of MSCs as cell of origin for certain mesenchymal tumors. PMID:26273308

  1. Study of the Glutaminase Inhibitor CB-839 in Solid Tumors

    ClinicalTrials.gov

    2016-08-18

    Solid Tumors; Triple-Negative Breast Cancer; Non Small Cell Lung Cancer; Renal Cell Carcinoma; Mesothelioma; Fumarate Hydratase (FH)-Deficient Tumors; Succinate Dehydrogenase (SDH)-Deficient Gastrointestinal Stromal Tumors (GIST); Succinate Dehydrogenase (SDH)-Deficient Non-gastrointestinal Stromal Tumors; Tumors Harboring Isocitrate Dehydrogenase-1 (IDH1) and IDH2 Mutations; Tumors Harboring Amplifications in the cMyc Gene

  2. Laparoscopic excision of large lower rectal gastrointestinal stromal tumour (GIST): A case report

    PubMed Central

    Somu, Karthik; Dashore, Amit R.; Shah, Aashish R.; Anandh, Rajiv

    2016-01-01

    Gastrointestinal stromal tumour (GIST) involving rectum is rare. No definite method of treatment has been established because of a small number of cases being reported. It is usually managed with invasive or ablative surgery, such as abdominoperineal resection (APR). The acceptance of minimally invasive (laparoscopic) surgery in colorectal disease plays a pivotal role in improving the postoperative quality of life. We report a case of a large lower rectal GIST who underwent laparoscopic excision of tumour through a subserosal approach whilst preserving the anal sphincter and without any rectal resection. PMID:27279404

  3. Cooperative laparoscopic endoscopic and hybrid laparoscopic surgery for upper gastrointestinal tumors: Current status

    PubMed Central

    Ntourakis, Dimitrios; Mavrogenis, Georgios

    2015-01-01

    AIM: To investigate the cooperative laparoscopic and endoscopic techniques used for the resection of upper gastrointestinal tumors. METHODS: A systematic research of the literature was performed in PubMed for English and French language articles about laparoscopic and endoscopic cooperative, combined, hybrid and rendezvous techniques. Only original studies using these techniques for the resection of early gastric cancer, benign tumors and gastrointestinal stromal tumors of the stomach and the duodenum were included. By excluding case series of less than 10 patients, 25 studies were identified. The study design, number of cases, tumor pathology size and location, the operative technique name, the endoscopy team and surgical team role, operative time, type of closure of visceral wall defect, blood loss, complications and length of hospital stay of these studies were evaluated. Additionally all cooperative techniques found were classified and are presented in a systematic approach. RESULTS: The studies identified were case series and retrospective cohort studies. A total of 706 patients were operated on with a cooperative technique. The tumors resected were only gastrointestinal stromal tumors (GIST) in 4 studies, GIST and various benign submucosal tumors in 22 studies, early gastric cancer (pT1a and pT1b) in 6 studies and early duodenal cancer in 1 study. There was important heterogeneity between the studies. The operative techniques identified were: laparoscopic assisted endoscopic resection, endoscopic assisted wedge resection, endoscopic assisted transgastric and intragastric surgery, laparoscopic endoscopic cooperative surgery (LECS), laparoscopic assisted endoscopic full thickness resection (LAEFR), clean non exposure technique and non-exposed endoscopic wall-inversion surgery (NEWS). Each technique is illustrated with the roles of the endoscopic and laparoscopic teams; the indications, characteristics and short term results are described. CONCLUSION: Along with

  4. Irinotecan, Fluorouracil, and Leucovorin in Treating Patients With Advanced Gastrointestinal Cancer

    ClinicalTrials.gov

    2016-04-19

    Anal Cancer; Carcinoma of the Appendix; Colorectal Cancer; Esophageal Cancer; Extrahepatic Bile Duct Cancer; Gallbladder Cancer; Gastric Cancer; Gastrointestinal Carcinoid Tumor; Gastrointestinal Stromal Tumor; Liver Cancer; Pancreatic Cancer; Small Intestine Cancer

  5. Mesenchymal Stem Cell-Based Tumor-Targeted Gene Therapy in Gastrointestinal Cancer

    PubMed Central

    Bao, Qi; Zhao, Yue; Niess, Hanno; Conrad, Claudius; Schwarz, Bettina; Jauch, Karl-Walter; Huss, Ralf; Nelson, Peter J.

    2012-01-01

    Mesenchymal stem (or stromal) cells (MSCs) are nonhematopoietic progenitor cells that can be obtained from bone marrow aspirates or adipose tissue, expanded and genetically modified in vitro, and then used for cancer therapeutic strategies in vivo. Here, we review available data regarding the application of MSC-based tumor-targeted therapy in gastrointestinal cancer, provide an overview of the general history of MSC-based gene therapy in cancer research, and discuss potential problems associated with the utility of MSC-based therapy such as biosafety, immunoprivilege, transfection methods, and distribution in the host. PMID:22530882

  6. Resolving Cancer-Stroma Interfacial Signaling and Interventions with Micropatterned Tumor-Stromal Assays

    PubMed Central

    Shen, Keyue; Luk, Samantha; Hicks, Daniel F; Elman, Jessica S; Bohr, Stefan; Iwamoto, Yoshiko; Murray, Ryan; Pena, Kristen; Wang, Fangjing; Seker, Erkin; Weissleder, Ralph; Yarmush, Martin L; Toner, Mehmet; Sgroi, Dennis; Parekkadan, Biju

    2014-01-01

    Tumor-stromal interactions are a determining factor in cancer progression. In vivo, the interaction interface is associated with spatially-resolved distributions of cancer and stromal phenotypes. Here, we establish a micropatterned tumor-stromal assay (μTSA) with laser capture microdissection to control the location of co-cultured cells and analyze bulk and interfacial tumor-stromal signaling in driving cancer progression. μTSA reveals a spatial distribution of phenotypes in concordance with human estrogen receptor-positive (ER+) breast cancer samples, and heterogeneous drug activity relative to the tumor-stroma interface. Specifically, an unknown mechanism of reversine is shown in targeting tumor-stromal interfacial interactions using ER+ MCF-7 breast cancer and bone marrow-derived stromal cells. Reversine suppresses MCF-7 tumor growth and bone metastasis in vivo by reducing tumor stromalization including collagen deposition and recruitment of activated stromal cells. This study advocates μTSA as a platform for studying tumor microenvironmental interactions and cancer field effects with applications in drug discovery and development. PMID:25489927

  7. Tissue microarrays characterise the clinical significance of a VEGF-A protein expression signature in gastrointestinal stromal tumours

    PubMed Central

    Salto-Tellez, M; Nga, M E; Han, H C; Wong, A S-C; Lee, C K; Anuar, D; Ng, S S; Ho, M; Wee, A; Chan, Y H; Soong, R

    2007-01-01

    A tissue microarray analysis of 22 proteins in gastrointestinal stromal tumours (GIST), followed by an unsupervised, hierarchical monothetic cluster statistical analysis of the results, allowed us to detect a vascular endothelial growth factor (VEGF) protein overexpression signature discriminator of prognosis in GIST, and discover novel VEGF-A DNA variants that may have functional significance. PMID:17299397

  8. The stromal genome heterogeneity between breast and prostate tumors revealed by a comparative transcriptomic analysis.

    PubMed

    He, Kan; Lv, Wenwen; Zheng, Dongni; Cheng, Fei; Zhou, Tao; Ye, Shoudong; Ban, Qian; Ying, Qilong; Huang, Bei; Chen, Lei; Wu, Guohua; Liu, Dahai

    2015-04-20

    Stromal microenvironment increases tumor cell survival, proliferation and migration, and promotes angiogenesis. In order to provide comprehensive information on the stromal heterogeneity of diverse tumors, here we employed the microarray datasets of human invasive breast and prostate cancer-associated stromals and applied Gene Set Enrichment Analysis (GSEA) to compare the gene expression profiles between them. As a result, 8 up-regulated pathways and 73 down-regulated pathways were identified in the breast tumor stroma, while 32 up-regulated pathways and 18 down-regulated pathways were identified in the prostate tumor stroma. Only 9 pathways such as tryptophan metabolism were commonly up or down regulated, but most of them (including ABC transporters) were specific for these two tumors. Several essential tumors stromal marker genes were also significantly identified. For example, CDH3 was significantly up-regulated in the stromals of both breast and prostate tumors, however EGFR was only significantly down-regulated in the stromal of breast tumor. Our study would be helpful for future therapeutic and predictive applications in breast and prostate cancers. PMID:25826086

  9. Huge Perineal Tumour: A Rare Presentation of Gastrointestinal Stromal Tumour of Rectum.

    PubMed

    Nahar, K; Salahuddin, G M; Islam, M R; Islam, M S; Quddus, M A; Islam, M A; Debnath, B C

    2016-04-01

    Gastrointestinal stromal tumour (GIST) is a relatively rare neoplasm of gastrointestinal tract of which Rectal GIST is uncommon. It produces symptoms of per rectal bleeding or change in bowel habit. Recurrences following curative resection are predominantly intraabdominal, hepatic metastasis occurring at a median 20-25 months following the primary surgery. A 42 years old male presented a huge mass in hypogastrium, the size of which was reduced ofter neoadjuvant therapy for period of 1.5 years. He underwent abdominoperineal resection. He developed recurrences in perineum three times and in thigh at short intervals after primary resection. He also developed liver metastasis. He died two and half years after primary diagnosis. Rectal GIST should be included in differential diagnosis of intraabdominal mass and preoperative diagnosis based on histopathological as well as the immunohistochemical feature of the CD(117) and CD(34). Although complete surgical resection with negative tumour margin is the principal curative procedure for primary and non metastatic tumours, further studies are still needed for the determination of the most effective treatment strategy for patients of rectal GIST. PMID:27277373

  10. Gastrointestinal stromal tumour masquerading as a cyst in the lesser sac

    PubMed Central

    Hamza, Ahmed Mahmoud; Ayyash, Emad Helmi; Alzafiri, Raed; Francis, Issam; Asfar, Sami

    2016-01-01

    Gastrointestinal stromal tumours (GISTs) are solid tumours of the gastrointestinal tract, mostly found in the stomach and intestine. They rarely present as cystic lesions. A 74-year-old woman referred to the hepatopancreaticobiliary unit, with 3 months history of upper abdominal discomfort. Abdominal ultrasound scan showed a large cystic lesion in the epigastric region suggestive of a pancreatic pseudocyst. The CT-scan showed a 6.6×6×6.3 cm size cyst related to the pancreas and extending to the hepatogastric omentum. Endoscopic ultrasound (EUS) scan was suggestive of a pancreatic pseudocyst. Aspirated Cyst fluid via EUS showed benign cytology with normal amylase, lipase and tumour markers (CEA, CA-19.9 and CA-125). She was referred as a case of pancreatic pseudocyst. After surgical excision, the histopathology confirmed the presence GIST in the wall of the cystic lesion. The possibility of GIST should be kept in mind in the presence of unusual features of a cyst on abdominal imaging. PMID:27469382

  11. Management of Gastrointestinal Stromal Tumour: Current Practices and Visions for the Future.

    PubMed

    Blay, Jean-Yves; Casali, Paolo G; Dei Tos, Angelo Paolo; Le Cesne, Axel; Reichardt, Peter

    2015-01-01

    Gastrointestinal stromal tumour (GIST), while relatively rare, is the most common mesenchymal tumour of the gastrointestinal tract. These tumours are largely resistant to cytotoxic chemotherapy and, in the past, were typically managed surgically. However, as a result of the identification of activating mutations in the proto-oncogene KIT and the development of compounds that inhibit the KIT receptor tyrosine kinase, GISTs have, in the last 14 years, become the archetype of a targeted agent-responsive tumour. Due to the almost continual emergence of new data from clinical trials and other studies on GIST diagnosis and treatment, the management of this disease requires regular review. The 2013 ArcheoloGIST summit was convened in Prague, Czech Republic. Interaction between attending physicians and the expert faculty was a core component of the summit. The current article is based on discussions held during two interactive sessions at ArcheoloGIST 2013 in which the authors aimed to: (1) reach a consensus on the current management of GIST and (2) provide a vision for the future diagnosis and treatment of this disease. PMID:25720422

  12. Gastrointestinal stromal tumour masquerading as a cyst in the lesser sac.

    PubMed

    Hamza, Ahmed Mahmoud; Ayyash, Emad Helmi; Alzafiri, Raed; Francis, Issam; Asfar, Sami

    2016-01-01

    Gastrointestinal stromal tumours (GISTs) are solid tumours of the gastrointestinal tract, mostly found in the stomach and intestine. They rarely present as cystic lesions. A 74-year-old woman referred to the hepatopancreaticobiliary unit, with 3 months history of upper abdominal discomfort. Abdominal ultrasound scan showed a large cystic lesion in the epigastric region suggestive of a pancreatic pseudocyst. The CT-scan showed a 6.6×6×6.3 cm size cyst related to the pancreas and extending to the hepatogastric omentum. Endoscopic ultrasound (EUS) scan was suggestive of a pancreatic pseudocyst. Aspirated Cyst fluid via EUS showed benign cytology with normal amylase, lipase and tumour markers (CEA, CA-19.9 and CA-125). She was referred as a case of pancreatic pseudocyst. After surgical excision, the histopathology confirmed the presence GIST in the wall of the cystic lesion. The possibility of GIST should be kept in mind in the presence of unusual features of a cyst on abdominal imaging. PMID:27469382

  13. Pancreatic extragastrointestinal stromal tumor: A case report and comprehensive literature review

    PubMed Central

    Akbulut, Sami; Yavuz, Rıdvan; Otan, Emrah; Hatipoglu, Sinan

    2014-01-01

    AIM: To provide an overview of the literature on pancreatic extragastrointestinal stromal tumors (EGISTs). METHODS: We report a case of pancreatic EGIST and review published studies on pancreatic EGIST accessed via the PubMed, MEDLINE, Google Scholar, and Google databases. The keywords used were “pancreas and GIST”, “pancreas and extra GIST”, “pancreas and gastrointestinal stromal tumor”, and “pancreas and extragastrointestinal stromal tumor”. Literature reviews and/or duplicate studies were excluded. The search included articles published in the English language between January 1, 2000 and May 15, 2014. RESULTS: From our literature survey, 30 manuscripts on pancreatic EGISTs were considered, of which 27 met the search criteria and three were excluded. The studies involved 30 patients (15 men, 15 women) with a mean age of 55.3 ± 14.3 years (range 30-84 years). The mean age of the male patients was 50.8 ± 13.7 years (range 30-84 years); that of the female patients was 59.9 ± 13.3 years (range 38-81 years). Tumor dimensions were obtained for 28 cases (mean 114.4 ± 78.6 mm; range 20-350 mm). Tumors were diagnosed incidentally in 23.3% of patients; abdominal discomfort and weight loss were the major complaints in symptomatic patients. Risk of aggressive behavior according to Fletcher criteria was determined in 25 of 30 patients (68%: high risk, 28%: intermediate risk, 4%: low risk). Histopathological examination revealed the presence of spindle cells in 96.1% of cases; CD117 and CD34 were present immunohistochemically in 96.6% and 84% of patients, respectively. The most common surgical procedures were distal pancreatectomy with splenectomy (n = 9) and pancreaticoduodenectomy (n = 7). The total follow-up period for the 28 patients ranged from 3-66 mo, during which locoregional or distant metastases were diagnosed in six patients and two patients died. CONCLUSION: Studies on EGISTs have only been published in the last decade. The lack of studies with

  14. What Happens After Treatment for Gastrointestinal Stromal Tumor?

    MedlinePlus

    ... or surgeries Copies of imaging tests (CT or MRI scans, etc.), which can usually be stored on a CD, DVD, etc. If you had surgery, a copy of your operative report(s) If you stayed in the hospital, a copy ...

  15. New Therapeutic Approaches for Advanced Gastrointestinal Stromal Tumors (GISTs)

    PubMed Central

    Somaiah, Neeta

    2010-01-01

    Synopsis The management of advanced GIST is increasingly complex due to imatinib refractory disease. Primary resistance to imatinib is uncommon, and most patients progress after development of additional genetic changes. This article reviews management strategies including surgical approaches, local modalities for progressive liver metastases, as well as novel therapeutic agents. PMID:19248977

  16. Do We Know What Causes Gastrointestinal Stromal Tumors?

    MedlinePlus

    ... a DNA mutation passed down from parent to child. But most DNA mutations related to GISTs are not inherited. These changes occur for no apparent reason, and are called acquired or sporadic . The cancer ...

  17. Primary extragastrointestinal stromal tumor arising in the vaginal wall: Significant clinicopathological characteristics of a rare aggressive soft tissue neoplasm.

    PubMed

    Liu, Qiu-Yu; Kan, Yun-Zhen; Zhang, Meng-Yang; Sun, Ting-Yi; Kong, Ling-Fei

    2016-04-16

    Gastrointestinal (GI) stromal tumor is the most common mesenchymal neoplasm of the GI tract but also occurs with a lower frequency in extragastrointestinal regions and is called extragastrointestinal stromal tumor (EGIST). We report an unusual case of EGIST presenting as a vaginal mass. A 41-year-old woman presented with a gradually enlarging vaginal mass for the last 2 years. Physical examination revealed an elliptical, non-tender mass about 7.5 cm × 7 cm in size in the posterior vaginal wall and was resected completely. Under histological examination, the tumor showed a spindle cell type with coagulation necrosis, hemorrhage and high mitotic count. Immunohistochemical analysis revealed tumor cells were positive for DOG1, CD117, CD34 and p53 protein. Ki-67 labeling was 8%. Genetic analysis showed a deletion of exon 11 of the c-kit gene at codons 557-558. EGISTs should be kept in mind in the differential diagnosis in patients presenting with solid mass of the vaginal wall. PMID:27099863

  18. Primary extragastrointestinal stromal tumor arising in the vaginal wall: Significant clinicopathological characteristics of a rare aggressive soft tissue neoplasm

    PubMed Central

    Liu, Qiu-Yu; Kan, Yun-Zhen; Zhang, Meng-Yang; Sun, Ting-Yi; Kong, Ling-Fei

    2016-01-01

    Gastrointestinal (GI) stromal tumor is the most common mesenchymal neoplasm of the GI tract but also occurs with a lower frequency in extragastrointestinal regions and is called extragastrointestinal stromal tumor (EGIST). We report an unusual case of EGIST presenting as a vaginal mass. A 41-year-old woman presented with a gradually enlarging vaginal mass for the last 2 years. Physical examination revealed an elliptical, non-tender mass about 7.5 cm × 7 cm in size in the posterior vaginal wall and was resected completely. Under histological examination, the tumor showed a spindle cell type with coagulation necrosis, hemorrhage and high mitotic count. Immunohistochemical analysis revealed tumor cells were positive for DOG1, CD117, CD34 and p53 protein. Ki-67 labeling was 8%. Genetic analysis showed a deletion of exon 11 of the c-kit gene at codons 557-558. EGISTs should be kept in mind in the differential diagnosis in patients presenting with solid mass of the vaginal wall. PMID:27099863

  19. Treatment of Gastrointestinal Carcinoid Tumors by Stage

    MedlinePlus

    ... partial gastrectomy) along with nearby lymph nodes. Small intestine Some small tumors in the duodenum (the first ... vessels and lymph nodes) for larger tumors. Large intestine (other than appendix and rectum) The usual treatment ...

  20. Treatment Options for Gastrointestinal Carcinoid Tumors

    MedlinePlus

    ... symptoms of GI carcinoid tumors in the jejunum (middle part of the small intestine) and ileum (last part ... Treatment of GI carcinoid tumors in the jejunum (middle part of the small intestine) and ileum (last part ...

  1. General Information about Gastrointestinal Carcinoid Tumors

    MedlinePlus

    ... symptoms of GI carcinoid tumors in the jejunum (middle part of the small intestine) and ileum (last part ... Treatment of GI carcinoid tumors in the jejunum (middle part of the small intestine) and ileum (last part ...

  2. Treatment Option Overview (Gastrointestinal Carcinoid Tumors)

    MedlinePlus

    ... symptoms of GI carcinoid tumors in the jejunum (middle part of the small intestine) and ileum (last part ... Treatment of GI carcinoid tumors in the jejunum (middle part of the small intestine) and ileum (last part ...

  3. How Are Gastrointestinal Carcinoid Tumors Diagnosed?

    MedlinePlus

    ... as symptoms that might be caused by a mass (tumor) in the stomach, intestines, or rectum. Some ... attention to the abdomen, looking for a tumor mass or enlarged liver. If your medical history and ...

  4. Thymic stromal lymphopoietin (TSLP) inhibits human colon tumor growth by promoting apoptosis of tumor cells

    PubMed Central

    Yang, Xuguang; Li, Bingji; Liu, Jie; He, Rui

    2016-01-01

    Thymic stromal lymphopoietin (TSLP) has recently been suggested in several epithelial cancers, either pro-tumor or anti-tumor. However, the role of TSLP in colon cancer remains unknown. We here found significantly decreased TSLP levels in tumor tissues compared with tumor-surrounding tissues of patients with colon cancer and TSLP levels negatively correlated with the clinical staging score of colon cancer. TSLPR, the receptor of TSLP, was expressed in all three colon cancer cell lines investigated and colon tumor tissues. The addition of TSLP significantly enhanced apoptosis of colon cancer cells in a TSLPR-dependent manner. Interestingly, TSLP selectively induced the apoptosis of colon cancer cells, but not normal colonic epithelial cells. Furthermore, we demonstrated that TSLP induced JNK and p38 activation and initiated apoptosis mainly through the extrinsic pathway, as caspase-8 inhibitor significantly reversed the apoptosis-promoting effect of TSLP. Finally, using a xenograft mouse model, we demonstrated that peritumoral administration of TSLP greatly reduced tumor growth accompanied with extensive tumor apoptotic response, which was abolished by tumor cell-specific knockdown of TSLPR. Collectively, our study reveals a novel anti-tumor effect of TSLP via direct promotion of the apoptosis of colon cancer cells, and suggests that TSLP could be of value in treating colon cancer. PMID:26919238

  5. Diagnostic procedures for submucosal tumors in the gastrointestinal tract

    PubMed Central

    Ponsaing, Laura Graves; Kiss, Katalin; Loft, Annika; Jensen, Lise Ingemann; Hansen, Mark Berner

    2007-01-01

    This review is part one of three, which will present an update on diagnostic procedures for gastrointestinal (GI) submucosal tumors (SMTs). Part two identifies the classification and part three the therapeutic methods regarding GI SMTs. Submucosal tumors are typically asymptomatic and therefore encountered incidentally. Advances in diagnostic tools for gastrointestinal submucosal tumors have emerged over the past decade. The aim of this paper is to provide the readers with guidelines for the use of diagnostic procedures, when a submucosal tumor is suspected. Literature searches were performed to find information on diagnostics for gastrointestinal submucosal tumors. Based on the searches, the optimal diagnostic procedures and specific features of the submucosal tumors could be outlined. Standard endoscppy, capsule endoscopy and push-and-pull enteroscopy (PPE) together with barium contrast X-ray do not alone provide sufficient information, when examining submucosal tumors. Endoscopic ultrasound (EUS), computed tomography (CT), magnetic resonance imaging (MRI) and fluorodeoxyglucose-labeled positron emission tomography (FDG-PET) are recommended as supplementary tools. PMID:17659668

  6. Transanal minimally invasive surgery (TAMIS) approach for large juxta-anal gastrointestinal stromal tumour

    PubMed Central

    Wachter, Nicolas; Wörns, Marcus-Alexander; dos Santos, Daniel Pinto; Lang, Hauke; Huber, Tobias; Kneist, Werner

    2016-01-01

    Gastrointestinal stromal tumours (GISTs) are rarely found in the rectum. Large rectal GISTs in the narrow pelvis sometimes require extended abdominal surgery to obtain free resection margins, and it is a challenge to preserve sufficient anal sphincter and urogenital function. Here we present a 56-year-old male with a locally advanced juxta-anal non-metastatic GIST of approximately 10 cm in diameter. Therapy with imatinib reduced the tumour size and allowed partial intersphincteric resection (pISR). The patient underwent an electrophysiology-controlled nerve-sparing hybrid of laparoscopic and transanal minimally invasive surgery (TAMIS) in a multimodal setting. The down-to-up approach provided sufficient dissection plane visualisation and allowed the confirmed nerve-sparing. Lateroterminal coloanal anastomosis was performed. Follow-up showed preserved urogenital function and good anorectal function, and the patient remains disease-free under adjuvant chemotherapy as of 12 months after surgery. This report suggests that the TAMIS approach enables extraluminal high-quality oncological and function-preserving excision of high-risk GISTs. PMID:27279406

  7. Targeting Human Gastrointestinal Stromal Tumour Cells with a Quadruplex-binding Small Molecule

    PubMed Central

    Gunaratnam, Mekala; Beltran, Monica; Galesa, Katja; Haider, Shozeb M.; Reszka, Anthony P.; Cuenca, Francisco; Fletcher, Jonathan A.; Neidle, Stephen

    2010-01-01

    The majority of human gastrointestinal stromal tumours (GIST) are driven by activating mutations in the proto-oncogene KIT, a tyrosine kinase receptor. Clinical treatment with imatinib targets the kinase domain of KIT, but tumour regrowth occurs as a result of the development of resistant mutations in the kinase active site. An alternative small-molecule approach to GIST therapy is described, in which the KIT gene is directly targeted, and thus kinase resistance may be circumvented. A naphthalene dimiide derivative has been used to demonstrate the concept of dual quadruplex targeting. This compound strongly stabilises both telomeric quadruplex DNA and quadruplex sites in the KIT promoter in vitro. It is shown here that the compound is a potent inducer of growth arrest in a patient-derived GIST cell line at a concentration (ca 1μM) that also results in effective inhibition of telomerase activity and almost complete suppression of KIT mRNA and KIT protein expression. Molecular modelling studies with a telomeric quadruplex have been used to rationalise aspects of the experimental quadruplex melting data. PMID:19469547

  8. Molecular and morphological correlation in gastrointestinal stromal tumours (GISTs): an update and primer.

    PubMed

    Chetty, Runjan; Serra, Stefano

    2016-09-01

    Gastrointestinal stromal tumours (GISTs) are a commonly encountered tumour in routine practice. In the main, the morphology of spindle, epithelioid or mixed are well recognised along with mutations of c-kit However, there are other genes that are mutated resulting in characteristic clinicopathological correlations. GISTs harbouring platelet-derived growth factor receptor α (PDGFRα) gene mutations lead to a typical morphological constellation of findings: gastric and omental location, gross tumour that is cystic and haemorrhagic, composed of epithelioid, plasmacytoid cells exhibiting pleomorphism, low mitotic count and containing characteristic giant cells with peripherally placed nuclei. These cells are set in a myxoid stroma containing several mast cells. In addition, perivascular/intratumoural hyalinisation is often seen. These tumours are CD117 and DOG-1 positive. GISTs with SDH mutations are multinodular/bilobed/dumb-bell shape tumour masses with mucosal ulceration and histologically characterised by fibrous bands around and within nodules of epithelioid or mixed epithelioid/spindle cells. Lymphovascular invasion with lymph node metastases are usual. Immunohistochemically, the GISTs are CD117, DOG-1 positive, SDHA negative (if SDHA mutated), SDHA positive (if SDHA intact) and SDHB negative. BRAF and NF-1 mutated GISTs do not have any characteristic morphological features. PMID:27317811

  9. Endoscopic resection of superficial gastrointestinal tumors

    PubMed Central

    Marc, Giovannini; Lopes, Cesar Vivian

    2008-01-01

    Therapeutic endoscopy plays a major role in the management of gastrointestinal (GI) neoplasia. Its indications can be generalized into four broad categories; to remove or obliterate neoplastic lesion, to palliate malignant obstruction, or to treat bleeding. Only endoscopic resection allows complete histological staging of the cancer, which is critical as it allows stratification and refinement for further treatment. Although other endoscopic techniques, such as ablation therapy, may also cure early GI cancer, they can not provide a definitive pathological specimen. Early stage lesions reveal low frequency of lymph node metastasis which allows for less invasive treatments and thereby improving the quality of life when compared to surgery. Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are now accepted worldwide as treatment modalities for early cancers of the GI tract. PMID:18698673

  10. Analysis of c-KIT exon 11 mutations in canine gastrointestinal stromal tumours.

    PubMed

    Takanosu, M; Amano, S; Kagawa, Y

    2016-01-01

    The aim of this study was to determine the type and frequency of c-KIT exon 11 mutations in canine gastrointestinal stromal tumours (GISTs) and investigate the association between the c-KIT mutation status and KIT immunohistochemical staining pattern. Mutations in exon 11 of c-KIT were examined in 46 formalin-fixed paraffin-embedded canine GISTs using PCR of genomic DNA and reverse transcription-PCR (RT-PCR) of cDNA. Exon 11 c-KIT mutations were detected in 15/46 (32.6%) cases by conventional PCR and 34/46 (73.9%) cases by RT-PCR; the mutation detection rate was significantly higher for RT-PCR (P = 0.004, Fisher's exact test). Ten different mutations, including deletion, internal tandem duplication and point mutations, were identified by RT-PCR. Immunohistochemistry was performed using an anti-KIT antibody; diffuse KIT staining was detected in the tumour cell cytoplasm in 32/46 (69.6%) cases and partial or stippled cytoplasmic staining of KIT was observed in 14/46 (30.4%) cases. Neither pattern was significantly associated with c-KIT exon 11 mutation status (P = 1.000, chi-square test). These data indicate that c-KIT exon 11 mutations occur frequently in canine GISTs, similar to human GISTs; however, there is no association between c-KIT mutations and the KIT expression pattern in canine GISTs. This study suggests that RT-PCR is more sensitive than conventional PCR for the detection of c-KIT mutations in canine GISTs. PMID:26631948

  11. microRNA expression signatures of gastrointestinal stromal tumours: associations with imatinib resistance and patient outcome

    PubMed Central

    Akçakaya, P; Caramuta, S; Åhlen, J; Ghaderi, M; Berglund, E; Östman, A; Bränström, R; Larsson, C; Lui, W-O

    2014-01-01

    Background: Gastrointestinal stromal tumour (GIST) is mainly initialised by receptor tyrosine kinase gene mutations. Although the tyrosine kinase inhibitor imatinib mesylate considerably improved the outcome of patients, imatinib resistance still remains a major therapeutic challenge in GIST therapy. Herein we evaluated the clinical impact of microRNAs in imatinib-treated GISTs. Methods: The expression levels of microRNAs were quantified using microarray and RT–qPCR in GIST specimens from patients treated with neoadjuvant imatinib. The functional roles of miR-125a-5p and PTPN18 were evaluated in GIST cells. PTPN18 expression was quantified by western blotting in GIST samples. Results: We showed that overexpression levels of miR-125a-5p and miR-107 were associated with imatinib resistance in GIST specimens. Functionally, miR-125a-5p expression modulated imatinib sensitivity in GIST882 cells with a homozygous KIT mutation but not in GIST48 cells with double KIT mutations. Overexpression of miR-125a-5p suppressed PTPN18 expression, and silencing of PTPN18 expression increased cell viability in GIST882 cells upon imatinib treatment. PTPN18 protein levels were significantly lower in the imatinib-resistant GISTs and inversely correlated with miR-125a-5p. Furthermore, several microRNAs were significantly associated with metastasis, KIT mutational status and survival. Conclusions: Our findings highlight a novel functional role of miR-125a-5p on imatinib response through PTPN18 regulation in GIST. PMID:25349971

  12. [Early Diagnosis And Endoscopic Minimally Invasive Treatment of Gastrointestinal Tumor].

    PubMed

    Wang, Yi-ping; Wu, Jun-chao

    2015-11-01

    Gastrointestinal tumor could be aggressive and life threaten if it was not be diagnosed and treated at early stage. Digestive endoscopy plays a very important role in the early diagnosis and treatment of gastrointestinal tumor, and shows rapid evolution with novel technologies in the past years, such as endoscopic ultrasonography, magnifying endoscopy, electronic staining endoscopy, endoscopic confocal laser microscopy. Nowaday it becomes feasible to learn more about the endoscopic manifestation in early stage GI tumor. Besides, several new endoscopic surgical techniques, such as endoscopic submucosal dissection (ESD), endoscopicsubmucosal tunnel dissection (ESTD), submucosal tunneling endoscopic resection (STER), has been applied in clinical treatment of early stage GI tumor with curative effect. However, there are some new problems emerged, such as how to determine the depth of the lesion, how to avoid or reduce the incidence of postoperative complications, and how to standardize the pathological classification and the treatment of positive margin, which need multidisciplinary solution with the efforts from endoscopist, clinician and pathologist. With the deep insight on, molecular pathogenesis of GI tumor, new technologies combinding endoscopy, imaging and pathological measures, will promote more GI tumor early diagnosed and effectively treated, thus improve the survival and prognosis of GI tumor patients. PMID:26867326

  13. Loss of stromal JUNB does not affect tumor growth and angiogenesis.

    PubMed

    Braun, Jennifer; Strittmatter, Karin; Nübel, Tobias; Komljenovic, Dorde; Sator-Schmitt, Melanie; Bäuerle, Tobias; Angel, Peter; Schorpp-Kistner, Marina

    2014-03-15

    The transcription factor AP-1 subunit JUNB has been shown to play a pivotal role in angiogenesis. It positively controls angiogenesis by regulating Vegfa as well as the transcriptional regulator Cbfb and its target Mmp13. In line with these findings, it has been demonstrated that tumor cell-derived JUNB promotes tumor growth and angiogenesis. In contrast to JUNB's function in tumor cells, the role of host-derived stromal JUNB has not been elucidated so far. Here, we show that ablation of Junb in stromal cells including endothelial cells (ECs), vascular smooth muscle cells (SMCs) and fibroblasts does not affect tumor growth in two different syngeneic mouse models, the B16-F1 melanoma and the Lewis lung carcinoma model. In-depth analyses of the tumors revealed that tumor angiogenesis remains unaffected as assessed by measurements of the microvascular density and relative blood volume in the tumor. Furthermore, we could show that the maturation status of the tumor vasculature, analyzed by the SMC marker expression, α-smooth muscle actin and Desmin, as well as the attachment of pericytes to the endothelium, is not changed upon ablation of Junb. Taken together, these results indicate that the pro-angiogenic functions of stromal JUNB are well compensated with regard to tumor angiogenesis and tumor growth. PMID:24027048

  14. The activity of paclitaxel in gastrointestinal tumors.

    PubMed

    Ajani, J A; Ilson, D H; Kelsen, D P

    1995-10-01

    Gastrointestinal malignancies, which are common around the world, are relatively refractory to available cancer chemotherapeutic agents, necessitating a search for new agents able to improve palliation and survival of patients with advanced disease. Currently, metastatic or local-regional unresectable carcinoma of the esophagus or gastroesophageal junction carries a dismal prognosis. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), a new mitotic spindle inhibitor, has been studied in patients with advanced gastrointestinal carcinoma. In this phase II National Cancer Institute-sponsored study, previously untreated patients with unresectable local-regional or metastatic carcinoma of the esophagus or gastroesophageal junction (either squamous cell carcinoma or adenocarcinoma) received a starting dose of paclitaxel of 250 mg/m2 administered by a 24-hour intravenous infusion (with premedication) repeated every 21 days; all patients received subcutaneous granulocyte colony-stimulating factor 5 micrograms/kg daily 24 hours after the completion of the paclitaxel infusion. Fifty-one of 53 patients were assessable for response and response duration. Thirty-three patients had adenocarcinoma and 18 had squamous cell carcinoma. Sixteen (31%) patients achieved a response (one complete and 15 partial) and 11 (22%) achieved a minor response. Among 33 patients with adenocarcinoma, 12 (36%; 95% confidence interval, 14% to 58%) achieved either a complete (one patient) or partial (11 patients) response and six patients (18%) had a minor response. Four (22%; 95% confidence interval, 3% to 41%) of 18 patients with squamous cell carcinoma had a partial response and four (22%) had a minor response. At a median follow-up of 12+ months, 28 patients remain alive with an actuarial median survival duration of 10.2 months (range, 2 to 20+ months). These data suggest that paclitaxel is active against adenocarcinoma as well as squamous cell carcinoma of the esophagus. In a

  15. Inhibition of tumor-stromal interaction through HGF/Met signaling by valproic acid

    SciTech Connect

    Matsumoto, Yohsuke; Motoki, Takahiro; Kubota, Satoshi; Takigawa, Masaharu; Tsubouchi, Hirohito; Gohda, Eiichi

    2008-02-01

    Hepatocyte growth factor (HGF), which is produced by surrounding stromal cells, including fibroblasts and endothelial cells, has been shown to be a significant factor responsible for cancer cell invasion mediated by tumor-stromal interactions. We found in this study that the anti-tumor agent valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, strongly inhibited tumor-stromal interaction. VPA inhibited HGF production in fibroblasts induced by epidermal growth factor (EGF), platelet-derived growth factor, basic fibroblast growth factor, phorbol 12-myristate 13-acetate (PMA) and prostaglandin E{sub 2} without any appreciable cytotoxic effect. Other HDAC inhibitors, including butyric acid and trichostatin A (TSA), showed similar inhibitory effects on HGF production stimulated by various inducers. Up-regulations of HGF gene expression induced by PMA and EGF were also suppressed by VPA and TSA. Furthermore, VPA significantly inhibited HGF-induced invasion of HepG2 hepatocellular carcinoma cells. VPA, however, did not affect the increases in phosphorylation of MAPK and Akt in HGF-treated HepG2 cells. These results demonstrated that VPA inhibited two critical processes of tumor-stromal interaction, induction of fibroblastic HGF production and HGF-induced invasion of HepG2 cells, and suggest that those activities serve for other anti-tumor mechanisms of VPA besides causing proliferation arrest, differentiation, and/or apoptosis of tumor cells.

  16. Nested stromal epithelial tumor of liver presenting with Cushing syndrome: a rare case report.

    PubMed

    Geramizadeh, Bita; Foroutan, Hamidreza; Foroutan, Ali; Bordbar, Mohammadreza

    2012-01-01

    Nested stromal and epithelial tumor of the liver is an extremely rare pediatric hepatic tumor. To the best of our knowledge, about 25 cases have been reported in the English literature so far, few of which accompanied with Cushing syndrome. Herein we report our experience with an 8-year-old boy presented with Cushing's syndrome because of ectopic ACTH production by this tumor. PMID:22771659

  17. Reliability of nutritional assessment in patients with gastrointestinal tumors.

    PubMed

    Poziomyck, Aline Kirjner; Fruchtenicht, Ana Valeria Gonçalves; Kabke, Georgia Brum; Volkweis, Bernardo Silveira; Antoniazzi, Jorge Luiz; Moreira, Luis Fernando

    2016-01-01

    Patients with gastrointestinal cancer and malnutrition are less likely to tolerate major surgical procedures, radiotherapy or chemotherapy. In general, they display a higher incidence of complications such as infection, dehiscence and sepsis, which increases the length of stay and risk of death, and reduces quality of life. The aim of this review is to discuss the pros and cons of different points of view to assess nutritional risk in patients with gastrointestinal tract (GIT) tumors and their viability, considering the current understanding and screening approaches in the field. A better combination of anthropometric, laboratory and subjective evaluations is needed in patients with GIT cancer, since malnutrition in these patients is usually much more severe than in those patients with tumors at sites other than the GIT. RESUMO Pacientes com neoplasia gastrointestinal e desnutridos são menos propensos a tolerar procedimentos cirúrgicos de grande porte, radioterapia ou quimioterapia. Em geral, apresentam maior incidência de complicações, como infecção, deiscência e sepse, o que aumenta o tempo de internação e o risco de morte, e reduz a qualidade de vida. O objetivo desta revisão é abordar os prós e contras de diferentes pontos de vista que avaliam risco nutricional em pacientes com tumores do Trato Gastrointestinal (TGI) e sua viabilidade, considerando o atual entendimento e abordagens de triagem neste campo. Melhor combinação de avaliações antropométricas, laboratoriais e subjetivas se faz necessária em pacientes com câncer do TGI, uma vez que a desnutrição nestes pacientes costuma ser muito mais grave do que naqueles indivíduos com tumores em outros sítios que não o TGI. PMID:27556544

  18. On the pathogenesis of sclerosing stromal tumor of the ovary: a neoplasm in transition.

    PubMed

    Roth, Lawrence M; Gaba, Arthur R; Cheng, Liang

    2014-09-01

    Sclerosing stromal tumor (SST) is a distinctive benign ovarian stromal neoplasm first reported in 1973. Although its initial description supports its characterization as an ovarian stromal tumor, its exact pathogenesis remains uncertain. It is usually hormonally inactive, but occasional tumors are estrogenic or androgenic, and virilization can occur during pregnancy. We report 11 cases of SST, 6 of which were associated with another type or other types of ovarian stromal tumor. In 4 of these, a transition from thecoma of either typical or luteinized type to SST was observed. Our index case was that of a 16-yr-old girl who had a typical thecoma that underwent involutional changes in an extensive subserosal portion of the tumor with conversion to SST. In our series, 3 cases of SST underwent transformation to ovarian myxoma, one of which also contained a component of thecoma. The active SST components stained for inhibin, steroidogenic factor 1, and α-smooth muscle actin, but were negative or occasionally weakly positive for desmin. PMID:25083960

  19. Stromal Activation by Tumor Cells: An in Vitro Study in Breast Cancer

    PubMed Central

    Merlino, Giuseppe; Miodini, Patrizia; Paolini, Biagio; Carcangiu, Maria Luisa; Gennaro, Massimiliano; Dugo, Matteo; Daidone, Maria Grazia; Cappelletti, Vera

    2016-01-01

    Background: The tumor microenvironment participates in the regulation of tumor progression and influences treatment sensitivity. In breast cancer, it also may play a role in determining the fate of non-invasive lesions such as ductal carcinoma in situ (DCIS), a non-obligate precursor of invasive diseases, which is aggressively treated despite its indolent nature in many patients since no biomarkers are available to predict the progression of DCIS to invasive disease. In vitro models of stromal activation by breast tumor cells might provide clues as to specific stromal genes crucial for the transition from DCIS to invasive disease. Methods: normal human dermal fibroblasts (NHDF) were treated under serum-free conditions with cell culture media conditioned by breast cancer cell lines (SkBr3, MDA-MB-468, T47D) for 72 h and subjected to gene expression profiling with Illumina platform. Results: TGM2, coding for a tissue transglutaminase, was identified as candidate gene for stromal activation. In public transcriptomic datasets of invasive breast tumors TGM2 expression proved to provide prognostic information. Conversely, its role as an early biosensor of tumor invasiveness needs to be further investigated by in situ analyses. Conclusion: Stromal TGM2 might probably be associated with precancerous evolution at earlier stages compared to DCIS. PMID:27600076

  20. A case of tumor-forming pseudoangiomatous stromal hyperplasia of the breast.

    PubMed

    Takagi, Hiroyuki; Miyairi, Junichi; Hata, Motoyuki; Kirii, Yasusi; Tsuchiya, Shinichi

    2013-04-01

    Pseudoangiomatous stromal hyperplasia (PASH), characterized by the presence of slit-like spaces embedded in a hyalinized stroma, is sometimes observed during pathologic examination of breast-tissue specimens. Because tumor-forming PASH is rare, we report a case of a 41-year-old woman admitted to our hospital with a tumor in her left breast. Ultrasonography and aspiration biopsy cytology revealed a benign tumor. After performing Mammotome(®) biopsy, the lesion was diagnosed as PASH of the breast based on characteristic findings of histology and immunohistochemical studies. Because PASH tumors do not usually become malignant, we decided to perform ultrasonographic follow-up without tumor excision. PMID:20072822

  1. Paclitaxel and Carboplatin or Bleomycin Sulfate, Etoposide Phosphate, and Cisplatin in Treating Patients With Advanced or Recurrent Sex Cord-Ovarian Stromal Tumors

    ClinicalTrials.gov

    2016-03-16

    Ovarian Granulosa Cell Tumor; Ovarian Gynandroblastoma; Ovarian Sertoli-Leydig Cell Tumor; Ovarian Sex Cord Tumor With Annular Tubules; Ovarian Sex Cord-Stromal Tumor; Ovarian Sex Cord-Stromal Tumor of Mixed or Unclassified Cell Types; Ovarian Steroid Cell Tumor

  2. Severe paraneoplastic hypoglycemia secondary to a gastrointestinal stromal tumour masquerading as a stroke

    PubMed Central

    Gopalakrishnan, K; Rao, R; Grammatopoulos, D K; Randeva, H S; Weickert, M O; Murthy, N

    2015-01-01

    Summary We report the case of a 70-year-old previously healthy female who presented acutely to the Accident and Emergency department with left-sided vasomotor symptoms including reduced muscle tone, weakness upon walking and slurred speech. Physical examination confirmed hemiparesis with VIIth nerve palsy and profound hepatomegaly. A random glucose was low at 1.7 mmol/l, which upon correction resolved her symptoms. In hindsight, the patient recalled having had similar episodes periodically over the past 3 months to which she did not give much attention. While hospitalized, she continued having episodes of symptomatic hypoglycaemia during most nights, requiring treatment with i.v. dextrose and/or glucagon. Blood tests including insulin and C-peptide were invariably suppressed, in correlation with low glucose. A Synacthen stimulation test was normal (Cort (0′) 390 nmol/l, Cort (30′) 773 nmol/l). A computed tomography scan showed multiple lobulated masses in the abdomen, liver and pelvis. An ultrasound guided biopsy of one of the pelvic masses was performed. Immunohistochemistry supported the diagnosis of a gastrointestinal stromal tumour (GIST) positive for CD34 and CD117. A diagnosis of a non islet cell tumour hypoglycaemia (NICTH) secondary to an IGF2 secreting GIST was confirmed with further biochemical investigations (IGF2=96.5 nmol/l; IGF2:IGF1 ratio 18.9, ULN <10). Treatment with growth hormone resolved the patient's hypoglycaemic symptoms and subsequent targeted therapy with Imatinib was successful in controlling disease progression over an 8-year observation period. Learning points NICTH can be a rare complication of GISTs that may manifest with severe hypoglycaemia and neuroglucopenic symptoms. NICTH can masquerade as other pathologies thus causing diagnostic confusion. Histological confirmation of GIST induced NICTH and exclusion of other conditions causing hypoglycaemia is essential. Mutational analysis of GISTs should be carried out in all

  3. Collision tumour involving a rectal gastrointestinal stromal tumour with invasion of the prostate and a prostatic adenocarcinoma

    PubMed Central

    2012-01-01

    Background Gastrointestinal stromal tumours (GISTs) are the most common primary mesenchymal neoplasia in the gastrointestinal tract, although they represent only a small fraction of total gastrointestinal malignancies in adults (<2%). GISTs can be located at any level of the gastrointestinal tract; the stomach is the most common location (60-70%), in contrast to the rectum, which is most rare (4%). When a GIST invades into the adjacent prostate tissue, it can simulate prostate cancer. In this study, we report on a case comprising the unexpected collision between a rectal GIST tumour and a prostatic adenocarcinoma. Findings We describe the complexity of the clinical, endoscopic and radiological diagnosis, of the differential diagnosis based on tumour biopsy, and of the role of neoadjuvant therapy using imatinib prior to surgical treatment. Conclusions Although isolated cases of coexisting GISTs and prostatic adenocarcinomas have previously been described, this is the first reported case in the medical literature of a collision tumour involving a rectal GIST and prostatic adenocarcinoma components. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1238437468776331. PMID:23111239

  4. Loss of Stromal Caveolin-1 Expression: A Novel Tumor Microenvironment Biomarker That Can Predict Poor Clinical Outcomes for Pancreatic Cancer

    PubMed Central

    Shan, Tao; Lu, Hongwei; Ji, Hong; Li, Yiming; Guo, Jian; Chen, Xi; Wu, Tao

    2014-01-01

    Aims Cancer development and progression is not only associated with the tumor cell proliferation but also depends on the interaction between tumor cells and the stromal microenvironment. A new understanding of the role of the tumor microenvironment suggests that the loss of stromal caveolin-1 (Cav-1) as a key regulator may become a potential therapy target. This study aims to elucidate whether stromal Cav-1 expression in pancreatic cancer can be a strong prognosis biomarker. Methods Tissue samples from 45 pancreatic cancer patients were studied. Parenchyma and stroma were separated and purified using laser capture microdissection. Stromal Cav-1 expression was measured from pancreatic cancer, paraneoplastic, and normal tissue using immunohistochemistry. We analyzed the correlation of stromal Cav-1 expression with clinicopathologic features and prognostic indicators, such as tumor marker HER-2/neu gene. Results Specimens from six patients (13.3%) showed high levels of stromal Cav-1 staining, those from eight patients (17.8%) showed a lower, intermediate level of staining, whereas those from 31 patients (68.9%) showed an absence of staining. Cav-1 expression in cancer-associated fibroblasts was lower than that in paracancer-associated and in normal fibroblasts. Stromal Cav-1 loss was associated with TNM stage (P = 0.018), lymph node metastasis (P = 0.014), distant metastasis (P = 0.027), and HER-2/neu amplification (P = 0.007). The relationships of age, sex, histological grade, and tumor size with stromal Cav-1 expression were not significant (P>0.05). A negative correlation was found between circulating tumor cells and stromal Cav-1 expression (P<0.05). Conclusion The loss of stromal Cav-1 in pancreatic cancer was an independent prognostic indicator, thus suggesting that stromal Cav-1 may be an effective therapeutic target for patients with pancreatic cancer. PMID:24949874

  5. Prognosis and Survival in Patients With Gastrointestinal Tract Carcinoid Tumors

    PubMed Central

    Shebani, Khaled O.; Souba, Wiley W.; Finkelstein, Dianne M.; Stark, Paul C.; Elgadi, Khaled M.; Tanabe, Kenneth K.; Ott, Mark J.

    1999-01-01

    Objective To determine the impact of clinical presentation variables on the management and survival of patients with gastrointestinal (GI) tract carcinoid tumors. Methods A 20-year (1975–1995) retrospective analysis of 150 patients with GI tract carcinoid tumors at the Massachusetts General Hospital was conducted. Median follow-up was 66 months (range 1–378). Survival estimates for prognostic factors were calculated using Kaplan-Meier product limit estimators, with death from carcinoid as the outcome. Univariate analyses for each factor were obtained using a log-rank test, and multivariate survival analysis was performed. Results All but two patients underwent surgical intervention with the intent to cure (90%) or debulk the tumor (9%). Mean age at presentation was 55 ± 18 years (range 11–90). There was a slight female/male predominance (80:70). Symptoms were nonspecific; the most common were abdominal pain (40%), nausea and vomiting (29%), weight loss (19%), and GI blood loss (15%). Incidental carcinoids, discovered at the time of another procedure, occurred in 40% of patients and were noted at multiple sites throughout the GI tract. The distribution of tumors was ileojejunum (37%), appendix (31%), colon (13%), rectum (12%), stomach (4%), duodenum (1.3%), and Meckel’s diverticulum (1.3%). Of the 27 patients with documented liver metastases, carcinoid syndrome developed in only 13 patients (48%), manifested by watery diarrhea (100%), upper body flushing (70%), asthma (38%), and tricuspid regurgitation (23%). All 13 patients with carcinoid syndrome had elevated levels of 5-HIAA, but the absolute levels did not correlate with the severity of symptoms. An additional 11 patients, 3 without liver metastases, had elevated levels of 5-HIAA without any evidence of carcinoid syndrome. Multicentric carcinoid tumors occurred in 15 patients (10%), and all but one of these tumors were centered around the ileocecal valve. There was no difference in the incidence of

  6. Stromal interactions as regulators of tumor growth and therapeutic response: A potential target for photodynamic therapy?

    PubMed Central

    Celli, Jonathan P.

    2013-01-01

    It has become increasingly widely recognized that the stroma plays several vital roles in tumor growth and development and that tumor-stroma interactions can in many cases account poor therapeutic response. Inspired by an emerging body of literature, we consider the potential role of photodynamic therapy (PDT) for targeting interactions with stromal fibroblasts and mechano-sensitive signaling with the extracellular matrix as a means to drive tumors toward a more therapeutically responsive state and synergize with other treatments. This concept is particularly relevant for cancer of the pancreas, which is characterized by tumors with a profoundly dense, rigid fibrous stroma. Here we introduce new in vitro systems to model interactions between pancreatic tumors and their mechanical microenvironment and restore signaling with stromal fibroblasts. Using one such model as a test bed it is shown here that PDT treatment is able to destroy fibroblasts in an in vitro 3D pancreatic tumor-fibroblast co-culture. These results and the literature suggest the further development of PDT as a potential modality for stromal depletion. PMID:23457416

  7. Understanding tumor-stroma interplays for targeted therapies by armed mesenchymal stromal progenitors: the Mesenkillers

    PubMed Central

    Grisendi, Giulia; Bussolari, Rita; Veronesi, Elena; Piccinno, Serena; Burns, Jorge S; De Santis, Giorgio; Loschi, Pietro; Pignatti, Marco; Di Benedetto, Fabrizio; Ballarin, Roberto; Di Gregorio, Carmela; Guarneri, Valentina; Piccinini, Lino; Horwitz, Edwin M; Paolucci, Paolo; Conte, PierFranco; Dominici, Massimo

    2011-01-01

    A tumor represents a complex structure containing malignant cells strictly coupled with a large variety of surrounding cells constituting the tumor stroma (TS). In recent years, the importance of TS for cancer initiation, development, local invasion and metastases has become increasingly clear allowing the identification of TS as one of the possible ways to indirectly target tumors. Inside the heterogeneous stromal cell population, tumor associated fibroblasts (TAF) play a crucial role providing both functional and supportive environments. During both tumor and stroma development, several findings suggest that TAF could be recruited from different sources such as locally derived host fibroblasts, via epithelial/endothelial mesenchymal transitions or from circulating pools of fibroblasts deriving form mesenchymal progenitors, namely mesenchymal stem/stromal cells (MSC). These insights prompted scientists to identify multimodal approaches to target TS by biomolecules, monoclonal antibodies, and more recently via cell based strategies. These latter strategies appear extremely promising, although still associated with debated and unclear findings. This review discusses crosstalk between cancers and their stroma, dissecting specific tumor types, such as sarcoma, pancreatic and breast carcinoma, where stroma plays distinct paradigmatic roles. The recognition of these distinct stromal functions may help in planning effective and safer approaches aimed either to eradicate or to substitute TS by novel compounds and/or MSC having specific killing activities. PMID:22016827

  8. Prostatic Stromal Tumor of Uncertain Malignant Potential Which Was Difficult to Diagnose

    PubMed Central

    Matsuyama, Satoko; Nohara, Takahiro; Kawaguchi, Shohei; Seto, Chikashi; Nakanishi, Yuko; Uchiyama, Akio; Ishizawa, Shin

    2015-01-01

    Here, we report a case of stromal tumor of uncertain malignant potential (STUMP) that was difficult to diagnose. A 53-year-old male was found to have a hard nodule on digital rectal examination; magnetic resonance imaging revealed a large nodule on the left side of the prostate, indicating prostate cancer. However, pathological diagnosis of the biopsy specimen was benign prostatic hyperplasia. Although a papillary tumor in the prostatic urethra was also seen on urethrocystoscopy, the tumor specimen obtained from transurethral resection was not malignant. The tumor in the prostatic urethra recurred only 3 months after transurethral resection, and pathological findings revealed benign hyperplasia not only in the stromal tissue but also in the epithelium; therefore, the prostate tumor was suspected to be STUMP. It took many prostate pathologists a long time to reach the final diagnosis of STUMP. STUMP is a rare benign tumor, difficult to diagnose, and sometimes transforms into stromal sarcoma. Thus, we should consider radical resection in such cases. PMID:26839730

  9. An overlooked tumor promoting immunoregulation by non-hematopoietic stromal cells.

    PubMed

    Bose, Anamika; Ghosh, Tithi; Baral, Rathindranath

    2016-08-01

    Multidirectional complex communication between tumor-residing hematopoietic and non-hematopoietic stromal cells (NHSCs) decisively regulates cancer development, progression and therapeutic responses. HSCs predominantly participate in the immune regulations, while, NHSCs, provide parenchymal support or serve as a conduit for other cells or support angiogenesis. However, recent reports suggest NHSCs can additionally participate in ongoing tumor promoting immune reactions within tumor-microenvironment (TME). In this review, based on the state-of-art knowledge and accumulated evidence by us, we discuss the role of quite a few NHSCs in tumor from immunological perspectives. Understanding such consequence of NHSCs will surely pave the way in crafting effective cancer management. PMID:27311851

  10. Pseudoangio-matous stromal hyperplasia: A rare tumor of the breast.

    PubMed

    Shahi, Kedar Singh; Bhandari, Geeta; Gupta, Rakesh Kumar; Sawai, Malvika

    2015-01-01

    Pseudoangiomatous stromal hyperplasia (PASH) is a benign breast entity described first by Vuitch et al., in 1986. PASH is a benign stromal lesion containing complex anastomosing channels lined by slender spindle cells. It can be mistaken with fibroadenoma on ultrasound examination and histologically with low-grade angiosarcoma and phyllodes tumor. Here, presented is a case report of a 30-year-old female who presented with huge palpable lump in left breast. Ultrasonography revealed the lesion as giant fibroadenoma and fine needle aspiration cytology report was suggestive of cystosarcoma phyllodes. Excision and reduction mammoplasty was done and histopathology report was suggestive of PASH. PMID:26881624

  11. Mesenchymal stromal cells inhibit murine syngeneic anti-tumor immune responses by attenuating inflammation and reorganizing the tumor microenvironment.

    PubMed

    Modiano, Jaime F; Lindborg, Beth A; McElmurry, Ron T; Lewellen, Mitzi; Forster, Colleen L; Zamora, Edward A; Schaack, Jerome; Bellgrau, Donald; O'Brien, Timothy D; Tolar, Jakub

    2015-11-01

    The potential of mesenchymal stromal cells (MSCs) to inhibit anti-tumor immunity is becoming increasingly well recognized, but the precise steps affected by these cells during the development of an anti-tumor immune response remain incompletely understood. Here, we examined how MSCs affect the steps required to mount an effective anti-tumor immune response following administration of adenovirus Fas ligand (Ad-FasL) in the Lewis lung carcinoma (LL3) model. Administration of bone marrow-derived MSCs with LL3 cells accelerated tumor growth significantly. MSCs inhibited the inflammation induced by Ad-FasL in the primary tumors, precluding their rejection; MSCs also reduced the consequent expansion of tumor-specific T cells in the treated hosts. When immune T cells were transferred to adoptive recipients, MSCs impaired, but did not completely abrogate the ability of these T cells to promote elimination of secondary tumors. This impairment was associated with a modest reduction in tumor-infiltrating T cells, with a significant reduction in tumor-infiltrating macrophages, and with a reorganization of the stromal environment. Our data indicate that MSCs in the tumor environment reduce the efficacy of immunotherapy by creating a functional and anatomic barrier that impairs inflammation, T cell priming and expansion, and T cell function-including recruitment of effector cells. PMID:26250807

  12. Gene expression down-regulation in CD90+ prostate tumor-associated stromal cells involves potential organ-specific genes

    PubMed Central

    2009-01-01

    Background The prostate stroma is a key mediator of epithelial differentiation and development, and potentially plays a role in the initiation and progression of prostate cancer. The tumor-associated stroma is marked by increased expression of CD90/THY1. Isolation and characterization of these stromal cells could provide valuable insight into the biology of the tumor microenvironment. Methods Prostate CD90+ stromal fibromuscular cells from tumor specimens were isolated by cell-sorting and analyzed by DNA microarray. Dataset analysis was used to compare gene expression between histologically normal and tumor-associated stromal cells. For comparison, stromal cells were also isolated and analyzed from the urinary bladder. Results The tumor-associated stromal cells were found to have decreased expression of genes involved in smooth muscle differentiation, and those detected in prostate but not bladder. Other differential expression between the stromal cell types included that of the CXC-chemokine genes. Conclusion CD90+ prostate tumor-associated stromal cells differed from their normal counterpart in expression of multiple genes, some of which are potentially involved in organ development. PMID:19737398

  13. Imatinib Mesylate in Treating Patients With Relapsed or Refractory Solid Tumors of Childhood

    ClinicalTrials.gov

    2015-04-14

    Childhood Desmoplastic Small Round Cell Tumor; Childhood Synovial Sarcoma; Gastrointestinal Stromal Tumor; Lung Metastases; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Neuroblastoma; Recurrent Osteosarcoma

  14. Sunitinib for the treatment of gastrointestinal stromal tumours: a critique of the submission from Pfizer.

    PubMed

    Bond, M; Hoyle, M; Moxham, T; Napier, M; Anderson, R

    2009-09-01

    The submission's evidence for the clinical effectiveness and cost-effectiveness of sunitinib for the treatment of gastrointestinal stromal tumours (GISTs) is based on a randomised controlled trial (RCT) comparing sunitinib with placebo for people with unresectable and/or metastatic GIST after failure of imatinib and with Eastern Cooperative Oncology Group (ECOG) progression status 0-1, and an ongoing, non-comparative cohort study of a similar population but with ECOG progression status 0-4. The searches are appropriate and include all relevant studies and the RCT is of high quality. In the RCT sunitinib arm overall survival was 73 median weeks [95% confidence interval (CI) 61 to 83] versus 75 median weeks (95% CI 68 to 84) for the cohort study. However, time to tumour progression in the cohort study was different from that in the RCT sunitinib arm [41 (95% CI 36 to 47) versus 29 (95% CI 22 to 41) median weeks respectively]. Median progression-free survival with sunitinib was 24.6 weeks (95% CI 12.1 to 28.4) versus 6.4 weeks (95% CI 4.4 to 10.0) on placebo (hazard ratio 0.333, 95% CI 0.238 to 0.467, p < 0.001). The manufacturer used a three-state Markov model to model the cost-effectiveness of sunitinib compared with best supportive care for GIST patients; the modelling approach and sources and justification of estimates are reasonable. The base-case incremental cost-effectiveness ratio (ICER) was 27,365 pounds per quality-adjusted life-year (QALY) with the first cycle of sunitinib treatment not costed; when we included the cost of the first treatment cycle we estimated a base-case ICER of 32,636 pounds per QALY. Pfizer's sensitivity analysis produced a range of ICERs from 15,536 pounds per QALY to 59,002 pounds per QALY. Weaknesses of the manufacturer's submission include that the evidence is based on only one published RCT; that 84% of the RCT control population crossed over to the intervention group, giving rise to the use of unusual rank preserved structural

  15. Solid tumor therapy by selectively targeting stromal endothelial cells.

    PubMed

    Liu, Shihui; Liu, Jie; Ma, Qian; Cao, Liu; Fattah, Rasem J; Yu, Zuxi; Bugge, Thomas H; Finkel, Toren; Leppla, Stephen H

    2016-07-12

    Engineered tumor-targeted anthrax lethal toxin proteins have been shown to strongly suppress growth of solid tumors in mice. These toxins work through the native toxin receptors tumor endothelium marker-8 and capillary morphogenesis protein-2 (CMG2), which, in other contexts, have been described as markers of tumor endothelium. We found that neither receptor is required for tumor growth. We further demonstrate that tumor cells, which are resistant to the toxin when grown in vitro, become highly sensitive when implanted in mice. Using a range of tissue-specific loss-of-function and gain-of-function genetic models, we determined that this in vivo toxin sensitivity requires CMG2 expression on host-derived tumor endothelial cells. Notably, engineered toxins were shown to suppress the proliferation of isolated tumor endothelial cells. Finally, we demonstrate that administering an immunosuppressive regimen allows animals to receive multiple toxin dosages and thereby produces a strong and durable antitumor effect. The ability to give repeated doses of toxins, coupled with the specific targeting of tumor endothelial cells, suggests that our strategy should be efficacious for a wide range of solid tumors. PMID:27357689

  16. Endogenous and exogenous fluorescence of gastrointestinal tumors: initial clinical observations

    NASA Astrophysics Data System (ADS)

    Borisova, Ekaterina; Plamenova, Lilia; Keremedchiev, Momchil; Vladimirov, Borislav; Avramov, Latchezar

    2013-03-01

    The limitations of standard endoscopy for detection and evaluation of cancerous changes in gastrointestinal tract (GIT) are significant challenge and initiate development of new diagnostic modalities. Therefore many spectral and optical techniques are applied recently into the clinical practice for obtaining qualitatively and quantitatively new data from gastrointestinal neoplasia with different level of clinical applicability and diagnostic success. One of the most promising approaches is fluorescence detection using naturally existing fluorescent molecules or added fluorescent markers. Deltaaminolevulinic acid / protoporphyrin IX is applied for exogenous fluorescent tumor detection in the upper part of gastrointestinal tract. The 5-ALA is administered per os six hours before measurements at dose 20mg/kg weight. Highpower light-emitting diode at 405 nm is used as a source and the excitation light is passed through the light-guide of standard video-endoscopic system to obtain 2-D visualization. Both kinds of spectra - autofluorescence signals and protoporphyrin IX signal are recorded and stored using a fiber-optic microspectrometer, as in endoscopy instrumental channel a fiber is applied to return information about fluorescence signals. In such way 1-D detection and 2-D visualization of the lesions' fluorescence are received. The results from in vivo detection show significant differentiation between normal and abnormal tissues in 1-D spectroscopic regime, but only moderate discrimination in 2-D imaging.

  17. Metastatic Periampullary Tumor from Hepatocellular Carcinoma Presenting as Gastrointestinal Bleeding

    PubMed Central

    Nissen, Nicholas N.; Guindi, Maha; Jamil, Laith H.

    2015-01-01

    Periampullary tumors constitute a number of diverse neoplastic lesions located within 2 cm of the major duodenal papilla; among these, metastatic lesions account for only a small proportion of the periampullary tumors. To our knowledge, a metastatic periampullary tumor from hepatocellular carcinoma has never been reported. A 62-year-old male reported to our institute for fatigue and low hemoglobin. His medical history was remarkable for multifocal hepatocellular carcinoma (HCC) treated with selective transcatheter arterial chemoembolization (TACE). An esophagogastroduodenoscopy (EGD) was performed which revealed a periampullary mass. Histopathology was consistent with metastatic moderately differentiated HCC. Two endoloops were deployed around the base of the mass one month apart. The mass eventually sloughed off and patient's hemoglobin level stabilized. We postulated that periampullary metastasis in this patient was the result of tumor fragments migration through the biliary tracts and that TACE which increases tumor fragments burden might have played a contributory role. Metastasis of HCC to the gastrointestinal (GI) tract should be considered as a cause of GI bleeding. PMID:26064707

  18. T cells stimulate catabolic gene expression by the stromal cells from giant cell tumor of bone

    SciTech Connect

    Cowan, Robert W.; Ghert, Michelle; Singh, Gurmit

    2012-03-23

    Highlights: Black-Right-Pointing-Pointer Two T cell lines stimulate PTHrP, RANKL, MMP13 gene expression in GCT cell cultures. Black-Right-Pointing-Pointer CD40 expressed by stromal cells; CD40L detected in whole tumor but not cultures. Black-Right-Pointing-Pointer Effect of CD40L treatment on GCT cells increased PTHrP and MMP13 gene expression. Black-Right-Pointing-Pointer PTHrP treatment increased MMP13 expression, while inhibition decreased expression. Black-Right-Pointing-Pointer T cells may stimulate GCT stromal cells and promote the osteolysis of the tumor. -- Abstract: The factors that promote the localized bone resorption by giant cell tumor of bone (GCT) are not fully understood. We investigated whether T cells could contribute to bone resorption by stimulating expression of genes for parathyroid hormone-related protein (PTHrP), matrix metalloproteinase (MMP)-13, and the receptor activator of nuclear-factor {kappa}B ligand (RANKL). Two cell lines, Jurkat clone E6-1 and D1.1, were co-cultured with isolated GCT stromal cells. Real-time PCR analyses demonstrated a significant increase of all three genes following 48 h incubation, and PTHrP and MMP-13 gene expression was also increased at 24 h. Further, we examined the expression of CD40 ligand (CD40L), a protein expressed by activated T cells, and its receptor, CD40, in GCT. Immunohistochemistry results revealed expression of the CD40 receptor in both the stromal cells and giant cells of the tumor. RNA collected from whole GCT tissues showed expression of CD40LG, which was absent in cultured stromal cells, and suggests that CD40L is expressed within GCT. Stimulation of GCT stromal cells with CD40L significantly increased expression of the PTHrP and MMP-13 genes. Moreover, we show that inhibition of PTHrP with neutralizing antibodies significantly decreased MMP13 expression by the stromal cells compared to IgG-matched controls, whereas stimulation with PTHrP (1-34) increased MMP-13 gene expression. These

  19. Pharmacoepigenetics in gastrointestinal tumors: MGMT methylation and beyond.

    PubMed

    Fornaro, Lorenzo; Vivaldi, Caterina; Caparello, Chiara; Musettini, Gianna; Baldini, Editta; Masi, Gianluca; Falcone, Alfredo

    2016-01-01

    Epigenetic mechanisms are involved in gastrointestinal (GI) cancer pathogenesis. Insights into the molecular basis of GI carcinogenesis led to the identification of different epigenetic pathways and signatures that may play a role as therapeutic targets in metastatic colorectal cancer (mCRC) and non-colorectal GI tumors. Among these alterations, O6-methylguanine DNA methyltransferase (MGMT) gene promoter methylation is the most investigated biomarker and seems to be an early and frequent event, at least in CRC. Loss of expression of MGMT as a result of gene promoter methylation has been associated with interesting activity of alkylating agents in mCRC. However, the optimal methods for the definition of the MGMT status and additional predictive factors beyond MGMT in GI malignancies are lacking. Here we review the current role of MGMT methylation and other epigenetic alterations as potential treatment targets in GI tumors. PMID:26709653

  20. A systematic review: perivascular epithelioid cell tumor of gastrointestinal tract.

    PubMed

    Chen, Zehong; Han, Siqi; Wu, Jialin; Xiong, Minmin; Huang, Yanqiao; Chen, Jianhui; Yuan, Yujie; Peng, Jianjun; Song, Wu

    2016-07-01

    Perivascular epithelioid cell tumor (PEComa) is a rare entity with distinctive morphology and of expressing myomelanocytic markers. Gastrointestinal tract (GI) is one of the most common anatomic sites of origin and counts for 20% to 25% of all reported cases of perivascular epithelioid cell tumors not otherwise specified (PEComas-NOS). However, the biologic behavior of perivascular epithelioid cell tumors of gastrointestinal tract (GI PEComas-NOS) is still unclear. The aim of conducting this systematic review is to sum up what is known so far of the epidemiology, natural history, management and prognosis of GI PEComas-NOS.A systematic research was performed on PubMed and EMBASE using the following terms: ("perivascular epithelioid cell tumor" or "PEComa") and ("gastrointestinal tract" or "GI" or "oral " or "mouth" or "esophagus" or "gullet" or "gastric" or "stomach" or "duodenum" or "jejunum" or "ileum" or "cecum" or "colon" or "colorectal" or "sigmoid" or "rectum" or "anus" or "mesentery") up to December 1, 2015. Retrieved GI PEComas-NOS publications, which included these terms, contains case reports, case series to case characteristic researches.A total of 168 articles were reviewed, 41 GI PEComa-NOS English studies among which were retrieved for analysis. We reviewed epidemiology, natural history, management and prognosis of GI PEComa-NOS. Generally GI PEComa-NOS is believed to have women predomination. The most frequently involved location is colon with non-specific clinical signs. Pathologically, GI PEComas-NOS shows epithelioid predominance (70%), meanwhile coexpresses melanocytic and muscle markers characteristically, while immunohistochemistry is a useful tool for identify, which indicates that HMB-45 is regarded as the most sensitive reagent. Complete resection served as mainstay of treatment, while chemotherapy should be unanimously considered to apply in malignant cases. Eventually, it is necessary for closed and long-term follow-up with endoscope and

  1. Shaping of the tumor microenvironment: Stromal cells and vessels.

    PubMed

    Blonska, Marzenna; Agarwal, Nitin K; Vega, Francisco

    2015-10-01

    Lymphomas develop and progress in a specialized tissue microenvironment such as bone marrow as well as secondary lymphoid organs such as lymph node and spleen. The lymphoma microenvironment is characterized by a heterogeneous population of stromal cells, including fibroblastic reticular cells, nurse-like cells, mesenchymal stem cells, follicular dendritic cells, and inflammatory cells such as macrophages, T- and B-cells. These cell populations interact with the lymphoma cells to promote lymphoma growth, survival and drug resistance through multiple mechanisms. Angiogenesis is also recognized as an important factor associated with lymphoma progression. In recent years, we have learned that the interaction between the malignant and non-malignant cells is bidirectional and resembles, at least in part, the pattern seen between non-neoplastic lymphoid cells and the normal microenvironment of lymphoid organs. A summary of the current knowledge of lymphoma microenvironment focusing on the cellular components will be reviewed here. PMID:25794825

  2. Visualizing stromal cell dynamics in different tumor microenvironments by spinning disk confocal microscopy

    PubMed Central

    Egeblad, Mikala; Ewald, Andrew J.; Askautrud, Hanne A.; Truitt, Morgan L.; Welm, Bryan E.; Bainbridge, Emma; Peeters, George; Krummel, Matthew F.; Werb, Zena

    2008-01-01

    SUMMARY The tumor microenvironment consists of stromal cells and extracellular factors that evolve in parallel with carcinoma cells. To gain insights into the activities of stromal cell populations, we developed and applied multicolor imaging techniques to analyze the behavior of these cells within different tumor microenvironments in the same live mouse. We found that regulatory T-lymphocytes (Tregs) migrated in proximity to blood vessels. Dendritic-like cells, myeloid cells and carcinoma-associated fibroblasts all exhibited higher motility in the microenvironment at the tumor periphery than within the tumor mass. Since oxygen levels differ between tumor microenvironments, we tested if acute hypoxia could account for the differences in cell migration. Direct visualization revealed that Tregs ceased migration under acute systemic hypoxia, whereas myeloid cells continued migrating. In the same mouse and microenvironment, we experimentally subdivided the myeloid cell population and revealed that uptake of fluorescent dextran defined a low-motility subpopulation expressing markers of tumor-promoting, alternatively activated macrophages. In contrast, fluorescent anti-Gr1 antibodies marked myeloid cells patrolling inside tumor vessels and in the stroma. Our techniques allow real-time combinatorial analysis of cell populations based on spatial location, gene expression, behavior and cell surface molecules within intact tumors. The techniques are not limited to investigations in cancer, but could give new insights into cell behavior more broadly in development and disease. PMID:19048079

  3. Using polarization-sensitive optical coherence tomography to identify tumor stromal fibrosis and increase tumor biopsy yield (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Hariri, Lida P.; Adams, David C.; Miller, Alyssa J.; Mino-Kenudson, Mari; Suter, Melissa J.

    2016-03-01

    Tissue biopsy is the principal method used to diagnose tumors in a variety of organ systems. It is essential to maximize tumor yield in biopsy specimens for both clinical diagnostic and research purposes. This is particularly important in tumors where additional tissue is needed for molecular analysis to identify patients who would benefit from mutation-specific targeted therapy, such as in lung carcinomas. Inadvertent sampling of fibrotic stroma within tumor nodules contaminates biopsies, decreases tumor yield, and can impede diagnosis. The ability to assess tumor composition and guide biopsy site selection in real time is likely to improve diagnostic yield. Polarization sensitive OCT (PS-OCT) measures birefringence in organized tissues, such as collagen, and could be used to distinguish tumor from fibrosis. In this study, PS-OCT was obtained in 65 lung nodule samples from surgical resection specimens containing varying ratios of tumor and fibrosis. PS-OCT was obtained with either a custom-built helical scanning catheter (0.8 or 1.6mm in diameter) or a dual-axis bench top scanner. Strong birefringence was observed in nodules containing dense fibrosis, with no birefringence in adjacent regions of tumor. Tumors admixed with early, loosely-organized collagen demonstrated mild-to-moderate birefringence, and tumors with little collagen content showed little to no birefringent signal. PS-OCT provides significant insights into tumor nodule composition, and has potential to differentiate tumor from stromal fibrosis during biopsy site selection to increase diagnostic tumor yield.

  4. Fibroblast Activation Protein Expression by Stromal Cells and Tumor-Associated Macrophages in Human Breast Cancer

    PubMed Central

    Julia, Tchou; Zhang Paul, J; Yingtao, Bi; Celine, Satija; Rajrupa, Marjumdar; Stephen, TL; Lo, A; Haiying, Chen; Carolyn, Mies; June, Carl H; Jose, Conejo-Garcia; Ellen, Puré

    2013-01-01

    Summary Fibroblast activation protein (FAP) has long been known to be expressed in the stroma of breast cancer. However, very little is known if the magnitude of FAP expression within the stroma may have prognostic value and reflect the heterogeneous biology of the tumor cell. An earlier study had suggested that stromal FAP expression in breast cancer was inversely proportional to prognosis. We, therefore, hypothesized that stromal FAP expression may correlate with clinicopathologic variables and may serve as an adjunct prognostic factor in breast cancer. We evaluated the expression of FAP in a panel of breast cancer tissues (n=52) using a combination of immunostain analyses at the tissue and single cell level using freshly frozen or freshly digested human breast tumor samples respectively. Our results showed that FAP expression was abundantly expressed in the stroma across all breast cancer subtypes without significant correlation with clinicopathologic factors. We further identified a subset of FAP positive or FAP+ stromal cells that also expressed CD45, a pan-leukocyte marker. Using freshly dissociated human breast tumor specimens (n=5), we demonstrated that some of these FAP+ CD45+ cells were CD11b+CD14+MHC-II+ indicating that they were likely tumor associated macrophages (TAMs). Although FAP+CD45+ cells have been demonstrated in the mouse tumor stroma, our results demonstrating that human breast TAMs expressed FAP was novel and suggested that existing and future FAP directed therapy may have dual therapeutic benefits targeting both stromal mesenchymal cells and immune cells such as TAMs. More work is needed to explore the role of FAP as a potential targetable molecule in breast cancer treatment. PMID:24074532

  5. T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

    PubMed Central

    Barnas, Jennifer L.; Simpson-Abelson, Michelle R.; Yokota, Sandra J.; Kelleher, Raymond J.

    2010-01-01

    The immune system of cancer patients recognizes tumor-associated antigens expressed on solid tumors and these antigens are able to induce tumor-specific humoral and cellular immune responses. Diverse immunotherapeutic strategies have been used in an attempt to enhance both antibody and T cell responses to tumors. While several tumor vaccination strategies significantly increase the number of tumor-specific lymphocytes in the blood of cancer patients, most vaccinated patients ultimately experience tumor progression. CD4+ and CD8+ T cells with an effector memory phenotype infiltrate human tumor microenvironments, but most are hyporesponsive to stimulation via the T cell receptor (TCR) and CD28 under conditions that activate memory T cells derived from the peripheral blood of the cancer patients or normal donors. Attempts to identify cells and molecules responsible for the TCR signaling arrest of tumor-infiltrating T cells have focused largely upon the immunosuppressive effects of tumor cells, tolerogenic dendritic cells and regulatory T cells. Here we review potential mechanisms by which human T cell function is arrested in the tumor microenvironment with a focus on the immunomodulatory effects of stromal fibroblasts. Determining in vivo which cells and molecules are responsible for the TCR arrest in human tumor-infiltrating T cells will be necessary to formulate and test strategies to prevent or reverse the signaling arrest of the human T cells in situ for a more effective design of tumor vaccines. These questions are now addressable using novel human xenograft models of tumor microenvironments. PMID:21209773

  6. The challenge of conducting pharmacoeconomic evaluations in oncology using crossover trials: the example of sunitinib for gastrointestinal stromal tumour.

    PubMed

    Chabot, Isabelle; LeLorier, Jacques; Blackstein, Martin E

    2008-05-01

    This paper examines the challenge of conducting economic evaluations to support patient access to cancer therapies when the cost-effectiveness estimation is hampered by crossover trial design. To demonstrate these limitations, we present the submission to the Canadian Drug Review (CDR) of a cost-effectiveness evaluation of sunitinib versus best supportive care (BSC) for the treatment of gastrointestinal stromal tumour in patients intolerant or resistant to imatinib. The economic model generated an incremental cost-effectiveness ratio for sunitinib versus BSC of dollars 79,884/quality-adjusted life-year gained. Eight months after initial submission, CDR granted a final recommendation to fund sunitinib following the manufacturer's appeal against their first recommendation. Although cost-effectiveness is an important consideration in reimbursement decisions, there is a need for improved decision-making processes for cancer drugs, as well as a better understanding of the limitations of clinical trial design. PMID:18372169

  7. A systematic review: perivascular epithelioid cell tumor of gastrointestinal tract

    PubMed Central

    Chen, Zehong; Han, Siqi; Wu, Jialin; Xiong, Minmin; Huang, Yanqiao; Chen, Jianhui; Yuan, Yujie; Peng, Jianjun; Song, Wu

    2016-01-01

    Abstract Perivascular epithelioid cell tumor (PEComa) is a rare entity with distinctive morphology and of expressing myomelanocytic markers. Gastrointestinal tract (GI) is one of the most common anatomic sites of origin and counts for 20% to 25% of all reported cases of perivascular epithelioid cell tumors not otherwise specified (PEComas-NOS). However, the biologic behavior of perivascular epithelioid cell tumors of gastrointestinal tract (GI PEComas-NOS) is still unclear. The aim of conducting this systematic review is to sum up what is known so far of the epidemiology, natural history, management and prognosis of GI PEComas-NOS. A systematic research was performed on PubMed and EMBASE using the following terms: (“perivascular epithelioid cell tumor” or “PEComa”) and (“gastrointestinal tract” or “GI” or “oral ” or “mouth” or “esophagus” or “gullet” or “gastric” or “stomach” or “duodenum” or “jejunum” or “ileum” or “cecum” or “colon” or “colorectal” or “sigmoid” or “rectum” or “anus” or “mesentery”) up to December 1, 2015. Retrieved GI PEComas-NOS publications, which included these terms, contains case reports, case series to case characteristic researches. A total of 168 articles were reviewed, 41 GI PEComa-NOS English studies among which were retrieved for analysis. We reviewed epidemiology, natural history, management and prognosis of GI PEComa-NOS. Generally GI PEComa-NOS is believed to have women predomination. The most frequently involved location is colon with non-specific clinical signs. Pathologically, GI PEComas-NOS shows epithelioid predominance (70%), meanwhile coexpresses melanocytic and muscle markers characteristically, while immunohistochemistry is a useful tool for identify, which indicates that HMB-45 is regarded as the most sensitive reagent. Complete resection served as mainstay of treatment, while chemotherapy should be unanimously considered to apply in malignant

  8. More than a scaffold: Stromal modulation of tumor immunity.

    PubMed

    Johansson, Anna; Hamzah, Juliana; Ganss, Ruth

    2016-01-01

    Current clinical success with anti-cancer immunotherapy provides exciting new treatment opportunities. While encouraging, more needs to be done to induce durable effects in a higher proportion of patients. Increasing anti-tumor effector T cell quantity or quality alone does not necessarily correlate with therapeutic outcome. Instead, the tumor microenvironment is a critical determinant of anti-cancer responsiveness to immunotherapy and can confer profound resistance. Yet, the tumor-promoting environment - due to its enormous plasticity - also delivers the best opportunities for adjuvant therapy aiming at recruiting, priming and sustaining anti-tumor cytotoxicity. While the tumor environment as an entity is increasingly well understood, current interventions are still broad and often systemic. In contrast, tumors grow in a highly compartmentalized environment which includes the vascular/perivascular niche, extracellular matrix components and in some tumors lymph node aggregates; all of these structures harbor and instruct subsets of immune cells. Targeting and re-programming specific compartments may provide better opportunities for adjuvant immunotherapy. PMID:26071879

  9. Tumor-Promoting Desmoplasia Is Disrupted by Depleting FAP-Expressing Stromal Cells.

    PubMed

    Lo, Albert; Wang, Liang-Chuan S; Scholler, John; Monslow, James; Avery, Diana; Newick, Kheng; O'Brien, Shaun; Evans, Rebecca A; Bajor, David J; Clendenin, Cynthia; Durham, Amy C; Buza, Elizabeth L; Vonderheide, Robert H; June, Carl H; Albelda, Steven M; Puré, Ellen

    2015-07-15

    Malignant cells drive the generation of a desmoplastic and immunosuppressive tumor microenvironment. Cancer-associated stromal cells (CASC) are a heterogeneous population that provides both negative and positive signals for tumor cell growth and metastasis. Fibroblast activation protein (FAP) is a marker of a major subset of CASCs in virtually all carcinomas. Clinically, FAP expression serves as an independent negative prognostic factor for multiple types of human malignancies. Prior studies established that depletion of FAP(+) cells inhibits tumor growth by augmenting antitumor immunity. However, the potential for immune-independent effects on tumor growth have not been defined. Herein, we demonstrate that FAP(+) CASCs are required for maintenance of the provisional tumor stroma because depletion of these cells, by adoptive transfer of FAP-targeted chimeric antigen receptor (CAR) T cells, reduced extracellular matrix proteins and glycosaminoglycans. Adoptive transfer of FAP-CAR T cells also decreased tumor vascular density and restrained growth of desmoplastic human lung cancer xenografts and syngeneic murine pancreatic cancers in an immune-independent fashion. Adoptive transfer of FAP-CAR T cells also restrained autochthonous pancreatic cancer growth. These data distinguish the function of FAP(+) CASCs from other CASC subsets and provide support for further development of FAP(+) stromal cell-targeted therapies for the treatment of solid tumors. PMID:25979873

  10. Mechanisms of tumor escape from immune system: role of mesenchymal stromal cells.

    PubMed

    Poggi, Alessandro; Musso, Alessandra; Dapino, Irene; Zocchi, Maria Raffaella

    2014-01-01

    Tumor microenvironment represents the site where the tumor tries to survive and escape from immune system-mediated recognition. Indeed, to proliferate tumor cells can divert the immune response inducing the generation of myeloid derived suppressor cells and regulatory T cells which can limit the efficiency of effector antitumor lymphocytes in eliminating neoplastic cells. Many components of the tumor microenvironment can serve as a double sword for the tumor and the host. Several types of fibroblast-like cells, which herein we define mesenchymal stromal cells (MSC), secrete extracellular matrix components and surrounding the tumor mass can limit the expansion of the tumor. On the other hand, MSC can interfere with the immune recognition of tumor cells producing immunoregulatory cytokines as transforming growth factor (TGF)ß, releasing soluble ligands of the activating receptors expressed on cytolytic effector cells as decoy molecules, affecting the correct interaction among lymphocytes and tumor cells. MSC can also serve as target for the same anti-tumor effector lymphocytes or simply impede the interaction between these lymphocytes and neoplastic cells. Thus, several evidences point out the role of MSC, both in epithelial solid tumors and hematological malignancies, in regulating tumor cell growth and immune response. Herein, we review these evidences and suggest that MSC can be a suitable target for a more efficient anti-tumor therapy. PMID:24657523

  11. Distinct effects of SIRT1 in cancer and stromal cells on tumor promotion.

    PubMed

    Shin, Dong Hoon; Choi, Yong-Joon; Jin, Peng; Yoon, Haejin; Chun, Yang-Sook; Shin, Hyun-Woo; Kim, Ja-Eun; Park, Jong-Wan

    2016-04-26

    The lysyl deacetylase SIRT1 acts as a metabolic sensor in adjusting metabolic imbalance. To explore the role of SIRT1 in tumor-stroma interplay, we designed an in vivo tumor model using SIRT1-transgenic mice. B16F10 mouse melanoma grew more quickly in SIRT1-transgenic mice than in wild-type mice, whereas SIRT1-overexpressing one grew slowly in both mice. Of human tumors, SIRT1 expression in stromal fibroblasts was found to correlate with poor prognosis in ovarian cancer. B16F10 and human ovarian cancer (SKOV3 and SNU840) cells were more proliferative in co-culture with SIRT1-overexpressiong fibroblasts. In contrast, SIRT1 within cancer cells has a negative effect on cell proliferation. In conditioned media from SIRT1-overexpressing fibroblasts, matrix metalloproteinase-3 (MMP3) was identified in cytokine arrays to be secreted from fibroblasts SIRT1-dependently. Fibroblast-derived MMP3 stimulated cancer cell proliferation, and such a role of MMP3 was also demonstrated in cancer/fibroblast co-grafts. In conclusion, SIRT1 plays differential roles in cancer and stromal cells. SIRT1 in stromal cells promotes cancer growth by producing MMP3, whereas SIRT1 in cancer cells inhibits growth via an intracellular event. The present study provides a basis for setting new anticancer strategies targeting SIRT1. PMID:26992208

  12. Ezrin expression in stromal cells of capillary hemangioblastoma. An immunohistochemical survey of brain tumors.

    PubMed Central

    Böhling, T.; Turunen, O.; Jääskeläinen, J.; Carpen, O.; Sainio, M.; Wahlström, T.; Vaheri, A.; Haltia, M.

    1996-01-01

    Ezrin is a cytoskeleton-associated protein that appears to link actin filaments to the plasma membrane. Immunocytochemical studies suggest that ezrin is expressed in epithelial cells but not in mesenchymal cells. In addition, ezrin is expressed by certain epithelial tumors, such as renal cell adenocarcinomas. Ezrin serves as a tyrosine kinase substrate, and is phosphorylated in epidermal growth factor-stimulated cells. Ezrin may thus mediate regulatory signals in different cell functions. We studied the distribution of ezrin in 104 cases of primary tumors of the central nervous system (CNS) by immunocytochemistry. Special interest was focused on capillary hemangioblastoma, owing to its resemblance to renal cell adenocarcinoma, and on malignant gliomas, owing to their frequent epidermal growth factor receptor amplification. The stromal cells of hemangioblastomas were found to be strongly positive for ezrin. No expression was detected in gliomas and, except for hemangioblastomas, ezrin expression was restricted to those few CNS tumors that show epithelial differentiation, ie, choroid plexus papillomas, craniopharyngiomas, ependymomas, and cysts. The diffuse cytoplasmic expression of ezrin in the stromal cells of capillary hemangioblastoma may indicate that stromal cells overexpress ezrin or express ezrin with deficient binding properties. Images Figure 1 Figure 2 PMID:8579099

  13. Lactate is a mediator of metabolic cooperation between stromal carcinoma associated fibroblasts and glycolytic tumor cells in the tumor microenvironment

    SciTech Connect

    Rattigan, Yanique I.; Patel, Brijesh B.; Ackerstaff, Ellen; Sukenick, George; Koutcher, Jason A.; Glod, John W.; and others

    2012-02-15

    Human mesenchymal stem cells (hMSCs) are bone marrow-derived stromal cells, which play a role in tumor progression. We have shown earlier that breast cancer cells secrete higher levels of interleukin-6 (IL-6) under hypoxia, leading to the recruitment of hMSCs towards hypoxic tumor cells. We found that (i) MDA-MB-231 cells secrete significantly higher levels of lactate (3-fold more) under hypoxia (1% O{sub 2}) than under 20% O{sub 2} and (ii) lactate recruits hMSCs towards tumor cells by activating signaling pathways to enhance migration. The mRNA and protein expression of functional MCT1 in hMSCs is increased in response to lactate exposure. Thus, we hypothesized that hMSCs and stromal carcinoma associated fibroblasts (CAFs) in the tumor microenvironment have the capacity to take up lactate expelled from tumor cells and use it as a source of energy. Our {sup 13}C NMR spectroscopic measurements indicate that {sup 13}C-lactate is converted to {sup 13}C-alpha ketoglutarate in hMSCs and CAFs supporting this hypothesis. To our knowledge this is the first in vitro model system demonstrating that hMSCs and CAFs can utilize lactate produced by tumor cells.

  14. Regorafenib as a single-agent in the treatment of patients with gastrointestinal tumors: an overview for pharmacists.

    PubMed

    Rey, Jean-Baptiste; Launay-Vacher, Vincent; Tournigand, Christophe

    2015-06-01

    Regorafenib (BAY 73-4506, Stivarga® Bayer HealthCare Pharmaceutical Inc) is an oral multikinase inhibitor with a distinct and wide-ranging profile of tyrosine kinase inhibition, resulting in antiangiogenic and antiproliferative properties in tumors. Single-agent regorafenib administered as a 160-mg daily dose for the first 21 days of a 28-day cycle is approved for use in patients with pretreated metastatic colorectal cancer (mCRC) and gastrointestinal stromal tumor (GIST) progressing on imatinib and sunitinib, following publication of data from the phase III CORRECT and GRID studies respectively. Regorafenib is currently under phase III investigation in patients with hepatocellular carcinoma and is in several phase II studies in patients with gastrointestinal (GI) tumors. This review describes the clinical development of regorafenib in patients with GI cancers, and highlights the key issues important for the modern day clinical pharmacist who forms part of the multidisciplinary team ensuring safe and effective delivery of the drug to the patient. This information is considered of particular importance to the clinical pharmacist for the future development of regorafenib in this treatment setting. PMID:25213039

  15. Regulators of Actin Dynamics in Gastrointestinal Tract Tumors

    PubMed Central

    Steinestel, Konrad; Wardelmann, Eva; Hartmann, Wolfgang; Grünewald, Inga

    2015-01-01

    Reorganization of the actin cytoskeleton underlies cell migration in a wide variety of physiological and pathological processes, such as embryonic development, wound healing, and tumor cell invasion. It has been shown that actin assembly and disassembly are precisely regulated by intracellular signaling cascades that respond to changes in the cell microenvironment, ligand binding to surface receptors, or oncogenic transformation of the cell. Actin-nucleating and actin-depolymerizing (ANFs/ADFs) and nucleation-promoting factors (NPFs) regulate cytoskeletal dynamics at the leading edge of migrating cells, thereby modulating cell shape; these proteins facilitate cellular movement and mediate degradation of the surrounding extracellular matrix by secretion of lytic proteases, thus eliminating barriers for tumor cell invasion. Accordingly, expression and activity of these actin-binding proteins have been linked to enhanced metastasis and poor prognosis in a variety of malignancies. In this review, we will summarize what is known about expression patterns and the functional role of actin regulators in gastrointestinal tumors and evaluate first pharmacological approaches to prevent invasion and metastatic dissemination of malignant cells. PMID:26345720

  16. Regulators of Actin Dynamics in Gastrointestinal Tract Tumors.

    PubMed

    Steinestel, Konrad; Wardelmann, Eva; Hartmann, Wolfgang; Grünewald, Inga

    2015-01-01

    Reorganization of the actin cytoskeleton underlies cell migration in a wide variety of physiological and pathological processes, such as embryonic development, wound healing, and tumor cell invasion. It has been shown that actin assembly and disassembly are precisely regulated by intracellular signaling cascades that respond to changes in the cell microenvironment, ligand binding to surface receptors, or oncogenic transformation of the cell. Actin-nucleating and actin-depolymerizing (ANFs/ADFs) and nucleation-promoting factors (NPFs) regulate cytoskeletal dynamics at the leading edge of migrating cells, thereby modulating cell shape; these proteins facilitate cellular movement and mediate degradation of the surrounding extracellular matrix by secretion of lytic proteases, thus eliminating barriers for tumor cell invasion. Accordingly, expression and activity of these actin-binding proteins have been linked to enhanced metastasis and poor prognosis in a variety of malignancies. In this review, we will summarize what is known about expression patterns and the functional role of actin regulators in gastrointestinal tumors and evaluate first pharmacological approaches to prevent invasion and metastatic dissemination of malignant cells. PMID:26345720

  17. Adipose-Derived Stromal Vascular Fraction Differentially Expands Breast Progenitors in Tissue Adjacent to Tumors Compared to Healthy Breast Tissue

    PubMed Central

    Chatterjee, Sumanta; Laliberte, Mike; Blelloch, Sarah; Ratanshi, Imran; Safneck, Janice; Buchel, Ed

    2015-01-01

    Background: Autologous fat grafts supplemented with adipose-derived stromal vascular fraction are used in reconstructive and cosmetic breast procedures. Stromal vascular fraction contains adipose-derived stem cells that are thought to encourage wound healing, tissue regeneration, and graft retention. Although use of stromal vascular fraction has provided exciting perspectives for aesthetic procedures, no studies have yet been conducted to determine whether its cells contribute to breast tissue regeneration. The authors examined the effect of these cells on the expansion of human breast epithelial progenitors. Methods: From patients undergoing reconstructive breast surgery following mastectomies, abdominal fat, matching tissue adjacent to breast tumors, and the contralateral non–tumor-containing breast tissue were obtained. Ex vivo co-cultures using breast epithelial cells and the stromal vascular fraction cells were used to study the expansion potential of breast progenitors. Breast reduction samples were collected as a source of healthy breast cells. Results: The authors observed that progenitors present in healthy breast tissue or contralateral non–tumor-containing breast tissue showed significant and robust expansion in the presence of stromal vascular fraction (5.2- and 4.8-fold, respectively). Whereas the healthy progenitors expanded up to 3-fold without the stromal vascular fraction cells, the expansion of tissue adjacent to breast tumor progenitors required the presence of stromal vascular fraction cells, leading to a 7-fold expansion, which was significantly higher than the expansion of healthy progenitors with stromal vascular fraction. Conclusions: The use of stromal vascular fraction might be more beneficial to reconstructive operations following mastectomies compared with cosmetic corrections of the healthy breast. Future studies are required to examine the potential risk factors associated with its use. CLINICAL QUESTION/LEVEL OF EVIDENCE

  18. Tumor and Stromal-Based Contributions to Head and Neck Squamous Cell Carcinoma Invasion

    PubMed Central

    Markwell, Steven M.; Weed, Scott A.

    2015-01-01

    Head and neck squamous cell carcinoma (HNSCC) is typically diagnosed at advanced stages with evident loco-regional and/or distal metastases. The prevalence of metastatic lesions directly correlates with poor patient outcome, resulting in high patient mortality rates following metastatic development. The progression to metastatic disease requires changes not only in the carcinoma cells, but also in the surrounding stromal cells and tumor microenvironment. Within the microenvironment, acellular contributions from the surrounding extracellular matrix, along with contributions from various infiltrating immune cells, tumor associated fibroblasts, and endothelial cells facilitate the spread of tumor cells from the primary site to the rest of the body. Thus far, most attempts to limit metastatic spread through therapeutic intervention have failed to show patient benefit in clinic trails. The goal of this review is highlight the complexity of invasion-promoting interactions in the HNSCC tumor microenvironment, focusing on contributions from tumor and stromal cells in order to assist future therapeutic development and patient treatment. PMID:25734659

  19. The Roles of Mesenchymal Stromal/Stem Cells in Tumor Microenvironment Associated with Inflammation

    PubMed Central

    Krstić, Jelena; Djordjević, Ivana Okić; Jauković, Aleksandra

    2016-01-01

    State of tumor microenvironment (TME) is closely linked to regulation of tumor growth and progression affecting the final outcome, refractoriness, and relapse of disease. Interactions of tumor, immune, and mesenchymal stromal/stem cells (MSCs) have been recognized as crucial for understanding tumorigenesis. Due to their outstanding features, stem cell-like properties, capacity to regulate immune response, and dynamic functional phenotype dependent on microenvironmental stimuli, MSCs have been perceived as important players in TME. Signals provided by tumor-associated chronic inflammation educate MSCs to alter their phenotype and immunomodulatory potential in favor of tumor-biased state of MSCs. Adjustment of phenotype to TME and acquisition of tumor-promoting ability by MSCs help tumor cells in maintenance of permissive TME and suppression of antitumor immune response. Potential utilization of MSCs in treatment of tumor is based on their inherent ability to home tumor tissue that makes them suitable delivery vehicles for immune-stimulating factors and vectors for targeted antitumor therapy. Here, we review data regarding intrusive effects of inflammatory TME on MSCs capacity to affect tumor development through modification of their phenotype and interactions with immune system.

  20. Ramucirumab Clinical Development: an Emerging Role in Gastrointestinal Tumors.

    PubMed

    Sanchez-Gastaldo, Amparo; Gonzalez-Exposito, Reyes; Garcia-Carbonero, Rocío

    2016-08-01

    Ramucirumab (IMC-1121B, LY3009806) is a fully human G1 monoclonal antibody that specifically targets vascular endotelial growth factor receptor 2 (VEGFR-2) with a substantially greater binding affinity than that of its natural ligands. Early clinical trials in patients with advanced solid tumors demonstrated that biologically relevant blood target concentrations are achievable with tolerable doses, and also showed some preliminary evidence of clinical activity. Several pivotal phase III trials have now been concluded and have led regulatory agencies to grant marketing authorization to ramucirumab for use as second line therapy in patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma (as single agent or in combination with paclitaxel), in patients with advanced colorectal carcinoma (CRC) (in combination with infusional fluorouracil and irinotecan (FOLFIRI regimen)) and in patients with advanced non-small cell lung cancer (NSCLC) (in combination with docetaxel). In contrast, ramucirumab failed to significantly improve survival versus placebo as second line therapy in patients with advanced hepatocellular carcinoma (HCC). The aim of this review is to summarize the clinical development and emerging role of ramucirumab in gastrointestinal (GI) tumors, including relevant aspects of its mechanism of action, pharmacology, safety profile, and antitumor activity in gastric, HCC, and CRC carcinomas. PMID:26887374

  1. Understanding the Warburg effect and the prognostic value of stromal caveolin-1 as a marker of a lethal tumor microenvironment

    PubMed Central

    2011-01-01

    Cancer cells show a broad spectrum of bioenergetic states, with some cells using aerobic glycolysis while others rely on oxidative phosphorylation as their main source of energy. In addition, there is mounting evidence that metabolic coupling occurs in aggressive tumors, between epithelial cancer cells and the stromal compartment, and between well-oxygenated and hypoxic compartments. We recently showed that oxidative stress in the tumor stroma, due to aerobic glycolysis and mitochondrial dysfunction, is important for cancer cell mutagenesis and tumor progression. More specifically , increased autophagy/mitophagy in the tumor stroma drives a form of parasitic epithelial-stromal metabolic coupling. These findings explain why it is effective to treat tumors with either inducers or inhibitors of autophagy, as both would disrupt this energetic coupling. We also discuss evidence that glutamine addiction in cancer cells produces ammonia via oxidative mitochondrial metabolism. Ammonia production in cancer cells, in turn, could then help maintain autophagy in the tumor stromal compartment. In this vicious cycle, the initial glutamine provided to cancer cells would be produced by autophagy in the tumor stroma. Thus, we believe that parasitic epithelial-stromal metabolic coupling has important implications for cancer diagnosis and therapy, for example, in designing novel metabolic imaging techniques and establishing new targeted therapies. In direct support of this notion, we identified a loss of stromal caveolin-1 as a marker of oxidative stress, hypoxia, and autophagy in the tumor microenvironment, explaining its powerful predictive value. Loss of stromal caveolin-1 in breast cancers is associated with early tumor recurrence, metastasis, and drug resistance, leading to poor clinical outcome. PMID:21867571

  2. Leptin as a mediator of tumor-stromal interactions promotes breast cancer stem cell activity.

    PubMed

    Giordano, Cinzia; Chemi, Francesca; Panza, Salvatore; Barone, Ines; Bonofiglio, Daniela; Lanzino, Marilena; Cordella, Angela; Campana, Antonella; Hashim, Adnan; Rizza, Pietro; Leggio, Antonella; Győrffy, Balázs; Simões, Bruno M; Clarke, Robert B; Weisz, Alessandro; Catalano, Stefania; Andò, Sebastiano

    2016-01-12

    Breast cancer stem cells (BCSCs) play crucial roles in tumor initiation, metastasis and therapeutic resistance. A strict dependency between BCSCs and stromal cell components of tumor microenvironment exists. Thus, novel therapeutic strategies aimed to target the crosstalk between activated microenvironment and BCSCs have the potential to improve clinical outcome. Here, we investigated how leptin, as a mediator of tumor-stromal interactions, may affect BCSC activity using patient-derived samples (n = 16) and breast cancer cell lines, and determined the potential benefit of targeting leptin signaling in these model systems. Conditioned media (CM) from cancer-associated fibroblasts and breast adipocytes significantly increased mammosphere formation in breast cancer cells and depletion of leptin from CM completely abrogated this effect. Mammosphere cultures exhibited increased leptin receptor (OBR) expression and leptin exposure enhanced mammosphere formation. Microarray analyses revealed a similar expression profile of genes involved in stem cell biology among mammospheres treated with CM and leptin. Interestingly, leptin increased mammosphere formation in metastatic breast cancers and expression of OBR as well as HSP90, a target of leptin signaling, were directly correlated with mammosphere formation in metastatic samples (r = 0.68/p = 0.05; r = 0.71/p = 0.036, respectively). Kaplan-Meier survival curves indicated that OBR and HSP90 expression were associated with reduced overall survival in breast cancer patients (HR = 1.9/p = 0.022; HR = 2.2/p = 0.00017, respectively). Furthermore, blocking leptin signaling by using a full leptin receptor antagonist significantly reduced mammosphere formation in breast cancer cell lines and patient-derived samples. Our results suggest that leptin/leptin receptor signaling may represent a potential therapeutic target that can block the stromal-tumor interactions driving BCSC-mediated disease progression. PMID:26556856

  3. Virilizing ovarian stromal tumor in a young woman with Carney complex.

    PubMed

    Carney, J Aidan; Stratakis, Constantine A

    2011-10-01

    A woman with Carney complex presented at the age of 22 years with abdominal pain and hirsutism. As a baby, she had undergone excision of a right eyelid lesion, and at age 14 years she had undergone removal of a left lower eyelid nodule that subsequently recurred. Investigation revealed an elevated level of serum testosterone and a 2-cm left ovarian tumor. A left salpingo-oophorectomy was performed. Postoperatively, she experienced relief from abdominal pain, the serum level of testosterone normalized, and the hirsutism ameliorated. The tumor featured sheets of eosinophilic cells with lipochrome pigment, myeloid metaplasia, stromal metaplasia, and markedly abnormal blood vessels. Immunocytochemically, the tumor cells were positive for vimentin, synaptophysin, inhibin-A, and calrenin. Because of the clinical setting in which the neoplasm occurred, it is likely that is occurrence was related to Carney complex. PMID:21934476

  4. Round cell pattern of prostatic stromal tumor of uncertain malignant potential: a subtle newly recognized variant.

    PubMed

    Sadimin, Evita T; Epstein, Jonathan I

    2016-06-01

    Prostatic stromal tumor of uncertain malignant potential (STUMP) is a distinct entity which includes several different patterns. Four patterns of STUMP have been described including stroma with (1) degenerative atypia, (2) hypercellular spindle cells, (3) myxoid spindle cells, and (4) phyllodes-like pattern. The current study identified a novel round cell pattern. We searched our database from 1999 to 2015 and identified 7 patients with round cell pattern out of a total number of 98 patients with STUMP. All 7 cases showed mildly increased stromal cellularity with rounded nuclei, diagnosed on core biopsies in 5 cases, transurethral resection in 1 case, and radical prostatectomy in 1 case. Some degree of glandular displacement was observed in 4 cases. In 2 of the cases, STUMP was not recognized histologically by the referring pathologists and was initially diagnosed as benign prostatic hyperplasia. As has been described with other patterns of STUMP, several cases showed associated epithelial proliferations that in some instances masked the neoplastic stromal process. The round cell pattern of STUMP is a new deceptively subtle pattern that may not be recognized as a neoplasm and may be misdiagnosed as benign prostatic hyperplasia. Although there was no direct evidence in our study that the round cell pattern of STUMP has the same behavior as other variants of STUMPs, increased recognition of this entity will hopefully lead to additional studies to further understand its malignant potential. PMID:26980017

  5. Bilateral pseudoangiomatous stromal hyperplasia tumors in axillary male gynecomastia: report of a case.

    PubMed

    Vega, Roger M; Pechman, David; Ergonul, Burco; Gomez, Carmen; Moller, Mecker G

    2015-01-01

    Pseudoangiomatous stromal hyperplasia (PASH) is a rare benign proliferation of breast stromal cells with a complex pattern of interanastomosing spaces lined by myofibroblasts. The exact etiology is still unknown, but a proliferative response of myofibroblasts to hormonal stimuli has been postulated. PASH is a relatively common incidental finding in breast tissue removed for other reasons and rarely manifests as a localized mass. Fewer than 150 cases of tumoral PASH have been reported since it was first described in 1986. Although PASH tends to grow over time, most lesions are cured by surgical excision and the prognosis is excellent. We report an unusual case of bilateral axillary tumoral PASH in a 44-year-old man. Awareness of this disease is important when considering the differential diagnosis of axillary masses. To our knowledge, only one other case of unilateral axillary tumoral PASH in a male patient has been described in English and this is the first case of PASH occurring in male bilateral axillary gynecomastia. PMID:24676934

  6. GI Stromal Tumors: 15 Years of Lessons From a Rare Cancer.

    PubMed

    Cioffi, Angela; Maki, Robert G

    2015-06-01

    A confluence of factors, most prominently the recognition of GI stromal tumor (GIST) as a specific sarcoma subtype and the availability of imatinib, led to the "Big Bang" of GIST therapy (ie, the successful treatment of the first patient with GIST with imatinib in 2000). The trail blazed by imatinib for chronic myelogenous leukemia and GIST has become a desired route to regulatory approval of an increasing number of oral kinase inhibitors and other novel therapeutics. In this review, the status of GIST management before and after GIST's "Big Bang" and new steps being taken to further improve on therapy are reviewed. PMID:25918303

  7. Prognosis and management of adult wild type gastrointestinal stromal tumours (GISTs): A pooled analysis and review of literature.

    PubMed

    Bhatt, N R; Collins, D; Crotty, P; Ridgway, P F

    2016-09-01

    A pooled review was performed to determine survival in adult WT GIST (Wild Type GastroIntestinal Stromal Tumours) and compare the same with pediatric WT GISTs. Electronic databases were searched using the terms "Wild type" AND "GIST". Eighty-two adult patients from 14 studies were included in the pooled analysis. Cumulative survival was greater than 50% in both age groups, hence medial survival could not be computed. Mean survival in adults was 15.7 years ± 0.78 and in children was 18.8 years ± 1.3 (p = 0.241). Median disease free survival in adults was 10 years while 5-year overall survival was 88%. There was no statistically significant difference in the survival between the two groups (p = 0.241). Overall survival in adults with WT GISTs is favourable compared to other adult GIST subtypes likely reflects a common molecular pathway similar to pediatric GIST. PMID:27566016

  8. Sporadic diffuse segmental interstitial cell of Cajal hyperplasia harbouring two gastric gastrointestinal stromal tumours (GIST) mimicking hereditary GIST syndromes

    PubMed Central

    Neves, Mafalda Costa; Stamp, Gordon; Mudan, Satvinder

    2015-01-01

    Introduction Gastrointestinal stromal tumours (GISTs) are thought to derive from or differentiate towards the interstitial cells of Cajal (ICC) as most demonstrate a similar immunoprofile: CD117+, CD34+ and DOG1+. ICC hyperplasia refers to KIT-expressing microscopic spindle cell proliferations involving the myenteric plexus. Case report 74 year-old male presented with a 5-year history of heartburn and dysphagia. Imaging revealed a 4 cm GIST in the gastric fundus. Pathology of the resected specimen revealed diffuse segmental ICC hyperplasia harbouring two macroscopic GISTs and a ‘tumorlet’. A mutation in c-KIT exon 11 was detected in both the solid and the diffuse components. Discussion ICC hyperplasia can occur either as a sporadic focal lesion or in a syndromic setting, known to predispose to multiple GIST tumours at different sites. The majority of cases of sporadic ICC hyperplasia previously reported were of localised type. The hereditary form is mostly caused by germline mutations in c-KIT and PDGFRA or in patients with NF-1 andpresents as a diffuse hyperplasia, usually with a confluent, nodular or multifocal growth pattern. Conclusion We describe a diffuse form of sporadic ICC hyperplasia harbouring multifocal GISTs, mimicking diffuse ICC hyperplasia in hereditary GIST syndromes. Detection of somatic c-KIT exon 11 mutation ruled out a hereditary disorder. PMID:26521201

  9. Effectiveness of Endoscopic Treatment for Gastrointestinal Neuroendocrine Tumors

    PubMed Central

    Sun, Weili; Wu, Siyuan; Han, Xiao; Yang, Chuanhua

    2016-01-01

    Abstract Several recent studies have explored efficacy and safety of different endoscopic treatments for gastrointestinal neuroendocrine tumors (GI-NETs). However, there is no definitive consensus regarding the best endoscopic approach for GI-NETs treatment. Therefore, the present study was conducted to investigate the application of various endoscopic techniques for the treatment of GI-NETs according to the previous conclusions and to summarize the optimal endoscopic modalities for GI-NETs. Ninety-eight patients with 100 GI-NETs removed by endoscopic therapies were reviewed. The pathological complete resection rate (PCRR), complication, local recurrence, and factors possibly associated with the pathological complete resection were analyzed. Twenty-two patients were treated by conventional polypectomy (including 6 cold biopsy forceps polypectomy and 16 snare polypectomy with electrocauterization), 41 by endoscopic mucosal resection (EMR), and 35 by endoscopic submucosal dissection (ESD). The PCRRs of conventional polypectomy, EMR, and ESD were 86.4%, 75.6%, and 85.7%, respectively. Sixteen GI-NETs that had a polypoid appearance, with a mean tumor size of 5.2 mm, were removed by snare polypectomy (PCRR 93.8%). The complication rates of conventional polypectomy, EMR, and ESD were 0.0% (0/22), 2.4% (1/41), and 2.9% (1/35), respectively. There were 2 local recurrences after cold biopsy forceps polypectomy treatment and no local recurrences in the EMR and ESD groups (P = 0.049). The results showed that PCRR was only associated with the depth of invasion (P = 0.038). Endoscopic resection of GI-NETs is safe and effective in properly selected patients. For submucosal GI-NETs, ESD was a feasible modality, with a higher PCRR compared with EMR. For ≤5 mm polypoid-like NETs, snare polypectomy with electrocauterization was a simple procedure with a high PCRR. PMID:27082572

  10. TGF-β in jaw tumor fluids induces RANKL expression in stromal fibroblasts.

    PubMed

    Yamada, Chiaki; Aikawa, Tomonao; Okuno, Emi; Miyagawa, Kazuaki; Amano, Katsuhiko; Takahata, Sosuke; Kimata, Masaaki; Okura, Masaya; Iida, Seiji; Kogo, Mikihiko

    2016-08-01

    Odontogenic tumors and cysts, arising in the jawbones, grow by resorption and destruction of the jawbones. However, mechanisms underlying bone resorption by odontogenic tumors/cysts remain unclear. Odontogenic tumors/cysts comprise odontogenic epithelial cells and stromal fibroblasts, which originate from the developing tooth germ. It has been demonstrated that odontogenic epithelial cells of the developing tooth germ induce osteoclastogenesis to prevent the tooth germ from invading the developing bone to maintain its structure in developing bones. Thus, we hypothesized that odontogenic epithelial cells of odontogenic tumors/cysts induce osteoclast formation, which plays potential roles in tumor/cyst outgrowth into the jawbone. The purpose of this study was to examine osteoclastogenesis by cytokines, focusing on transforming growth factor-β (TGF-β), produced by odontogenic epithelial cells. We observed two pathways for receptor activator of NF-κB ligand (RANKL) induction by keratocystic odontogenic tumor fluid: the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway through interleukin-1α (IL-1α) signaling and non-COX-2/PGE2 pathway through TGF-β receptor signaling. TGF-β1 and IL-1α produced by odontogenic tumors/cysts induced osteoclastogenesis directly in the osteoclast precursor cells and indirectly via increased RANKL induction in the stroma. PMID:27279422

  11. TGF-β in jaw tumor fluids induces RANKL expression in stromal fibroblasts

    PubMed Central

    Yamada, Chiaki; Aikawa, Tomonao; Okuno, Emi; Miyagawa, Kazuaki; Amano, Katsuhiko; Takahata, Sosuke; Kimata, Masaaki; Okura, Masaya; Iida, Seiji; Kogo, Mikihiko

    2016-01-01

    Odontogenic tumors and cysts, arising in the jawbones, grow by resorption and destruction of the jawbones. However, mechanisms underlying bone resorption by odontogenic tumors/cysts remain unclear. Odontogenic tumors/cysts comprise odontogenic epithelial cells and stromal fibroblasts, which originate from the developing tooth germ. It has been demonstrated that odontogenic epithelial cells of the developing tooth germ induce osteoclastogenesis to prevent the tooth germ from invading the developing bone to maintain its structure in developing bones. Thus, we hypothesized that odontogenic epithelial cells of odontogenic tumors/cysts induce osteoclast formation, which plays potential roles in tumor/cyst outgrowth into the jawbone. The purpose of this study was to examine osteoclastogenesis by cytokines, focusing on transforming growth factor-β (TGF-β), produced by odontogenic epithelial cells. We observed two pathways for receptor activator of NF-κB ligand (RANKL) induction by keratocystic odontogenic tumor fluid: the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway through interleukin-1α (IL-1α) signaling and non-COX-2/PGE2 pathway through TGF-β receptor signaling. TGF-β1 and IL-1α produced by odontogenic tumors/cysts induced osteoclastogenesis directly in the osteoclast precursor cells and indirectly via increased RANKL induction in the stroma. PMID:27279422

  12. Toward Brain Tumor Gene Therapy Using Multipotent Mesenchymal Stromal Cell Vectors

    PubMed Central

    Bexell, Daniel; Scheding, Stefan; Bengzon, Johan

    2010-01-01

    Gene therapy of solid cancers has been severely restricted by the limited distribution of vectors within tumors. However, cellular vectors have emerged as an effective migratory system for gene delivery to invasive cancers. Implanted and injected multipotent mesenchymal stromal cells (MSCs) have shown tropism for several types of primary tumors and metastases. This capacity of MSCs forms the basis for their use as a gene vector system in neoplasms. Here, we review the tumor-directed migratory potential of MSCs, mechanisms of the migration, and the choice of therapeutic transgenes, with a focus on malignant gliomas as a model system for invasive and highly vascularized tumors. We examine recent findings demonstrating that MSCs share many characteristics with pericytes and that implanted MSCs localize primarily to perivascular niches within tumors, which might have therapeutic implications. The use of MSC vectors in cancer gene therapy raises concerns, however, including a possible MSC contribution to tumor stroma and vasculature, MSC-mediated antitumor immune suppression, and the potential malignant transformation of cultured MSCs. Nonetheless, we highlight the novel prospects of MSC-based tumor therapy, which appears to be a promising approach. PMID:20407426

  13. Outcome and Prognostic Factors in Endometrial Stromal Tumors: A Rare Cancer Network Study

    SciTech Connect

    Schick, Ulrike; Bolukbasi, Yasmin; Thariat, Juliette; Abdah-Bortnyak, Roxolyana; Kuten, Abraham; Igdem, Sefik; Caglar, Hale; Ozsaran, Zeynep; Loessl, Kristina; Schleicher, Ursula; Zwahlen, Daniel; Villette, Sylviane; Vees, Hansjoerg

    2012-04-01

    Purpose: To provide further understanding regarding outcome and prognostic factors of endometrial stromal tumors (EST). Methods and Materials: A retrospective analysis was performed on the records of 59 women diagnosed with EST and treated with curative intent between 1983 and 2007 in the framework of the Rare Cancer Network. Results: Endometrial stromal sarcomas (ESS) were found in 44% and undifferentiated ESS (UES) in 49% of the cases. In 7% the grading was unclear. Of the total number of patients, 33 had Stage I, 4 Stage II, 20 Stage III, and 1 presented with Stage IVB disease. Adjuvant chemotherapy was administered to 12 patients, all with UES. External-beam radiotherapy (RT) was administered postoperatively to 48 women. The median follow-up was 41.4 months. The 5-year overall survival (OS) rate was 96.2% and 64.8% for ESS and UES, respectively, with a corresponding 5-year disease-free survival (DFS) rate of 49.4% and 43.4%, respectively. On multivariate analysis, adjuvant RT was an independent prognostic factor for OS (p = 0.007) and DFS (p = 0.013). Locoregional control, DFS, and OS were significantly associated with age ({<=}60 vs. >60 years), grade (ESS vs. UES), and International Federation of Gynecology and Obstetrics stage (I-II vs. III-IV). Positive lymph node staging had an impact on OS (p < 0.001). Conclusion: The prognosis of ESS differed from that of UES. Endometrial stromal sarcomas had an excellent 5-year OS, whereas the OS in UES was rather low. However, half of ESS patients had a relapse. For this reason, adjuvant treatment such as RT should be considered even in low-grade tumors. Multicenter randomized studies are still warranted to establish clear guidelines.

  14. Cystic nephroma/mixed epithelial stromal tumor: a benign neoplasm with potential for recurrence.

    PubMed

    Sun, Belinda L; Abern, Michael; Garzon, Steven; Setty, Suman

    2015-05-01

    Cystic nephroma (CN) is a rare, benign, renal neoplasm composed of epithelial and stromal elements. Only about 200 cases have been reported since 1892 and recurrence has rarely been observed. We report a 32-year-old Hispanic woman, with a history of a right, complex cystic, renal mass treated by robotic decortication 2 years ago, who presented with flank pain, hematuria, and recurrent urinary tract infection. A magnetic resonance imaging study showed a 3.4-cm multicystic lesion with thickened septa and enhancement at the right kidney. The partial nephrectomy specimen revealed a well-circumscribed, multicystic tumor abutting the renal pelvis, with thick septa and smooth walls, filled with clear fluid. Microscopic examination showed variably sized cysts lined by cuboidal epithelium with focal hobnailing, without significant cytologic atypia and mitosis. The epithelial lining was positive for CK19, high molecular weight cytokeratin, and α-methylacyl-CoA racemase suggesting a primitive tubular epithelial phenotype. Primitive glomeruli-like structures were also present. The ovarian-like stroma was condensed around the cysts and was variably cellular with areas of muscle differentiation and thick-walled vessels. The stroma was positive for desmin, estrogen receptor, progesterone receptor, and CD10. We suggest that CN represents a variable mixture of epithelial and stromal elements, immature glomerular, tubular, muscle, and vascular elements, which may be present in variable proportions creating a spectrum of lesions previously described as CN and mixed epithelial and stromal tumors (MEST). This case emphasizes that CN/MEST clinically/radiologically mimics other cystic renal neoplasms, especially cystic renal cell carcinoma and tubulocystic carcinoma, necessitating histopathological examination and immunohistochemial studies for definitive diagnosis. Additionally, CN has the tendency to recur when not completely excised initially. PMID:25525149

  15. [Specificities of sex-cord stromal tumors in children and adolescents].

    PubMed

    Thebaud, Estelle; Orbach, Daniel; Faure-Conter, Cécile; Patte, Catherine; Hameury, Frederic; Kalfa, Nicolas; Dijoud, Frédérique; Martelli, Hélène; Fresneau, Brice

    2015-06-01

    Sex-cord stromal tumors (SCT) are rare pediatric tumors accounting for less than 5% of gonadal tumors in children and adolescents. They differ from those diagnosed in adults by their presentation, histology, evolution and treatment modalities. Testicular SCT occur mostly in infants less than 6 months. Testicular swelling is often the only symptom, but signs of hormonal secretion with gynecomastia may be present. Juvenile granulosa SCT is the main histologic subtype. Sertoli SCTs are much less frequent while Leydig tumors occurred in older children and adolescents. Prognosis is excellent after inguinal orchiectomy. Testis sparing surgery could be performed but indications and modalities have to be strongly defined. Ovarian SCT are diagnosed in older children and adolescents and present with abdominal symptoms and/or signs of hormonal secretion: estrogenic manifestations (isosexual pseudoprecocity, menometrorrhagia) or virilization (hirsutism, amenorrhea). Main histologic subtype is juvenile granulosa (rarely Sertoli-Leydig). If oophorectomy (or salpingo-oophorectomy) may be curative for localized disease, adjuvant cisplatin-containing chemotherapy is mandatory in case of tumor rupture or peritoneal dissemination to prevent recurrences. Because of the rarity of these pediatric tumors, concerted multidisciplinary cares are required to best adapt therapeutic strategy before any surgical intervention. PMID:26028491

  16. Multifocal Tumorous Pseudoangiomatous Stromal Hyperplasia Presenting as Asymmetric Bilateral Breast Enlargement

    PubMed Central

    Vasconcelos, I.; Perez Fernandez, C. M.; Günzel, S.; Schoenegg, W.

    2015-01-01

    PASH is a benign proliferation of stromal myofibroblasts that affects mostly premenopausal women and typically shows estrogen and progesterone receptor expression, allowing speculation regarding a hormonal cause. It usually presents as an incidental finding on a mammogram or as a palpable mass. We present a case of diffuse asymmetrical massive breast enlargement in a premenopausal woman with history of previous multiple PASH excisions for recurrent lesions, caused by multifocal tumorous PASH virtually replacing the breast parenchyma. Immunohistochemistry examination showed no hormone receptor expression. Despite its benign nature, such presentation of PASH is managed with bilateral mastectomy and immediate reconstruction with expanders for cosmetic and comfort reasons, while tumor excision or expectant management is deemed to lead to recurrence and progression. Although a hormonal origin is speculated based on hormone expression studies and typical patient profile, this case showed 0 % estrogen/progesterone expression in the final histology specimen. PMID:25797961

  17. Tumor-associated macrophages and stromal TNF-α regulate collagen structure in a breast tumor model as visualized by second harmonic generation

    NASA Astrophysics Data System (ADS)

    Burke, Ryan M.; Madden, Kelley S.; Perry, Seth W.; Zettel, Martha L.; Brown, Edward B.

    2013-08-01

    Collagen fibers can be imaged with second harmonic generation (SHG) and are associated with efficient tumor cell locomotion. Preferential locomotion along these fibers correlates with a more aggressively metastatic phenotype, and changes in SHG emission properties accompany changes in metastatic outcome. We therefore attempted to elucidate the cellular and molecular machinery that influences SHG in order to understand how the microstructure of tumor collagen fibers is regulated. By quantifying SHG and immunofluorescence (IF) from tumors grown in mice with and without stromal tumor necrosis factor (TNF)-α and in the presence or absence of tumor-associated macrophages (TAMs), we determined that depletion of TAMs alters tumor collagen fibrillar microstructure as quantified by SHG and IF. Furthermore, we determined that abrogation of TNF-α expression by tumor stromal cells also alters fibrillar microstructure and that subsequent depletion of TAMs has no further effect. In each case, metastatic burden correlated with optical readouts of collagen microstructure. Our results implicate TAMs and stromal TNF-α as regulators of breast tumor collagen microstructure and suggest that this regulation plays a role in tumor metastasis. Furthermore, these results indicate that quantification of SHG represents a useful strategy for evaluating the cells and molecular pathways responsible for manipulating fibrillar collagen in breast tumor models.

  18. Stromal CCR6 drives tumor growth in a murine transplantable colon cancer through recruitment of tumor-promoting macrophages.

    PubMed

    Nandi, Bisweswar; Shapiro, Mia; Samur, Mehmet K; Pai, Christine; Frank, Natasha Y; Yoon, Charles; Prabhala, Rao H; Munshi, Nikhil C; Gold, Jason S

    2016-08-01

    Interactions between the inflammatory chemokine CCL20 and its receptor CCR6 have been implicated in promoting colon cancer; however, the mechanisms behind this effect are poorly understood. We have previously demonstrated that deficiency of CCR6 is associated with decreased tumor macrophage accumulation in a model of sporadic intestinal tumorigenesis. In this study, we aimed to determine the role of stromal CCR6 expression in a murine syngeneic transplantable colon cancer model. We show that deficiency of host CCR6 is associated with decreased growth of syngeneic CCR6-expressing colon cancers. Colon cancers adoptively transplanted into CCR6-deficient mice have decreased tumor-associated macrophages without alterations in the number of monocytes in blood or bone marrow. CCL20, the unique ligand for CCR6, promotes migration of monocytes in vitro and promotes accumulation of macrophages in vivo. Depletion of tumor-associated macrophages decreases the growth of tumors in the transplantable tumor model. Macrophages infiltrating the colon cancers in this model secrete the inflammatory mediators CCL2, IL-1α, IL-6 and TNFα. Ccl2, Il1α and Il6 are consequently downregulated in tumors from CCR6-deficient mice. CCL2, IL-1α and IL-6 also promote proliferation of colon cancer cells, linking the decreased macrophage migration into tumors mediated by CCL20-CCR6 interactions to the delay in tumor growth in CCR6-deficient hosts. The relevance of these findings in human colon cancer is demonstrated through correlation of CCR6 expression with that of the macrophage marker CD163 as well as that of CCL2, IL1α and TNFα. Our findings support the exploration of targeting the CCL20-CCR6 pathway for the treatment of colon cancer. PMID:27622061

  19. Whole transcriptome profiling of patient-derived xenograft models as a tool to identify both tumor and stromal specific biomarkers

    PubMed Central

    Bradford, James R.; Wappett, Mark; Beran, Garry; Logie, Armelle; Delpuech, Oona; Brown, Henry; Boros, Joanna; Camp, Nicola J.; McEwen, Robert; Mazzola, Anne Marie; D'Cruz, Celina; Barry, Simon T.

    2016-01-01

    The tumor microenvironment is emerging as a key regulator of cancer growth and progression, however the exact mechanisms of interaction with the tumor are poorly understood. Whilst the majority of genomic profiling efforts thus far have focused on the tumor, here we investigate RNA-Seq as a hypothesis-free tool to generate independent tumor and stromal biomarkers, and explore tumor-stroma interactions by exploiting the human-murine compartment specificity of patient-derived xenografts (PDX). Across a pan-cancer cohort of 79 PDX models, we determine that mouse stroma can be separated into distinct clusters, each corresponding to a specific stromal cell type. This implies heterogeneous recruitment of mouse stroma to the xenograft independent of tumor type. We then generate cross-species expression networks to recapitulate a known association between tumor epithelial cells and fibroblast activation, and propose a potentially novel relationship between two hypoxia-associated genes, human MIF and mouse Ddx6. Assessment of disease subtype also reveals MMP12 as a putative stromal marker of triple-negative breast cancer. Finally, we establish that our ability to dissect recruited stroma from trans-differentiated tumor cells is crucial to identifying stem-like poor-prognosis signatures in the tumor compartment. In conclusion, RNA-Seq is a powerful, cost-effective solution to global analysis of human tumor and mouse stroma simultaneously, providing new insights into mouse stromal heterogeneity and compartment-specific disease markers that are otherwise overlooked by alternative technologies. The study represents the first comprehensive analysis of its kind across multiple PDX models, and supports adoption of the approach in pre-clinical drug efficacy studies, and compartment-specific biomarker discovery. PMID:26980748

  20. Whole transcriptome profiling of patient-derived xenograft models as a tool to identify both tumor and stromal specific biomarkers.

    PubMed

    Bradford, James R; Wappett, Mark; Beran, Garry; Logie, Armelle; Delpuech, Oona; Brown, Henry; Boros, Joanna; Camp, Nicola J; McEwen, Robert; Mazzola, Anne Marie; D'Cruz, Celina; Barry, Simon T

    2016-04-12

    The tumor microenvironment is emerging as a key regulator of cancer growth and progression, however the exact mechanisms of interaction with the tumor are poorly understood. Whilst the majority of genomic profiling efforts thus far have focused on the tumor, here we investigate RNA-Seq as a hypothesis-free tool to generate independent tumor and stromal biomarkers, and explore tumor-stroma interactions by exploiting the human-murine compartment specificity of patient-derived xenografts (PDX).Across a pan-cancer cohort of 79 PDX models, we determine that mouse stroma can be separated into distinct clusters, each corresponding to a specific stromal cell type. This implies heterogeneous recruitment of mouse stroma to the xenograft independent of tumor type. We then generate cross-species expression networks to recapitulate a known association between tumor epithelial cells and fibroblast activation, and propose a potentially novel relationship between two hypoxia-associated genes, human MIF and mouse Ddx6. Assessment of disease subtype also reveals MMP12 as a putative stromal marker of triple-negative breast cancer. Finally, we establish that our ability to dissect recruited stroma from trans-differentiated tumor cells is crucial to identifying stem-like poor-prognosis signatures in the tumor compartment.In conclusion, RNA-Seq is a powerful, cost-effective solution to global analysis of human tumor and mouse stroma simultaneously, providing new insights into mouse stromal heterogeneity and compartment-specific disease markers that are otherwise overlooked by alternative technologies. The study represents the first comprehensive analysis of its kind across multiple PDX models, and supports adoption of the approach in pre-clinical drug efficacy studies, and compartment-specific biomarker discovery. PMID:26980748

  1. Folate-related polymorphisms in gastrointestinal stromal tumours: susceptibility and correlation with tumour characteristics and clinical outcome.

    PubMed

    Angelini, Sabrina; Ravegnini, Gloria; Nannini, Margherita; Bermejo, Justo Lorenzo; Musti, Muriel; Pantaleo, Maria A; Fumagalli, Elena; Venturoli, Nicola; Palassini, Elena; Consolini, Nicola; Casali, Paolo G; Biasco, Guido; Hrelia, Patrizia

    2015-06-01

    The folate metabolism pathway has a crucial role in tumorigenesis as it supports numerous critical intracellular reactions, including DNA synthesis, repair, and methylation. Despite its importance, little is known about the influence of the folate pathway on gastrointestinal stromal tumour (GIST), a rare tumour with an incidence ranging between 6 and 19.6 cases per million worldwide. The importance of folate metabolism led us to investigate the influence of polymorphisms in the genes coding folate-metabolising enzymes on GIST susceptibility, tumour characteristics and clinical outcome. We investigated a panel of 13 polymorphisms in 8 genes in 60 cases and 153 controls. The TS 6-bp deletion allele (formerly rs34489327, delTInsTTAAAG) was associated with reduced risk of GIST (OR=0.20, 95% CI 0.05-0.67, P=0.0032). Selected polymorphisms in patients stratified by age, gender, and other main molecular and clinical characteristics showed that few genotypes may show a likely correlation. We also observed a significant association between the RFC AA/AG genotype and time to progression (HR=0.107, 95% CI 0.014-0.82; P=0.032). Furthermore, we observed a tendency towards an association between the SHMT1 variant allele (TT, rs1979277) and early death (HR=4.53, 95% CI 0.77-26.58, P=0.087). Aware of the strengths and limitations of the study, these results suggest that polymorphisms may modify the risk of GIST and clinical outcome, pointing to the necessity for further investigations with information on folate plasma levels and a larger study population. PMID:25227144

  2. Folate-related polymorphisms in gastrointestinal stromal tumours: susceptibility and correlation with tumour characteristics and clinical outcome

    PubMed Central

    Angelini, Sabrina; Ravegnini, Gloria; Nannini, Margherita; Bermejo, Justo Lorenzo; Musti, Muriel; Pantaleo, Maria A; Fumagalli, Elena; Venturoli, Nicola; Palassini, Elena; Consolini, Nicola; Casali, Paolo G; Biasco, Guido; Hrelia, Patrizia

    2015-01-01

    The folate metabolism pathway has a crucial role in tumorigenesis as it supports numerous critical intracellular reactions, including DNA synthesis, repair, and methylation. Despite its importance, little is known about the influence of the folate pathway on gastrointestinal stromal tumour (GIST), a rare tumour with an incidence ranging between 6 and 19.6 cases per million worldwide. The importance of folate metabolism led us to investigate the influence of polymorphisms in the genes coding folate-metabolising enzymes on GIST susceptibility, tumour characteristics and clinical outcome. We investigated a panel of 13 polymorphisms in 8 genes in 60 cases and 153 controls. The TS 6-bp deletion allele (formerly rs34489327, delTInsTTAAAG) was associated with reduced risk of GIST (OR=0.20, 95% CI 0.05–0.67, P=0.0032). Selected polymorphisms in patients stratified by age, gender, and other main molecular and clinical characteristics showed that few genotypes may show a likely correlation. We also observed a significant association between the RFC AA/AG genotype and time to progression (HR=0.107, 95% CI 0.014–0.82; P=0.032). Furthermore, we observed a tendency towards an association between the SHMT1 variant allele (TT, rs1979277) and early death (HR=4.53, 95% CI 0.77–26.58, P=0.087). Aware of the strengths and limitations of the study, these results suggest that polymorphisms may modify the risk of GIST and clinical outcome, pointing to the necessity for further investigations with information on folate plasma levels and a larger study population. PMID:25227144

  3. Expression of CD117, DOG-1, and IGF-1R in gastrointestinal stromal tumours – an analysis of 70 cases from 2004 to 2010

    PubMed Central

    Zińczuk, Justyna; Kemona, Andrzej; Guzińska-Ustymowicz, Katarzyna; Żurawska, Joanna; Kędra, Bogusław

    2015-01-01

    Introduction Determination of the type of mutations in gastrointestinal stromal tumours (GIST) plays a major role in assessing the risk of progression of the disease, and also allows determination of the clinical management and treatment. More accurate GIST diagnosis is possible by using simultaneously various types of antibodies to immunohistochemistry methods in routine procedures. Aim To evaluate the expression of CD117, DOG-1, and IGF-1R in patients with gastrointestinal stromal tumours, and analysis of the impact of the examined protein expression on patient survival with emphasis on specific recognition and prognostication of these tumours. Material and methods The protein expression was analyzed in 70 patients who had undergone surgical treatment for mesenchymal tumours of the gastrointestinal tract, using the immunohistochemical method. Results Positive expression of CD117, DOG-1, and IGF1R included 95.71%, 88.57% and 11.43% of study GISTs, respectively. Statistical analysis showed positive significant correlation between DOG-1 expression and histological type of tumour (p = 0.024). Analysis of overall survival curves of 70 GIST patients according to expression of CD117, DOG-1, and IGF1R did not show a tendency towards longer survival of patients with positive expression (p > 0.05). Conclusions Predictive factors determining the survival time of patients are strongly associated with morphological features of tumours. A thorough analysis of each case plays a key role in predicting survival time of patients and may be a clue in targeting the therapeutic procedure. PMID:27350839

  4. Comparative proteomic analysis of normal and tumor stromal cells by tissue on chip based mass spectrometry (toc-MS)

    PubMed Central

    2010-01-01

    In carcinoma tissues, genetic and metabolic changes not only occur at the tumor cell level, but also in the surrounding stroma. This carcinoma-reactive stromal tissue is heterogeneous and consists e.g. of non-epithelial cells such as fibroblasts or fibrocytes, inflammatory cells and vasculature-related cells, which promote carcinoma growth and progression of carcinomas. Nevertheless, there is just little knowledge about the proteomic changes from normal connective tissue to tumor stroma. In the present study, we acquired and analysed specific protein patterns of small stromal sections surrounding head and neck cell complexes in comparison to normal subepithelial connective tissue. To gain defined stromal areas we used laser-based tissue microdissection. Because these stromal areas are limited in size we established the highly sensitive 'tissue on chip based mass spectrometry' (toc-MS). Therefore, the dissected areas were directly transferred to chromatographic arrays and the proteomic profiles were subsequently analysed with mass spectrometry. At least 100 cells were needed for an adequate spectrum. The locating of differentially expressed proteins enables a precise separation of normal and tumor stroma. The newly described toc-MS technology allows an initial insight into proteomic differences between small numbers of exactly defined cells from normal and tumor stroma. PMID:20205871

  5. Ferrociphenol lipid nanocapsule delivery by mesenchymal stromal cells in brain tumor therapy.

    PubMed

    Roger, Mathilde; Clavreul, Anne; Huynh, Ngoc Trinh; Passirani, Catherine; Schiller, Paul; Vessières, Anne; Montero-Menei, Claudia; Menei, Philippe

    2012-02-14

    The prognosis of patients with malignant glioma remains extremely poor despite surgery and improvements in radio- and chemo-therapies. Thus, treatment strategies that specifically target these tumors have the potential to greatly improve therapeutic outcomes. "Marrow-isolated adult multilineage inducible" cells (MIAMI cells) are a subpopulation of mesenchymal stromal cells (MSCs) which possess the ability to migrate to brain tumors. We have previously shown that MIAMI cells were able to efficiently incorporate lipid nanocapsules (LNCs) without altering either their stem cell properties or their migration capacity. In this study, we assessed whether the cytotoxic effects of MIAMI cells loaded with LNCs containing an organometallic complex (ferrociphenol or Fc-diOH) could be used to treat brain tumors. The results showed that MIAMI cells internalized Fc-diOH-LNCs and that this internalization did not induce MIAMI cell death. Furthermore, Fc-diOH-LNC-loaded MIAMI cells produced a cytotoxic effect on U87MG glioma cells in vitro. This cytotoxic effect was validated in vivo after intratumoral injection of Fc-diOH-LNC-loaded MIAMI cells in a heterotopic U87MG glioma model in nude mice. These promising results open up a new field of treatment in which cellular vehicles and nanoparticles can be combined to treat brain tumors. PMID:21554935

  6. Inorganic Arsenic–Related Changes in the Stromal Tumor Microenvironment in a Prostate Cancer Cell–Conditioned Media Model

    PubMed Central

    Shearer, Joseph J.; Wold, Eric A.; Umbaugh, Charles S.; Lichti, Cheryl F.; Nilsson, Carol L.; Figueiredo, Marxa L.

    2015-01-01

    Background: The tumor microenvironment plays an important role in the progression of cancer by mediating stromal–epithelial paracrine signaling, which can aberrantly modulate cellular proliferation and tumorigenesis. Exposure to environmental toxicants, such as inorganic arsenic (iAs), has also been implicated in the progression of prostate cancer. Objective: The role of iAs exposure in stromal signaling in the tumor microenvironment has been largely unexplored. Our objective was to elucidate molecular mechanisms of iAs-induced changes to stromal signaling by an enriched prostate tumor microenvironment cell population, adipose-derived mesenchymal stem/stromal cells (ASCs). Results: ASC-conditioned media (CM) collected after 1 week of iAs exposure increased prostate cancer cell viability, whereas CM from ASCs that received no iAs exposure decreased cell viability. Cytokine array analysis suggested changes to cytokine signaling associated with iAs exposure. Subsequent proteomic analysis suggested a concentration-dependent alteration to the HMOX1/THBS1/TGFβ signaling pathway by iAs. These results were validated by quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) and Western blotting, confirming a concentration-dependent increase in HMOX1 and a decrease in THBS1 expression in ASC following iAs exposure. Subsequently, we used a TGFβ pathway reporter construct to confirm a decrease in stromal TGFβ signaling in ASC following iAs exposure. Conclusions: Our results suggest a concentration-dependent alteration of stromal signaling: specifically, attenuation of stromal-mediated TGFβ signaling following exposure to iAs. Our results indicate iAs may enhance prostate cancer cell viability through a previously unreported stromal-based mechanism. These findings indicate that the stroma may mediate the effects of iAs in tumor progression, which may have future therapeutic implications. Citation: Shearer JJ, Wold EA, Umbaugh CS, Lichti CF, Nilsson CL

  7. Registered report: Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis.

    PubMed

    Fiering, Steven; Ang, Lay-Hong; Lacoste, Judith; Smith, Tim D; Griner, Erin

    2015-01-01

    The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replicating selected results from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012 were selected on the basis of citations and Altimetric scores (Errington et al., 2014). This Registered report describes the proposed replication plan of key experiments from 'Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis' by Goetz and colleagues, published in Cell in 2011 (Goetz et al., 2011). The key experiments being replicated are those reported in Figures 7C (a-d), Supplemental Figure S2A, and Supplemental Figure S7C (a-c) (Goetz et al., 2011). In these experiments, which are a subset of all the experiments reported in the original publication, Goetz and colleagues show in a subcutaneous xenograft model that stromal caveolin-1 remodels the intratumoral microenvironment, which is correlated with increased metastasis formation. The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange and the results of the replications will be published in eLife. PMID:26179155

  8. Nonlinear optical microscopy for label-free detection of gastrointestinal neuroendocrine tumors.

    PubMed

    Li, Lianhuang; Jiang, Liwei; Chen, Zhifen; Kang, Deyong; Yang, Zhenrong; Liu, Xing; Jiang, Weizhong; Zhuo, Shuangmu; Guan, Guoxian; Zhou, Yongjian; Chen, Jianxin

    2016-09-01

    Neuroendocrine tumors (NETs), which are rare and slow-growing neoplasms, pose a diagnostic challenge as they are clinically silent at the time of presentation. Here, gastrointestinal neuroendocrine tumors were researched by nonlinear microscopy, and results demonstrate that this technique has the capability to identify neuroendocrine tumors in the absence of labels and can, in particular, detect rare neuroendocrine tumor cells, vascular invasion, desmoplastic reaction, and fibroelastosis induced by neuroendocrine tumors. These conclusions highlight the possibility of nonlinear optical microscopy as a diagnostic tool for label-freely differentiating neuroendocrine tumors by these histopathologic features. PMID:27299572

  9. Stromal Fibroblasts in Digestive Cancer

    PubMed Central

    Worthley, Daniel L.; Giraud, Andrew S.

    2010-01-01

    The normal gastrointestinal stroma consists of extra-cellular matrix and a community of stromal cells including fibroblasts, myofibroblasts, smooth muscle cells, pericytes, endothelium and inflammatory cells. α-smooth muscle actin (α-SMA) positive stromal fibroblasts, often referred to as myofibroblasts or activated fibroblasts, are critical in the development of digestive cancer and help to create an environment that is permissive of tumor growth, angiogenesis and invasion. This review focusses on the contribution of activated fibroblasts in carcinogenesis and where possible directly applies this to, and draws on examples from, gastrointestinal cancer. In particular, the review expands on the definition, types and origins of activated fibroblasts. It examines the molecular biology of stromal fibroblasts and their contribution to the peritumoral microenvironment and concludes by exploring some of the potential clinical applications of this exciting branch of cancer research. Understanding the origin and biology of activated fibroblasts will help in the development of an integrated epithelial-stromal sequence to cancer that will ultimately inform cancer pathogenesis, natural history and future therapeutics. PMID:21209778

  10. p16(INK4A) represses the paracrine tumor-promoting effects of breast stromal fibroblasts.

    PubMed

    Al-Ansari, M M; Hendrayani, S F; Shehata, A I; Aboussekhra, A

    2013-05-01

    Cancer-associated fibroblasts (CAFs), the most abundant and probably the most active cellular component of breast cancer-associated stroma, promote carcinogenesis through paracrine effects; however, the molecular basis remains elusive. We have shown here that p16(INK4A) expression is reduced in 83% CAFs as compared with their normal adjacent counterparts cancer-free tissues isolated from the same patients. This decrease is mainly due to AUF1-dependent higher turnover of the CDKN2A mRNA in CAFs. Importantly, p16(INK4A) downregulation using specific siRNA activated breast fibroblasts and increased the expression/secretion levels of stromal cell-derived factor 1 (SDF-1) and matrix metalloproteinase (MMP)-2. Consequently, media conditioned with these cells stimulated the proliferation of epithelial cells. Furthermore, the migration/invasion of breast cancer cells was also enhanced in an SDF-1-dependent manner. This effect was mediated through inducing an epithelial-mesenchymal transition state. By contrast, increase in p16(INK4A) level through ectopic expression or AUF1 downregulation, reduced the secreted levels of SDF-1 and MMP-2 and suppressed the pro-carcinogenic effects of CAFs. In addition, p16(INK4A)-defective fibroblasts accelerated breast tumor xenograft formation and growth rate in mice. Importantly, tumors formed in the presence of p16(INK4A)-defective fibroblasts exhibited higher levels of active Akt, Cox-2, MMP-2 and MMP-9, showing their greater aggressiveness as compared with xenografts formed in the presence of p16(INK4A)-proficient fibroblasts. These results provide the first indication that p16(INK4A) downregulation in breast stromal fibroblasts is an important step toward their activation. PMID:22751126

  11. Adenovirus i-Leader Truncation Bioselected Against Cancer-associated Fibroblasts to Overcome Tumor Stromal Barriers

    PubMed Central

    Puig-Saus, Cristina; Gros, Alena; Alemany, Ramon; Cascalló, Manel

    2012-01-01

    Tumor-associated stromal cells constitute a major hurdle in the antitumor efficacy with oncolytic adenoviruses. To overcome this biological barrier, an in vitro bioselection of a mutagenized AdwtRGD stock in human cancer-associated fibroblasts (CAFs) was performed. Several rounds of harvest at early cytopathic effect (CPE) followed by plaque isolation led us to identify one mutant with large plaque phenotype, enhanced release in CAFs and enhanced cytotoxicity in CAF and several tumor cell lines. Whole genome sequencing and functional mapping identified the truncation of the last 17 amino acids in C-terminal end of the i-leader protein as the mutation responsible for this phenotype. Similar mutations have been previously isolated in two independent bioselection processes in tumor cell lines. Importantly, our results establish the enhanced antitumor activity in vivo of the i-leader C-terminal truncated mutants, especially in a desmotic fibroblast-embedded lung carcinoma model in mice. These results indicate that the i-leader truncation represents a promising trait to improve virotherapy with oncolytic adenoviruses. PMID:21863000

  12. Targeting Artificial Tumor Stromal Targets for Molecular Imaging of Tumor Vascular Hypoxia

    PubMed Central

    Koonce, Nathan A.; Levy, Joseph; Hardee, Matthew E.; Jamshidi-Parsian, Azemat; Vang, Kieng B.; Sharma, Sunil; Raleigh, James A.; Dings, Ruud P. M.; Griffin, Robert J.

    2015-01-01

    Developed and tested for many years, a variety of tumor hypoxia detection methods have been inconsistent in their ability to predict treatment outcomes or monitor treatment efficacy, limiting their present prognostic capability. These variable results might stem from the fact that these approaches are based on inherently wide-ranging global tumor oxygenation levels based on uncertain influences of necrotic regions present in most solid tumors. Here, we have developed a novel non-invasive and specific method for tumor vessel hypoxia detection, as hypoxemia (vascular hypoxia) has been implicated as a key driver of malignant progression, therapy resistance and metastasis. This method is based on high-frequency ultrasound imaging of α-pimonidazole targeted-microbubbles to the exogenously administered hypoxia marker pimonidazole. The degree of tumor vessel hypoxia was assessed in three mouse models of mammary gland carcinoma (4T1, SCK and MMTV-Wnt-1) and amassed up to 20% of the tumor vasculature. In the 4T1 mammary gland carcinoma model, the signal strength of α-pimonidazole targeted-microbubbles was on average 8-fold fold higher in tumors of pimonidazole-injected mice than in non-pimonidazole injected tumor bearing mice or non-targeted microbubbles in pimonidazole-injected tumor bearing mice. Overall, this provides proof of principle for generating and targeting artificial antigens able to be ‘created’ on-demand under tumor specific microenvironmental conditions, providing translational diagnostic, therapeutic and treatment planning potential in cancer and other hypoxia-associated diseases or conditions. PMID:26308944

  13. Weight reduction and pioglitazone ameliorate polycystic ovary syndrome after removal of a Sertoli-stromal cell tumor

    PubMed Central

    Baba, Tsuyoshi; Endo, Toshiaki; Ikeda, Keiko; Shimizu, Ayumi; Morishita, Miyuki; Kuno, Yoshika; Honnma, Hiroyuki; Kiya, Tamotsu; Ishioka, Shin-ichi; Saito, Tsuyoshi

    2012-01-01

    This report presents an unusual case of Sertoli-stromal cell tumor and polycystic ovary syndrome successfully treated with weight reduction and an insulin-sensitizing agent. A 22-year-old woman, gravida 0, para 0, visited our hospital for the first time with a 12-year history of secondary amenorrhea and hypertrichosis. Transvaginal ultrasonography revealed a solid tumor in the right ovary. Right salpingo-oophorectomy was performed and pathological examination confirmed a Sertoli-stromal cell tumor. The patient’s serum androgen levels declined postoperatively, but remained above normal. Pioglitazone treatment for 6 months also significantly reduced serum androgen levels, but they still remained above normal. However, after losing 12 kg of body weight, the patient’s serum androgen levels declined to normal, and spontaneous menstruation became regular. Weight reduction with pioglitazone is an effective means of treating hyperandrogenism. PMID:23226075

  14. Transcriptome analysis of individual stromal cell populations identifies stroma-tumor crosstalk in mouse lung cancer model.

    PubMed

    Choi, Hyejin; Sheng, Jianting; Gao, Dingcheng; Li, Fuhai; Durrans, Anna; Ryu, Seongho; Lee, Sharrell B; Narula, Navneet; Rafii, Shahin; Elemento, Olivier; Altorki, Nasser K; Wong, Stephen T C; Mittal, Vivek

    2015-02-24

    Emerging studies have begun to demonstrate that reprogrammed stromal cells play pivotal roles in tumor growth, metastasis, and resistance to therapy. However, the contribution of stromal cells to non-small-cell lung cancer (NSCLC) has remained underexplored. We used an orthotopic model of Kras-driven NSCLC to systematically dissect the contribution of specific hematopoietic stromal cells in lung cancer. RNA deep-sequencing analysis of individually sorted myeloid lineage and tumor epithelial cells revealed cell-type-specific differentially regulated genes, indicative of activated stroma. We developed a computational model for crosstalk signaling discovery based on ligand-receptor interactions and downstream signaling networks and identified known and novel tumor-stroma paracrine and tumor autocrine crosstalk-signaling pathways in NSCLC. We provide cellular and molecular insights into components of the lung cancer microenvironment that contribute to carcinogenesis. This study has the potential for development of therapeutic strategies that target tumor-stroma interactions and may complement conventional anti-cancer treatments. PMID:25704820

  15. Stromal cells in phyllodes tumors of the breast are enriched for EZH2 and stem cell marker expression.

    PubMed

    Zhang, Yanhong; Liss, Adam L; Chung, Eugene; Pierce, Lori J; Kleer, Celina G

    2016-07-01

    Phyllodes tumors (PTs) of the breast are fibroepithelial neoplasms with stromal hypercellularity, which is the basis for their classification as benign, borderline, and malignant. The histologic diagnosis of PTs is often difficult, and the pathological features may not always predict clinical behavior. The pathobiology of PT remains poorly understood. Enhancer of Zeste 2 (EZH2) epigenetically regulates cell-type identity, cellular differentiation, and breast cancer stem cells. EZH2 exerts oncogenic functions in breast cancer and is associated with metastasis. We hypothesized that in PTs, EZH2 and the stem cell marker ALDH1 may be expressed in stromal cells and may be associated with their degree of differentiation. Forty PTs were histologically characterized at our institution following the World Health Organization criteria. We investigated the expression of EZH2 and ALDH1 by immunohistochemistry and recorded as percentage of positive epithelial and stromal cells. EZH2 was positive when over 10 % of cells exhibited nuclear staining; ALDH1 was positive when over 5 % of cells had cytoplasmic staining. Of the 40 PTs, 24 (60 %) were histologically benign, 8 (20 %) borderline, and 8 (20 %) malignant. Stromal EZH2 was significantly associated with the diagnosis of malignant PT, as it was detected in 1 of 24 (4 %) benign, 3 of 8 (37.5 %) borderline, and 5 of 8 (62.5 %) malignant tumors. Stromal EZH2 was significantly associated with stromal overgrowth (p = 0.01), atypia (p = 0.01), hypercellularity (p = 0.01), and mitoses (p = 0.02), all features of malignant PT. Stromal EZH2 and ALDH1 were significantly associated with grade of PT (p = 0.01 and p < 0.05 respectively). In conclusion, EZH2 and ALDH1 expression in the stroma of PT may mark malignant progression and may be helpful to distinguish histologically benign from borderline and malignant tumors in challenging cases. Our study also suggests that PTs contain mesenchymal stem cells, shedding light

  16. [Chemotherapy of gastrointestinal tumors (review of the literature)].

    PubMed

    Mayr, A C

    1978-12-01

    There exist no common recommendations for palliative therapy of gastrointestinal cancer. Fluorouracil has been used for a long time, remission rates reported range from 0% to 80%. In larger series they figure about 20% but without prolongation of survival in responders. Although this drug is used for 20 years optimal dose and timing is still unknown. By combination of fluorouracil with other drugs remission rates were improved and in responders survival was prolonged (mitomycin C and/or adriamycin in gastric cancer, methyl-CCNU in colorectal cancer). The results of adjuvant chemotherapy of gastrointestinal cancer are contradictory, the routine usage is not recommendable. Adjuvant as well as palliative chemotherapy must be improved by controlled clinical trials. PMID:83561

  17. Flotillin-1 protein is upregulated in human endometrial cancer and localization shifts from epithelial to stromal with increasing tumor grade.

    PubMed

    Winship, Amy Louise; Rainczuk, Kate; Dimitriadis, Evdokia

    2016-01-01

    Endometrial cancer is the most common invasive gynecological malignancy. Flotillin-1 is an integral membrane protein and estrogen responsive gene. Flotillin-1 expression and localization in human endometrial cancers grades 1-3 was investigated using real-time RT-PCR and immunohistochemistry. Flotillin-1 mRNA levels were unchanged in endometrial cancer versus benign endometrium. Flotillin-1 protein was significantly reduced in the epithelial compartment with increasing tumor grade, although levels increased in the tumor stroma across grades. We have identified a novel factor in human endometrial cancer and observed a shift in epithelial to stromal localization with increasing tumor grade in women. PMID:26682635

  18. Fibroepithelioma of Pinkus: Solitary tumor or sign of a complex gastrointestinal syndrome

    PubMed Central

    LONGO, CATERINA; PELLACANI, GIOVANNI; TOMASI, ALDO; MANDEL, VICTOR DESMOND; PONTI, GIOVANNI

    2016-01-01

    Fibroepithelioma of Pinkus (FEP), which is considered to be an uncommon variant of basal cell carcinoma, has been described in association with other systemic diseases. However, no specific studies are currently available on this subject. The aim of our study was to evaluate the clinical and morphological characteristics of FEP and investigate whether this rare tumor is a single entity or seen in the context of a more complex syndrome. We retrospectively analyzed 49 cases of FEP diagnosed and excised in a single academic institution from 1995 to 2011. The tumors were mainly located on the trunk (77.55%), followed by the lower extremities (12.20%) and the head and neck (10.20%). In 9 of the 49 cases (18%), FEP was associated with gastrointestinal tumors. The abovementioned cases are presented in an attempt to make clinicians more aware of a possible association between FEP and gastrointestinal cancer. Although a possible underlying common genetic background between FEP and gastrointestinal tumors was not provided, our study suggests that patients with FEP should be screened for the occurrence of gastrointestinal tumors. PMID:27123282

  19. Conservative Resectoscopic Surgery, Successful Delivery, and 60 Months of Follow-Up in a Patient with Endometrial Stromal Tumor with Sex-Cord-Like Differentiation

    PubMed Central

    De Franciscis, Pasquale; Grauso, Flavio; Ambrosio, Domenico; Torella, Marco; Messalli, Enrico Michelino; Colacurci, Nicola

    2016-01-01

    Uterine tumors with sex-cord-like differentiation are extremely rare types of uterine stromal neoplasm. These tumors were classified into two groups with considerable practical relevance because clinical behaviour of uterine tumor resembling ovarian sex cord tumor (UTROSCT) differs widely from its closely related endometrial stromal tumors with sex-cord-like elements (ESTSCLE). Treatment and prognosis of these tumors are unresolved issues because of the exiguous number of reported cases. We describe a rare case of endometrial stromal tumor with sex-cord-like differentiation successfully treated by resectoscopic surgery and conservation of the uterus, in an infertile patient affected by metrorrhagia. This procedure resulted in a pregnancy immediately after treatment and in a successful delivery. During 60 months of follow-up no evidence of recurrence was observed. PMID:27213063

  20. Clinical Applicability of Various Treatment Approaches for Upper Gastrointestinal Submucosal Tumors

    PubMed Central

    Zhang, Jing; Huang, Kaili; Ding, Shigang; Wang, Ye; Nai, Te; Huang, Yonghui; Zhou, Liya

    2016-01-01

    Submucosal tumor (SMT) is a disease that is commonly discovered during endoscopic examination. With advances in endoscopic ultrasonography (EUS) technology, this technique has become the primary screening method for the diagnosis of upper gastrointestinal SMTs. The present study summarized the clinical data of patients who were examined and diagnosed with upper gastrointestinal SMTs by EUS, underwent endoscopic therapy or surgical treatment, and received final pathological results in our hospital between January 2011 and September 2014. Our results show that endoscopic therapy has become the main approach for the treatment of upper gastrointestinal SMTs with the development and maturation of endoscopic technology in recent years. Our conclusion suggests that the selection of endoscopic methods, such as endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), and peroral submucosal tunneling endoscopic resection (STER), under the guidance of EUS is safe and effective for the treatment of upper gastrointestinal SMTs. PMID:26933439

  1. Endothelial Differentiation of Adipose Tissue-Derived Mesenchymal Stromal Cells in Glioma Tumors: Implications for Cell-Based Therapy

    PubMed Central

    Bagó, Juli R; Alieva, Maria; Soler, Carolina; Rubio, Núria; Blanco, Jerónimo

    2013-01-01

    Multipotent human adipose tissue mesenchymal stromal cells (hAMSCs) are promising therapy vehicles with tumor-homing capacity that can be easily modified to deliver cytotoxicity activating systems in the proximity of tumors. In a previous work, we observed that hAMSCs are very effective delivering cytotoxicity to glioma tumors. However, these results were difficult to reconcile with the relatively few hAMSCs surviving implantation. We use a bioluminescence imaging (BLI) platform to analyze the behavior of bioluminescent hAMSCs expressing HSV-tTK in a U87 glioma model and gain insight into the therapeutic mechanisms. Tumor-implanted hAMSCs express the endothelial marker PECAM1(CD31), integrate in tumor vessels and associate with CD133-expressing glioma stem cells (GSC). Inhibition of endothelial lineage differentiation in hAMSCs by Notch1 shRNA had no effect on their tumor homing and growth-promoting capacity but abolished the association of hAMSCs with tumor vessels and CD133+ tumor cells and significantly reduced their tumor-killing capacity. The current strategy allowed the study of tumor/stroma interactions, showed that tumor promotion and tumor-killing capacities of hAMSCs are based on different mechanisms. Our data strongly suggest that the therapeutic effectiveness of hAMSCs results from their association with special tumor vascular structures that also contain GSCs. PMID:23760448

  2. A virilizing Leydig cell tumor of the ovary associated with stromal hyperplasia under gonadotropin control.

    PubMed

    Marcondes, J A; Nery, M; Mendonça, B B; Hayashida, S A; Halbe, H W; Carvalho, F M; Wajchenberg, B L

    1997-12-01

    A 34-yr-old nulliparous black woman presented with hair loss, facial hirsutism, irregular menses and infertility associated with greatly increased serum total testosterone levels. The adrenal glands and the ovaries were normal on radiological and ultrasonographic investigation. Catheterization of the veins draining from the adrenal glands and the ovaries yielded testosterone levels of 20.3 nmol/L and 20.0 nmol/L in the right and the left adrenal veins, respectively, and 17.9 nmol/L and 27.4 nmol/L in the right and left ovaries venous plexus, respectively. Sequencial dexamethasone and ethynyl estradiol suppression test showed a decrease in cortisol level with no change in total testosterone level on dexamethasone while an increase in testosterone from 10.5 nmol/L to 20.1 nmol/L was observed ten days after ethynil estradiol had been associated to dexamethasone. When a gonadotropin-releasing hormone agonist (gonadorelin 3.5 mg i.m.) was administered for 2 months, serum gonadotropins levels decreased to less than 2 IU/L, total testosterone to 3.8 nmol/L and estradiol to less than 36 pmol/L. The patient was submitted to a pelvic exploratory laparotomy and a left salpingo-oophorectomy was performed. A solid and circumscribed ovarian tumor of 1.0 cm in diameter was found. The pathological diagnosis was a Leydig cell tumor with surrounding stromal hyperplasia. These findings may suggest that this tumor was gonadotropin-dependent being indirectly stimulated by ethynil estradiol, through a sensitization of the pituitary gonadotropes and increase in gonadotropin levels and suppressed by a gonadotropin-releasing hormone agonist. PMID:9492110

  3. Enrichment of c-Met+ tumorigenic stromal cells of giant cell tumor of bone and targeting by cabozantinib

    PubMed Central

    Liu, L; Aleksandrowicz, E; Fan, P; Schönsiegel, F; Zhang, Y; Sähr, H; Gladkich, J; Mattern, J; Depeweg, D; Lehner, B; Fellenberg, J; Herr, I

    2014-01-01

    Giant cell tumor of bone (GCTB) is a very rare tumor entity, which is little examined owing to the lack of established cell lines and mouse models and the restriction of available primary cell lines. The stromal cells of GCTB have been made responsible for the aggressive growth and metastasis, emphasizing the presence of a cancer stem cell population. To identify and target such tumor-initiating cells, stromal cells were isolated from eight freshly resected GCTB tissues. Tumorigenic properties were examined by colony and spheroid formation, differentiation, migration, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, immunohistochemistry, antibody protein array, Alu in situ hybridization, FACS analysis and xenotransplantation into fertilized chicken eggs and mice. A sub-population of the neoplastic stromal cells formed spheroids and colonies, differentiated to osteoblasts, migrated to wounded regions and expressed the metastasis marker CXC-chemokine receptor type 4, indicating self-renewal, invasion and differentiation potential. Compared with adherent-growing cells, markers for pluripotency, stemness and cancer progression, including the CSC surface marker c-Met, were enhanced in spheroidal cells. This c-Met-enriched sub-population formed xenograft tumors in fertilized chicken eggs and mice. Cabozantinib, an inhibitor of c-Met in phase II trials, eliminated CSC features with a higher therapeutic effect than standard chemotherapy. This study identifies a c-Met+ tumorigenic sub-population within stromal GCTB cells and suggests the c-Met inhibitor cabozantinib as a new therapeutic option for targeted elimination of unresectable or recurrent GCTB. PMID:25321478

  4. Stromal Integrin α11β1 Affects RM11 Prostate and 4T1 Breast Xenograft Tumors Differently

    PubMed Central

    Skogstrand, Trude; Sortland, Kristina; Schmid, Marei Caroline; Reed, Rolf K.; Stuhr, Linda

    2016-01-01

    Purpose It has been implied that the collagen binding integrin α11β1 plays a role in carcinogenesis. As still relatively little is known about how the stromal integrin α11β1 affects different aspects of tumor development, we wanted to examine the direct effects on primary tumor growth, fibrosis, tumor interstitial fluid pressure (PIF) and metastasis in murine 4T1 mammary and RM11 prostate tumors, using an in vivo SCID integrin α11-deficient mouse model. Methods Tumor growth was measured using a caliper, PIF by the wick-in-needle technique, activated fibroblasts by α-SMA immunofluorescence staining and fibrosis by transmission electron microscopy and picrosirius-red staining. Metastases were evaluated using hematoxylin and eosin stained sections. Results RM11 tumor growth was significantly reduced in the SCID integrin α11-deficient (α11-KO) compared to in SCID integrin α11 wild type (WT) mice, whereas there was no similar effect in the 4T1 tumor model. The 4T1 model demonstrated an alteration in collagen fibril diameter in the integrin α11-KO mice compared to WT, which was not found in the RM11 model. There were no significant differences in the amount of activated fibroblasts, total collagen content, collagen organization or PIF in the tumors in integrin α11-deficient mice compared to WT mice. There was also no difference in lung metastases between the two groups. Conclusion Deficiency of stromal integrin α11β1 showed different effects on tumor growth and collagen fibril diameter depending on tumor type, but no effect on tumor PIF or development of lung metastasis. PMID:26990302

  5. [Prevalence and trend of gastrointestinal malignant tumors in the elderly over 75 years old in China].

    PubMed

    Zheng, Ying; Wu, Chunxiao

    2016-05-25

    Gastrointestinal malignant tumors are the most common malignant neoplasms among the elderly people over 75 years old in China. There are 122.1 thousand new gastric cases and 78.2 thousand new colorectal cancer cases diagnosed each year in China, which accounts for 42.73% and 18.08% respectively of the cases with same age in the world. The gastric cancer accounts for 25.13% and colorectal cancer accounts for 28.86%of all the malignancies in the elderly. The gastric cancer death accounts for 36.38% and colorectal cancer death accounts for 44.68% in those people over 75 years old in China. It was estimated that the risk of developing gastrointestinal malignant tumors of these elderly people was about 5-6 times and the risk of death of gastrointestinal malignant tumors was about 7-8 times of the general population. Compared with the general population and the people of 55-74 years old, the incidence of gastric cancer in the elderly decreased more slowly and the incidence of colorectal cancer increased more quickly over the past 40 years, which brought significant double burden. The survival rate of gastrointestinal malignant tumors in these elderly was lower than that of the general population. We summarized the incidence, mortality, survival and trend of gastrointestinal malignant tumors in the Chinese elderly, in order to provide data for predicting the age distribution and disease burden in the future, to improve the awareness for cancer prevention and control among these elderly, and to call attention to epidemiology, preclinical and clinical medicine for the elderly, especially in the field of study on the influence between comorbidity and cancer treatment, with the aim of improving survival and quality of life among the elderly. PMID:27215509

  6. Spectrophotometric Determination of the Characteristics of Stromal and Parenchymal Components of Colon Tumors

    NASA Astrophysics Data System (ADS)

    Motevich, I. G.; Strekal, N. D.; Shulha, A. V.; Maskevich, S. A.

    2016-05-01

    We consider the dependence of the spectral properties of eosin and hematoxylin (dyes routinely used in histology as contrast agents) on their localization in biological tissues with different levels of pathology: benign and malignant neoplasms and sigmoid colonic crypts. We have analyzed the fluorescent images and fluorescence spectra of the parenchyma and stromal elements. We have established that on going from physiologically normal cells to tumor cells, the contribution to the absorption cross section of histologic sections due to hematoxylin increases. In pathologically altered cells in a colonic crypt, we observe a hypsochromic effect in the fluorescence spectra of the samples with appreciable quenching of the fluorescence, while in the model systems the reverse effect occurs: a shift of the fluorescence maximum toward the red region. We discuss the influence on the indicated effects from local pH and the polarity of the dye environment in the model systems and histologic sections. As the systems modeling the polarity and acidity of the biological media, we use aqueous solutions of the dyes with different pH values and synthetic polyelectrolytes.

  7. Microcystic stromal tumor of the ovary: report of 16 cases of a hitherto uncharacterized distinctive ovarian neoplasm.

    PubMed

    Irving, Julie A; Young, Robert H

    2009-03-01

    We have encountered 16 ovarian neoplasms of probable stromal origin whose most distinctive feature is microcystic change, which is usually conspicuous. On the basis of our extensive experience with ovarian tumors, the neoplasm is unique and warrants separate categorization; we have elected to designate it "microcystic stromal tumor" because of its most striking feature. The patients ranged from 26 to 63 (mean 45) years of age and typically presented with a pelvic mass. Hormonal manifestations were possibly present in only 2. All tumors were unilateral with a mean size of 8.7 (range: 2 to 27) cm and none had evidence of extraovarian spread. The tumors were solid-cystic (11 cases), solid (3 cases), or predominantly cystic (2 cases). The solid component was usually firm and tan or white-tan, but in 1 case was yellowish; soft foci were present in 3 cases and small foci of hemorrhage, necrosis, or both, in 3. On microscopic examination the appearance of the tumors varied according to the relative prominence of their 3 fundamental components: microcysts, solid cellular regions, and fibrous stroma. Microcysts dominated in 9 cases, were roughly equal to noncystic morphology in 5 cases and were minor in 2. The microcystic pattern was characterized by small rounded to oval cystic spaces, in areas coalescing to larger irregular channels; intracytoplasmic vacuoles were also frequently present. The solid cellular areas were usually focally intersected by fibrous bands and hyaline plaques reminiscent of thecoma. The cells contained moderately conspicuous finely granular, lightly eosinophilic cytoplasm, with generally bland, round to oval or spindle-shaped nuclei with fine chromatin and small indistinct nucleoli. Foci of bizarre nuclei were, however, present in 10 cases. Mitotic rate was low in all cases, ranging from 0 to 2 mitoses/10 high-power fields. Immunohistochemical results were as follows: CD10, 16/16 cases positive; vimentin, 16/16 cases positive; inhibin, 1/16 cases

  8. The critical roles of tumor-initiating cells and the lymph node stromal microenvironment in human colorectal cancer extranodal metastasis using a unique humanized orthotopic mouse model.

    PubMed

    Margolin, David A; Myers, Tamara; Zhang, Xin; Bertoni, Danielle M; Reuter, Brian A; Obokhare, Izi; Borgovan, Theodor; Grimes, Chelsea; Green, Heather; Driscoll, Tiffany; Lee, Chung-Gi; Davis, Nancy K; Li, Li

    2015-08-01

    Colorectal cancer (CRC) is the second-most common cause of cancer-related mortality. The most important prognostic factors are lymph node (LN) involvement and extranodal metastasis. Our objective is to investigate the interactions between CD133(+)CXCR4(+) (CXC receptor 4) colorectal cancer tumor-initiating cells (Co-TICs) and the LN stromal microenvironment in human CRC extranodal metastasis. We established a unique humanized orthotopic xenograft model. Luciferase-tagged CRC cell lines and human cancer cells were injected intrarectally into nonobese diabetic/SCID mice. Mesenteric LN stromal cells, stromal cell line HK, or CXCL12 knockdown HK (HK-KD-A3) cells were coinoculated with CRC cells. Tumor growth and metastasis were monitored by bioluminescent imaging and immunohistochemistry. We found that this model mimics the human CRC metastatic pattern with CRC cell lines or patient specimens. Adding LN stromal cells promotes CRC tumor growth and extranodal metastasis (P < 0.001). Knocking down CXCL12 impaired HK cell support of CRC tumor formation and extranodal metastasis. When HK cells were added, sorted CD133(+)CXCR4(+) Co-TICs showed increased tumor formation and extranodal metastasis capacities compared to unseparated and non-Co-TIC populations. In conclusion, both Co-TIC and LN stromal factors play crucial roles in CRC metastasis through the CXCL12/CXCR4 axis. Blocking Co-TIC/LN-stromal interactions may lead to effective therapy to prevent extranodal metastasis. PMID:25962655

  9. The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells.

    PubMed

    Coffelt, Seth B; Marini, Frank C; Watson, Keri; Zwezdaryk, Kevin J; Dembinski, Jennifer L; LaMarca, Heather L; Tomchuck, Suzanne L; Honer zu Bentrup, Kerstin; Danka, Elizabeth S; Henkle, Sarah L; Scandurro, Aline B

    2009-03-10

    Bone marrow-derived mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs) have been shown to engraft into the stroma of several tumor types, where they contribute to tumor progression and metastasis. However, the chemotactic signals mediating MSC migration to tumors remain poorly understood. Previous studies have shown that LL-37 (leucine, leucine-37), the C-terminal peptide of human cationic antimicrobial protein 18, stimulates the migration of various cell types and is overexpressed in ovarian, breast, and lung cancers. Although there is evidence to support a pro-tumorigenic role for LL-37, the function of the peptide in tumors remains unclear. Here, we demonstrate that neutralization of LL-37 in vivo significantly reduces the engraftment of MSCs into ovarian tumor xenografts, resulting in inhibition of tumor growth as well as disruption of the fibrovascular network. Migration and invasion experiments conducted in vitro indicated that the LL-37-mediated migration of MSCs to tumors likely occurs through formyl peptide receptor like-1. To assess the response of MSCs to the LL-37-rich tumor microenvironment, conditioned medium from LL-37-treated MSCs was assessed and found to contain increased levels of several cytokines and pro-angiogenic factors compared with controls, including IL-1 receptor antagonist, IL-6, IL-10, CCL5, VEGF, and matrix metalloproteinase-2. Similarly, Matrigel mixed with LL-37, MSCs, or the combination of the two resulted in a significant number of vascular channels in nude mice. These data indicate that LL-37 facilitates ovarian tumor progression through recruitment of progenitor cell populations to serve as pro-angiogenic factor-expressing tumor stromal cells. PMID:19234121

  10. The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells

    PubMed Central

    Coffelt, Seth B.; Marini, Frank C.; Watson, Keri; Zwezdaryk, Kevin J.; Dembinski, Jennifer L.; LaMarca, Heather L.; Tomchuck, Suzanne L.; zu Bentrup, Kerstin Honer; Danka, Elizabeth S.; Henkle, Sarah L.; Scandurro, Aline B.

    2009-01-01

    Bone marrow-derived mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs) have been shown to engraft into the stroma of several tumor types, where they contribute to tumor progression and metastasis. However, the chemotactic signals mediating MSC migration to tumors remain poorly understood. Previous studies have shown that LL-37 (leucine, leucine-37), the C-terminal peptide of human cationic antimicrobial protein 18, stimulates the migration of various cell types and is overexpressed in ovarian, breast, and lung cancers. Although there is evidence to support a pro-tumorigenic role for LL-37, the function of the peptide in tumors remains unclear. Here, we demonstrate that neutralization of LL-37 in vivo significantly reduces the engraftment of MSCs into ovarian tumor xenografts, resulting in inhibition of tumor growth as well as disruption of the fibrovascular network. Migration and invasion experiments conducted in vitro indicated that the LL-37-mediated migration of MSCs to tumors likely occurs through formyl peptide receptor like-1. To assess the response of MSCs to the LL-37-rich tumor microenvironment, conditioned medium from LL-37-treated MSCs was assessed and found to contain increased levels of several cytokines and pro-angiogenic factors compared with controls, including IL-1 receptor antagonist, IL-6, IL-10, CCL5, VEGF, and matrix metalloproteinase-2. Similarly, Matrigel mixed with LL-37, MSCs, or the combination of the two resulted in a significant number of vascular channels in nude mice. These data indicate that LL-37 facilitates ovarian tumor progression through recruitment of progenitor cell populations to serve as pro-angiogenic factor-expressing tumor stromal cells. PMID:19234121

  11. Myeloma cells can corrupt senescent mesenchymal stromal cells and impair their anti-tumor activity

    PubMed Central

    Özcan, Servet; Alessio, Nicola; Acar, Mustafa Burak; Toprak, Güler; Gönen, Zeynep Burcin; Peluso, Gianfranco; Galderisi, Umberto

    2015-01-01

    Senescent cells secrete several molecules that help to prevent the progression of cancer. However, cancer cells can also misuse these secreted elements to survive and grow. Since the molecular and functional bases of these different elements remain poorly understood, we analyzed the effect of senescent mesenchymal stromal cell (MSC) secretome on the biology of ARH-77 myeloma cells. In addition to differentiating in mesodermal derivatives, MSCs have sustained interest among researchers by supporting hematopoiesis, contributing to tissue homeostasis, and modulating inflammatory response, all activities accomplished primarily by the secretion of cytokines and growth factors. Moreover, senescence profoundly affects the composition of MSC secretome. In this study, we induced MSC senescence by oxidative stress, DNA damage, and replicative exhaustion. While the first two are considered to induce acute senescence, extensive proliferation triggers replicative (i.e., chronic) senescence. We cultivated cancer cells in the presence of acute and chronic senescent MSC-conditioned media and evaluated their proliferation, DNA damage, apoptosis, and senescence. Our findings revealed that senescent secretomes induced apoptosis or senescence, if not both, to different extents. This anti-tumor activity became heavily impaired when secretomes were collected from senescent cells previously in contact (i.e., primed) with cancer cells. Our analysis of senescent MSC secretomes with LC-MS/MS followed by Gene Ontology classification further indicated that priming with cancer profoundly affected secretome composition by abrogating the production of pro-senescent and apoptotic factors. We thus showed for the first time that compared with cancer-primed MSCs, naïve senescent MSCs can exert different effects on tumor progression. PMID:26498687

  12. Wide-field endoscopic fluorescence imaging for gastrointestinal tumor detection with glucose analogue

    NASA Astrophysics Data System (ADS)

    He, Yun; Qu, Yawei; Bai, Jing; Liu, Haifeng

    2014-05-01

    The lack of functional information and targeted imaging in conventional white-light endoscopy leads to a high miss-rate of gastrointestinal tumor. The combination of near-infrared fluorescence imaging and endoscopy presents a promising approach. Here we introduce a new endoscopy method employing a home-made flexible wide-field epi-fluorescence endoscope, that can be inserted through the biopsy channel of a gastrointestinal endoscope, with the glucose analogue 2- DeoxyGlucosone as the near-infrared fluorescent probe. System characterization indicates a good sensitivity and linearity over a large field of view. Its capability of tumor identification and location is demonstrated with in-vivo imaging of xenografted tumor model.

  13. [Neoadjuvant therapy for tumors of the upper gastrointestinal tract : Complication management].

    PubMed

    Gockel, I; Hoffmeister, A; Lordick, F

    2015-11-01

    Recent studies could demonstrate that neoadjuvant chemotherapy and radiochemotherapy for esophageal and gastric cancer do not significantly increase the risk of postoperative morbidity and mortality as compared to surgery alone. With respect to patient safety and effectiveness of neoadjuvant concepts, quality assured performance of each treatment modality and close interdisciplinary cooperation play an important role. The majority of potential side effects and complications, which might occur during neoadjuvant therapy can be adequately controlled by correct prophylaxis and professional medical complication management. Complications before, during and after neoadjuvant therapy of upper gastrointestinal tract tumors can also be caused by the tumor itself or by medicinal therapy. These comprise bleeding, fistulas, perforations and stenoses. Modern endoscopic techniques are the therapy of choice in these situations. Preoperative conditioning during the period of neoadjuvant therapy opens the possibility of reduced postoperative complications to patients with tumors of the upper gastrointestinal tract. PMID:26374651

  14. What Are the Risk Factors for Gastrointestinal Carcinoid Tumors?

    MedlinePlus

    ... is a risk factor for skin cancer, while smoking is a risk factor for cancer of the lung and several ... affected. Factors with uncertain or unproven effects Smoking Smoking may increase the risk of getting a carcinoid tumor of the small ...

  15. Successful treatment of bleeding large duodenal gastrointestinal stromal tumour in a patient under dual antiplatelet therapy after recent drug-eluting coronary stent implantation

    PubMed Central

    Fukuyama, Keita; Fujikawa, Takahisa; Kuramitsu, Shoichi; Tanaka, Akira

    2014-01-01

    We report a case of a 69-year-old man who started dual antiplatelet therapy (APT) with aspirin and clopidogrel after recent implantation of drug-eluting coronary stent and developed massive bleeding due to large duodenal gastrointestinal stromal tumour (GIST). Following endoscopic haemostasis and discontinuation of dual APT, neoadjuvant chemotherapy with imatinib was started under continuation of ‘single’ APT with aspirin. A good chemotherapeutic response was achieved without recurrence of bleeding, and subsequent less invasive surgical resection of the tumour was performed, while preoperative single APT was continued for prevention of stent thrombosis. The patient recovered well without any thromboembolic or bleeding events. Neoadjuvant imatinib therapy and subsequent less invasive surgery under continuation of APT is one of the preferred approaches for patients with duodenal GIST with severe thromboembolic comorbidities, as in the current case. PMID:24777088

  16. Suppression of CD51 in pancreatic stellate cells inhibits tumor growth by reducing stroma and altering tumor-stromal interaction in pancreatic cancer.

    PubMed

    Horioka, Kohei; Ohuchida, Kenoki; Sada, Masafumi; Zheng, Biao; Moriyama, Taiki; Fujita, Hayato; Manabe, Tatsuya; Ohtsuka, Takao; Shimamoto, Masaya; Miyazaki, Tetsuyuki; Mizumoto, Kazuhiro; Oda, Yoshinao; Nakamura, Masafumi

    2016-04-01

    Pancreatic stellate cells (PSCs) enhance the malignant behavior of pancreatic cancer by interacting with cancer cells and producing extracellular matrix (ECM). To date, several stroma-targeted therapies for pancreatic cancer have been attempted, but these therapies are still not in practical use. Integrins expressed in stromal cells are involved in fibrosis of several organs, as well as promoting tumor malignancy. We investigated whether CD51, also known as integrin αV, expressed in PSCs was associated with stromal formation of pancreatic cancer and enhancement of tumor malignancy. We also assessed the effects of suppression of CD51 in PSCs on pancreatic cancer. Immunohistochemistry for CD51 in resected pancreatic cancer tissues showed that high expression of CD51 in the tumor stroma was associated with lymph node metastasis (P=0.025), positive pathologic margin (P=0.025), and shorter patient survival times (P=0.043). Lentivirus-mediated short hairpin RNA knockdown of CD51 decreased the proliferation and migration of PSCs. Quantitative real-time polymerase chain reaction showed that expression levels of genes related with ECM and tumor-stromal interactions were decreased by CD51 knockdown in PSCs. In a co-implantation model of pancreatic cancer cells and PSCs, tumor growth in vivo was inhibited by CD51 knockdown in PSCs (P<0.05). We also found reduced tumor stroma and decreased proliferation of cancer cells in implanted cancer tissues with CD51-silenced PSCs (P<0.05). Our results showed that CD51 expression in pancreatic cancer stroma is associated with enhanced tumor malignancy and that CD51 may be a potential therapeutic target for pancreatic cancer. PMID:26846197

  17. Mixed epithelial and stromal tumor of the kidney: a rare case report and review of the literatures

    PubMed Central

    Yang, Cheng; Wang, Jianzhong; Du, Hexi; Chen, Mingwei; Zhu, Xia; Zhou, Jun; Hao, Zongyao; Shi, Haoqiang; Zhang, Li; Liang, Chaozhao

    2015-01-01

    Mixed epithelial and stromal tumor of the kidney (MESTK) is a rare complex renal neoplasm composed of a mixture of cystic and solid components. Until date only few cases of MESTK have been reported. We present here a rare case of MESTK that was diagnosed in a 56-year-old female. The patients were referred to our hospital due to a mass on the right kidney identified incidentally in a routine physical examination. A pre-operative diagnosis of cystic renal cell carcinoma was made and a right radical nephrectomy was carried out. Macroscopically, a cystic tumor was noticed in the upper portion of the right kidney. Various-sized cysts accompanied by multiple cysts and few solid areas were observed. Immunohistochemically, various epithelial markers as well as stromal markers were identified. Taken together with all the immunohistochemical results and morphological pattern of the tumor, a diagnosis of MESTK was made. MESTK is relatively rare and generally benign. However, it is difficult to distinguish between benign or malignant tumors according to the current radiological method. Therefore a complete resection of the tumor by partial or radical nephrectomy is suggested. PMID:26550392

  18. Advances in the application of nanotechnology in the diagnosis and treatment of gastrointestinal tumors

    PubMed Central

    SUN, BO; FANG, YANTIAN; LI, ZHENGYANG; CHEN, ZONGYOU; XIANG, JIANBIN

    2015-01-01

    Nanotechnology has broad application prospects in the diagnosis and treatment of cancer. Integrating chemistry, engineering, biology and medicine, nanotechnology is a multidisciplinary research field. Nanoscale imaging technology significantly improves the precision and accuracy of tumor diagnosis. Nanocarriers are able to significantly improve the accuracy of dose and targeted drug delivery and reduce the toxic side effects. This review focuses on the emerging roles of these innovative technologies in gastrointestinal cancer diagnostics and therapeutics. Although several problems and barriers are hampering the development of nanodevices, the potential for nanotechnologies to function as multimodal nanotheranostic agents will likely pave the way for the fight against gastrointestinal cancer. PMID:25798253

  19. Therapeutic inhibition of Jak activity inhibits progression of gastrointestinal tumors in mice.

    PubMed

    Stuart, Emma; Buchert, Michael; Putoczki, Tracy; Thiem, Stefan; Farid, Ryan; Elzer, Joachim; Huszar, Dennis; Waring, Paul M; Phesse, Toby J; Ernst, Matthias

    2014-02-01

    Aberrant activation of the latent transcription factor STAT3 and its downstream targets is a common feature of epithelial-derived human cancers, including those of the gastrointestinal tract. Mouse models of gastrointestinal malignancy implicate Stat3 as a key mediator of inflammatory-driven tumorigenesis, in which its cytokine/gp130/Janus kinase (Jak)-dependent activation provides a functional link through which the microenvironment sustains tumor promotion. Although therapeutic targeting of STAT3 is highly desirable, such molecules are not available for immediate clinical assessment. Here, we investigated whether the small-molecule Jak1/2 inhibitor AZD1480 confers therapeutic benefits in two mouse models of inflammation-associated gastrointestinal cancer, which are strictly dependent of excessive Stat3 activation. We confirm genetically that Cre-mediated, tumor cell-specific reduction of Stat3 expression arrests the growth of intestinal-type gastric tumors in gp130(F/F) mice. We find that systemic administration of AZD1480 readily replicates this effect, which is associated with reduced Stat3 activation and correlates with diminished tumor cell proliferation and increased apoptosis. Likewise, AZD1480 therapy also conferred a cytostatic effect on established tumors in a colitis-associated colon cancer model in wild-type mice. As predicted from our genetic observations in gp130(F/F) mice, the therapeutic effect of AZD1480 remains fully reversible upon cessation of compound administration. Collectively, our results provide the first evidence that pharmacologic targeting of excessively activated wild-type Jak kinases affords therapeutic suppression of inflammation-associated gastrointestinal cancers progression in vivo. PMID:24398427

  20. Study on the Evolution of Genes Mutation Related With Gastrointestinal Stromal Tumors

    ClinicalTrials.gov

    2012-01-05

    Full Gene Sequences of c-KIT、PDGFRA and DOG1 Are Analyzed With the Screening-sequencing Approach; Investigate the Characteristics and Variations Associated With the Different Gene Mutations of c-KIT、PDGFRA and DOG1 in GIST Patients

  1. Pivotal role of pervasive neoplastic and stromal cells reprogramming in circulating tumor cells dissemination and metastatic colonization.

    PubMed

    Meseure, Didier; Drak Alsibai, Kinan; Nicolas, Andre

    2014-12-01

    Reciprocal interactions between neoplastic cells and their microenvironment are crucial events in carcinogenesis and tumor progression. Pervasive stromal reprogramming and remodeling that transform a normal to a tumorigenic microenvironment modify numerous stromal cells functions, status redox, oxidative stress, pH, ECM stiffness and energy metabolism. These environmental factors allow selection of more aggressive cancer cells that develop important adaptive strategies. Subpopulations of cancer cells acquire new properties associating plasticity, stem-like phenotype, unfolded protein response, metabolic reprogramming and autophagy, production of exosomes, survival to anoikis, invasion, immunosuppression and therapeutic resistance. Moreover, by inducing vascular transdifferentiation of cancer cells and recruiting endothelial cells and pericytes, the tumorigenic microenvironment induces development of tumor-associated vessels that allow invasive cells to gain access to the tumor vessels and to intravasate. Circulating cancer cells can survive in the blood stream by interacting with the intravascular microenvironment, extravasate through the microvasculature and interact with the metastatic microenvironment of target organs. In this review, we will focus on many recent paradigms involved in the field of tumor progression. PMID:25523234

  2. Collection of Biospecimen & Clinical Information in Patients w/ Gastrointestinal Cancers

    ClinicalTrials.gov

    2012-05-24

    Gastrointestinal Neoplasms; Gynecologic Cancers; Gynecologic Cancers Cervical Cancer; Gastric (Stomach) Cancer; Gastro-Esophageal(GE) Junction Cancer; Gastrointenstinal Stromal Tumor (GIST); Colon/Rectal Cancer; Colon/Rectal Cancer Colon Cancer; Colon/Rectal Cancer Rectal Cancer; Colon/Rectal Cancer Anal Cancer; Anal Cancer; Hepatobiliary Cancers; Hepatobiliary Cancers Liver; Pancreatic Cancer

  3. Fluorescent Endoscopy of Tumors in Upper Part of Gastrointestinal Tract

    NASA Astrophysics Data System (ADS)

    Borisova, E.; Vladimirov, B.; Angelov, I.; Avramov, L.

    2007-04-01

    In the recent study delta-aminolevulinic acid/Protoporphyrin IX (5-ALA/PpIX) is used as fluorescent marker for dysplasia and tumor detection in esophagus and stomach. The 5-ALA is administered per os six hours before measurements at dose 20mg/kg weight. High-power light-emitting diode at 405 nm is used as an excitation source. Special opto-mechanical device is built for LED to use the light guide of standard video-endoscopic system (Olimpus Corp.). Through endoscopic instrumental channel a fiber is applied to return information about fluorescence to microspectrometer (USB4000, OceanOptics Inc.). Very good correlation between fluorescence signals and histology examination of the lesions investigated is achieved.

  4. High Stromal Carbonic Anhydrase IX Expression Is Associated With Decreased Survival in p16-Negative Head-and-Neck Tumors

    SciTech Connect

    Brockton, Nigel; Dort, Joseph; Lau, Harold; Hao, Desiree; Brar, Sony; Klimowicz, Alexander; Petrillo, Stephanie; Diaz, Roman; Doll, Corinne; Magliocco, Anthony

    2011-05-01

    Purpose: Head-and-neck squamous cell carcinoma (HNSCC) is the fifth most common malignancy worldwide. Alcohol use and tobacco use are the most established risk factors; however, human papilloma virus (HPV) infection is a major risk factor for a subset of HNSCCs. Although HPV-positive tumors typically present at a more advanced stage at diagnosis, they are associated with a better prognosis. Tumor hypoxia confers poor prognosis and treatment failure, but direct tumor oxygen measurement is challenging. Endogenous markers of hypoxia (EMHs) have been proposed but have not replicated the prognostic utility of direct oxygen measurement. The expression of endogenous markers of hypoxia may be influenced by oxygen-independent factors, such as the HPV status of the tumor. Methods and Materials: Consecutive cases of locally advanced HNSCC, treated with a uniform regimen of combined radiotherapy and chemotherapy, were identified. Tissue microarrays were assembled from triplicate 0.6-mm cores of archived tumor tissue. HPV status was inferred from semiquantitative p16 immunostaining and directly measured by use of HPV-specific chromogenic in situ hybridization and polymerase chain reaction. Automated quantitative fluorescent immunohistochemistry was conducted to measure epithelial and stromal expression of carbonic anhydrase IX (CAIX) and glucose transporter 1 (GLUT1). Results: High stromal CAIX expression was associated with significantly reduced overall survival (p = 0.03) in patients with p16-negative tumors. Conclusions: This is the first study to use quantitative immunohistochemistry to examine endogenous markers of hypoxia stratified by tumor p16/HPV status. Assessment of CAIX expression in p16-negative HNSCC could identify patients with the least favorable prognosis and inform therapeutic strategies.

  5. Clear cell sarcoma-like tumor of the gastrointestinal tract: an evolving entity.

    PubMed

    Wang, Jayson; Thway, Khin

    2015-03-01

    Clear cell sarcoma-like tumor of the gastrointestinal tract (CCSLGT) is a rare malignant neoplasm that occurs in the wall of the small bowel, stomach, or large bowel, predominantly in young adults. It is an aggressive neoplasm that frequently presents with metastatic disease and has a high mortality rate. Histologically, it is usually composed of medium-sized primitive ovoid or epithelioid cells with pale or clear cytoplasm that are arranged in sheets or in papillary or alveolar architectures. Clear cell sarcoma-like tumor of the gastrointestinal tract is positive for S100 protein, invariably negative for melanocyte-specific markers and is often also positive for neuroendocrine markers. The etiology of CCSLGT is unknown, but many studies have shown associations with EWSR1-CREB1 gene fusions and, less frequently, with EWSR1-ATF1 fusions. Here, we discuss the current status of CCSLGT, including histologic, immunophenotypic, and molecular findings. PMID:25724038

  6. Membrane Glycolipids Content Variety in Gastrointestinal Tumors and Transplantable Hepatomas in Mice

    PubMed Central

    Lv, Jun; Lv, Can Qun; Wang, Bo-Liang; Mei, Ping; Xu, Lei

    2016-01-01

    Background The aim of this study was to investigate the variety of plasma contents of membrane glycolipids in 65 gastrointestinal tumors and 31 transplant hepatomas in mice. Material/Methods The experimental model was a transplantable murine hepatoma. Experimental mice were divided into 3 groups. Results The LSA and TSA content in the 2 groups were significantly difference (p<0.01), and were significantly lower in the therapeutic group than in the control group (p<0.01). Conclusions These results indicate that membrane glycolipids index LSA and TSA are sensitive markers in gastrointestinal tumors. In the transplanted hepatomas in mice, they may be considered as ancillary indicators for judging the therapeutic effect of hepatoma. PMID:27554918

  7. GUIDELINE FOR THE MANAGEMENT OF BILE DUCT CANCERS BY THE BRAZILIAN GASTROINTESTINAL TUMOR GROUP.

    PubMed

    Riechelmann, Rachel; Coutinho, Anelisa K; Weschenfelder, Rui F; Andrade DE Paulo, Gustavo; Fernandes, Gustavo Dos Santos; Gifoni, Markus; Oliveira, Maria de Lourdes; Gansl, Rene; Gil, Roberto; Luersen, Gustavo; Lucas, Lucio; Reisner, Marcio; Vieira, Fernando Meton; Machado, Marcel Autran; Murad, Andre; Osvaldt, Alessandro; Brandão, Miguel; Carvalho, Elisangela; Souza, Tulio; Pfiffer, Tulio; Prolla, Gabriel

    2016-01-01

    The Brazilian Gastrointestinal Tumor Group developed guidelines for the surgical and clinical management of patients with billiary cancers. The multidisciplinary panel was composed of experts in the field of radiology, medical oncology, surgical oncology, radiotherapy, endoscopy and pathology. The panel utilized the most recent literature to develop a series of evidence-based recommendations on different treatment and diagnostic strategies for cholangiocarcinomas and gallbladder cancers. PMID:27276097

  8. Clinical curative effect of oxaliplatin combined with flurouracil in the treatment of gastrointestinal tumor.

    PubMed

    Li, Baodong; Liu, Yonggang; Wang, Jinbang; Xu, Dongli; Feng, Weiyu; Zhuang, Jing

    2015-05-01

    Aiming at exploring clinical curative effect of oxaliplatin combined with flurouracil in the treatment of gastrointestinal tumor, this study divided 60 patients with gastrointestinal tumor into control and observation groups, each containing 30 patients. The observation group was treated with oxaliplatin combined with flurouracil, while the control was treated with FOLFOX4, i.e., intravenously dropping 85mg/m(2)Oxaliplatin (L-OHP), 200mg/m(2) calcium folinate (CF) and intravenously injecting 400mg/m(2) 5-fluorouracil (5-Fu), and 600mg/m(2) 5-Fu; then continuously performing intravenous drop infusion for 22h, every two weeks for a cycle. Hypodermic injection of granulocyte colony-stimulating factor (G-CSF) was conducted immediately when leukocytes occurred the III, IV degree of inhibition. The observation results of curative effect and negative reaction indicated higher effective rate with 83.33% in the observation and 50.00% in the control. Besides, in the observation, negative reactions possessed 10.00% that was much lower than 33.33% in the control. Thereby, the conclusion reached that the treatment of gastrointestinal tumor with oxaliplatin combined with flurouracil was worth promoting. PMID:26051738

  9. Prognostic Impact of Reduced Connexin43 Expression and Gap Junction Coupling of Neoplastic Stromal Cells in Giant Cell Tumor of Bone

    PubMed Central

    Balla, Peter; Maros, Mate Elod; Barna, Gabor; Antal, Imre; Papp, Gergo; Sapi, Zoltan; Athanasou, Nicholas Anthony; Benassi, Maria Serena; Picci, Pierro; Krenacs, Tibor

    2015-01-01

    Missense mutations of the GJA1 gene encoding the gap junction channel protein connexin43 (Cx43) cause bone malformations resulting in oculodentodigital dysplasia (ODDD), while GJA1 null and ODDD mutant mice develop osteopenia. In this study we investigated Cx43 expression and channel functions in giant cell tumor of bone (GCTB), a locally aggressive osteolytic lesion with uncertain progression. Cx43 protein levels assessed by immunohistochemistry were correlated with GCTB cell types, clinico-radiological stages and progression free survival in tissue microarrays of 89 primary and 34 recurrent GCTB cases. Cx43 expression, phosphorylation, subcellular distribution and gap junction coupling was also investigated and compared between cultured neoplastic GCTB stromal cells and bone marow stromal cells or HDFa fibroblasts as a control. In GCTB tissues, most Cx43 was produced by CD163 negative neoplastic stromal cells and less by CD163 positive reactive monocytes/macrophages or by giant cells. Significantly less Cx43 was detected in α-smooth muscle actin positive than α-smooth muscle actin negative stromal cells and in osteoclast-rich tumor nests than in the adjacent reactive stroma. Progressively reduced Cx43 production in GCTB was significantly linked to advanced clinico-radiological stages and worse progression free survival. In neoplastic GCTB stromal cell cultures most Cx43 protein was localized in the paranuclear-Golgi region, while it was concentrated in the cell membranes both in bone marrow stromal cells and HDFa fibroblasts. In Western blots, alkaline phosphatase sensitive bands, linked to serine residues (Ser369, Ser372 or Ser373) detected in control cells, were missing in GCTB stromal cells. Defective cell membrane localization of Cx43 channels was in line with the significantly reduced transfer of the 622 Da fluorescing calcein dye between GCTB stromal cells. Our results show that significant downregulation of Cx43 expression and gap junction coupling in

  10. Gene Expression Profiling of Ewing Sarcoma Tumors Reveals the Prognostic Importance of Tumor-Stromal Interactions: A Report from the Children’s Oncology Group

    PubMed Central

    Volchenboum, Samuel L.; Andrade, Jorge; Huang, Lei; Barkauskas, Donald A.; Krailo, Mark; Womer, Richard B.; Ranft, Andreas; Potratz, Jenny; Dirksen, Uta; Triche, Timothy J.; Lawlor, Elizabeth R.

    2015-01-01

    Relapse of Ewing sarcoma (ES) can occur months or years after initial remission and salvage therapy for relapsed disease is usually ineffective. Thus, there is great need to develop biomarkers that can predict which patients are at risk for relapse so that therapy and post-therapy evaluation can be adjusted accordingly. For the current study we performed whole genome expression profiling on two independent cohorts of clinically annotated ES tumors in an effort to identify and validate prognostic gene signatures. ES specimens were obtained from the Children’s Oncology Group (COG) and whole genome expression profiling performed using Affymetrix Human Exon 1.0 ST arrays. Lists of differentially expressed genes between survivors and non-survivors were used to identify prognostic gene signatures. An independent cohort of tumors from the Euro-Ewing cooperative group was similarly analyzed as a validation cohort. Unsupervised clustering of gene expression data failed to segregate tumors based on outcome. Supervised analysis of survivors vs. non-survivors revealed a small number of differentially expressed genes and several statistically significant gene signatures. Gene specific enrichment analysis (GSEA) demonstrated that integrin and chemokine genes were associated with survival in tumors where stromal contamination was present. Tumors that did not harbor stromal contamination showed no association of any genes or pathways with clinical outcome. Our results reflect the challenges of performing RNA-based assays on archived bone tumor specimens. In addition, they reveal a key role for tumor stroma in determining ES prognosis. Future biologic and clinical investigations should focus on elucidating the contribution of tumor:microenvironment interactions on ES progression and response to therapy. Key words: ES, gene expression profiling, prognostic signature PMID:26052443

  11. Fluorescence spectroscopy of gastrointestinal tumors: in vitro studies and in vivo clinical applications

    NASA Astrophysics Data System (ADS)

    Angelova, L.; Borisova, E.; Zhelyazkova, Al.; Keremedchiev, M.; Vladimirov, B.; Avramov, L.

    2013-11-01

    The limitations of standard endoscopy for detection and evaluation of cancerous changes in the gastrointestinal tract (GIT) are significant challenges and initiate development of new diagnostic modalities. Therefore many spectral and optical techniques are applied recently into the clinical practice for obtaining qualitatively and quantitatively new data from gastrointestinal neoplasia with different levels of clinical applicability and diagnostic success. Fluorescence imaging has been one of the most promising technologies in this area. The technique is very topical with its practical application in intra-operative, image-guided resection of tumors, because it permits minimal surgery intervention and friendly therapeutic conditions. The investigations presented here are based on in vitro measurements of excitation-emission matrices (EEM) for GIT neoplasia and in vivo measurements in the frames of initial clinical trial for tumor fluorescence spectra detection, applied for introduction of spectroscopic diagnostic system for optical biopsy of GIT tumors in the daily clinical practice of the University Hospital "Queen Jiovanna - ISUL"- Sofia. Autofluorescence and exogenous fluorescence signals are detected from normal mucosa, inflammation, dysphasia and carcinoma and main spectral features are evaluated. The systems and methods developed for diagnosis and monitoring could open new dimensions in diagnostic and real-time tumor resection. This will make the entire procedure more personal, patient friendly and effective and will help for further understanding of the tumor nature.

  12. The Action of Discoidin Domain Receptor 2 in Basal Tumor Cells and Stromal Cancer-Associated Fibroblasts Is Critical for Breast Cancer Metastasis.

    PubMed

    Corsa, Callie A S; Brenot, Audrey; Grither, Whitney R; Van Hove, Samantha; Loza, Andrew J; Zhang, Kun; Ponik, Suzanne M; Liu, Yuming; DeNardo, David G; Eliceiri, Kevin W; Keely, Patricia J; Longmore, Gregory D

    2016-06-14

    High levels of collagen deposition in human and mouse breast tumors are associated with poor outcome due to increased local invasion and distant metastases. Using a genetic approach, we show that, in mice, the action of the fibrillar collagen receptor discoidin domain receptor 2 (DDR2) in both tumor and tumor-stromal cells is critical for breast cancer metastasis yet does not affect primary tumor growth. In tumor cells, DDR2 in basal epithelial cells regulates the collective invasion of tumor organoids. In stromal cancer-associated fibroblasts (CAFs), DDR2 is critical for extracellular matrix production and the organization of collagen fibers. The action of DDR2 in CAFs also enhances tumor cell collective invasion through a pathway distinct from the tumor-cell-intrinsic function of DDR2. This work identifies DDR2 as a potential therapeutic target that controls breast cancer metastases through its action in both tumor cells and tumor-stromal cells at the primary tumor site. PMID:27264173

  13. Molecular mechanisms of lymphatic metastasis in solid tumors of the gastrointestinal tract

    PubMed Central

    Langheinrich, Melanie C; Schellerer, Vera; Perrakis, Aristotelis; Lohmüller, Clemens; Schildberg, Claus; Naschberger, Elisabeth; Stürzl, Michael; Hohenberger, Werner; Croner, Roland S

    2012-01-01

    Tumor cell dissemination from the primary tumor site to distant organs is one of the characteristic properties of malignant tumors and represents a crucial step in the progression of disease. Although the pattern of spread may vary in different types of carcinomas, dissemination via the lymphatic system represents a common event in metastasis. The extent of lymph node metastasis is one of the major determinants for the prognosis of patients with gastrointestinal carcinomas and guides the therapeutically management. During the last decades, significant attention has been given to the molecular mechanisms that control lymphatic metastasis. The process of lymphangiogenesis has come into the focus. Lymphangiogenesis, the formation of newly lymphatics, comprises a series of complex cellular events and is controlled by a balance between pro- and anti-lymphangiogenic signals. This article will briefly describe the lymphatic system and then provide an overview of the molecular players involved in tumor lymphangiogenesis. PMID:22977656

  14. Improved sensitivity in the diagnosis of gastro-intestinal tumors by fuzzy logic-based tumor marker profiles including the tumor M2-PK.

    PubMed

    Schneider, Joachim; Bitterlich, Norman; Schulze, Guntram

    2005-01-01

    The aim of this study was to improve diagnostic efficiency in the detection of gastro-intestinal cancers by using fuzzy logic modeling in combination with a tumor marker panel (CEA, CA72-4, CA19-9) including Tumor M2-PK. In this prospective study histologically confirmed colorectal (n=247), esophageal (n=86) and gastric cancer (n=122) patients were investigated and compared to control (n=53) persons without any malignant diseases. Tumor M2-PK was measured in plasma with an ELISA (ScheBoBiotech, Germany); all other markers were measured in sera (Roche, Germany). At 95% specificity, tumor detection was possible by the best single marker in colorectal cancer patients in 48% (Tumor M2-PK), in gastric cancers in 61% (CA72-4) and in esophageal cancers in 56% (Tumor M2-PK). A fuzzy logic rule-based system employing a tumor marker panel increased sensitivity significantly in colorectal cancers (p<0. 001) to 63% (Tumor M2-PK and CEA), in gastric cancers (p<0.001) to 81% (Tumor M2-PK and CA 72-4) and in esophageal cancers (p<0.02) to 74% (Tumor M2-PK and CA72-4). Adding a third marker further improved the sensitivity only marginally. Fuzzy logic analysis has proven to be more powerful than measurement of single markers alone or combinations using multiple logistic regression analysis of the markers. Therefore, with the fuzzy logic method and a tumor marker panel (including Tumor M2-PK), a new diagnostic tool for the detection of gastro-intestinal cancers is available. PMID:16033052

  15. Paracrine effect of GTP cyclohydrolase and angiopoietin-1 interaction in stromal fibroblasts on tumor Tie2 activation and breast cancer growth.

    PubMed

    Chen, Liye; Zeng, Xin; Kleibeuker, Esther; Buffa, Francesca; Barberis, Alessandro; Leek, Russell D; Roxanis, Ioannis; Zhang, Wei; Worth, Andrew; Beech, John S; Harris, Adrian L; Cai, Shijie

    2016-02-23

    Cancer-associated fibroblasts (CAFs) play a key role in promoting tumor growth, acting through complex paracrine regulation. GTP cyclohydrolase (GTPCH) expression for tetrahydrobiopterin synthesis in tumor stroma is implicated in angiogenesis and tumor development. However, the clinical significance of GTPCH expression in breast cancer is still elusive and how GTPCH regulates stromal fibroblast and tumor cell communication remains unknown. We found that GTPCH was upregulated in breast CAFs and epithelia, and high GTPCH RNA was significantly correlated with larger high grade tumors and worse prognosis. In cocultures, GTPCH expressing fibroblasts stimulated breast cancer cell proliferation and motility, cancer cell Tie2 phosphorylation and consequent downstream pathway activation. GTPCH interacted with Ang-1 in stromal fibroblasts and enhanced Ang-1 expression and function, which in turn phosphorylated tumor Tie2 and induced cell proliferation. In coimplantation xenografts, GTPCH in fibroblasts enhanced tumor growth, upregulating Ang-1 and alpha-smooth muscle actin mainly in fibroblast-like cells. GTPCH inhibition resulted in the attenuation of tumor growth and angiogenesis. GTPCH/Ang-1 interaction in stromal fibroblasts and activation of Tie2 on breast tumor cells could play an important role in supporting breast cancer growth. GTPCH may be an important mechanism of paracrine tumor growth and hence a target for therapy in breast cancer. PMID:26814432

  16. Paracrine effect of GTP cyclohydrolase and angiopoietin-1 interaction in stromal fibroblasts on tumor Tie2 activation and breast cancer growth

    PubMed Central

    Kleibeuker, Esther; Buffa, Francesca; Barberis, Alessandro; Leek, Russell D.; Roxanis, Ioannis; Zhang, Wei; Worth, Andrew; Beech, John S.; Harris, Adrian L.; Cai, Shijie

    2016-01-01

    Cancer-associated fibroblasts (CAFs) play a key role in promoting tumor growth, acting through complex paracrine regulation. GTP cyclohydrolase (GTPCH) expression for tetrahydrobiopterin synthesis in tumor stroma is implicated in angiogenesis and tumor development. However, the clinical significance of GTPCH expression in breast cancer is still elusive and how GTPCH regulates stromal fibroblast and tumor cell communication remains unknown. We found that GTPCH was upregulated in breast CAFs and epithelia, and high GTPCH RNA was significantly correlated with larger high grade tumors and worse prognosis. In cocultures, GTPCH expressing fibroblasts stimulated breast cancer cell proliferation and motility, cancer cell Tie2 phosphorylation and consequent downstream pathway activation. GTPCH interacted with Ang-1 in stromal fibroblasts and enhanced Ang-1 expression and function, which in turn phosphorylated tumor Tie2 and induced cell proliferation. In coimplantation xenografts, GTPCH in fibroblasts enhanced tumor growth, upregulating Ang-1 and alpha-smooth muscle actin mainly in fibroblast-like cells. GTPCH inhibition resulted in the attenuation of tumor growth and angiogenesis. GTPCH/Ang-1 interaction in stromal fibroblasts and activation of Tie2 on breast tumor cells could play an important role in supporting breast cancer growth. GTPCH may be an important mechanism of paracrine tumor growth and hence a target for therapy in breast cancer. PMID:26814432

  17. RNA Sequencing of Tumor-Associated Microglia Reveals Ccl5 as a Stromal Chemokine Critical for Neurofibromatosis-1 Glioma Growth.

    PubMed

    Solga, Anne C; Pong, Winnie W; Kim, Keun-Young; Cimino, Patrick J; Toonen, Joseph A; Walker, Jason; Wylie, Todd; Magrini, Vincent; Griffith, Malachi; Griffith, Obi L; Ly, Amy; Ellisman, Mark H; Mardis, Elaine R; Gutmann, David H

    2015-10-01

    Solid cancers develop within a supportive microenvironment that promotes tumor formation and growth through the elaboration of mitogens and chemokines. Within these tumors, monocytes (macrophages and microglia) represent rich sources of these stromal factors. Leveraging a genetically engineered mouse model of neurofibromatosis type 1 (NF1) low-grade brain tumor (optic glioma), we have previously demonstrated that microglia are essential for glioma formation and maintenance. To identify potential tumor-associated microglial factors that support glioma growth (gliomagens), we initiated a comprehensive large-scale discovery effort using optimized RNA-sequencing methods focused specifically on glioma-associated microglia. Candidate microglial gliomagens were prioritized to identify potential secreted or membrane-bound proteins, which were next validated by quantitative real-time polymerase chain reaction as well as by RNA fluorescence in situ hybridization following minocycline-mediated microglial inactivation in vivo. Using these selection criteria, chemokine (C-C motif) ligand 5 (Ccl5) was identified as a chemokine highly expressed in genetically engineered Nf1 mouse optic gliomas relative to nonneoplastic optic nerves. As a candidate gliomagen, recombinant Ccl5 increased Nf1-deficient optic nerve astrocyte growth in vitro. Importantly, consistent with its critical role in maintaining tumor growth, treatment with Ccl5 neutralizing antibodies reduced Nf1 mouse optic glioma growth and improved retinal dysfunction in vivo. Collectively, these findings establish Ccl5 as an important microglial growth factor for low-grade glioma maintenance relevant to the development of future stroma-targeted brain tumor therapies. PMID:26585233

  18. Feto-maternal outcomes of pregnancy complicated by ovarian sex-cord stromal tumor: a systematic review of literature.

    PubMed

    Blake, Erin A; Carter, Charelle M; Kashani, Banafsheh N; Kodama, Michiko; Mabuchi, Seiji; Yoshino, Kiyoshi; Matsuo, Koji

    2014-04-01

    Sex-cord stromal tumors (SCSTs) are rare ovarian cancers and their behavior during pregnancy is not well understood. To evaluate the maternal and fetal outcomes of pregnancy complicated by ovarian SCST, a systematic literature search was conducted in PubMed/MEDLINE using entry key words "pregnancy" and each type of ovarian SCST ("sex cord stromal tumor," "granulosa cell tumor," "thecoma," "Sertoli-Leydig cell tumor," or "gynandroblastoma") between 1955 and 2012 that identified 46 cases eligible for the analysis. Clinical characteristics, pregnancy outcome, tumor characteristics, and survival outcomes were evaluated. Serious adverse events were defined as complications related to the SCST that resulted in severe morbidity or mortality for mother, fetus, or both. The most common histology was granulosa cell tumor (22.0%), followed by thecoma (18.6%) and Sertoli-Leydig cell tumor (8.5%). Abdomino-pelvic pain (45.7%), palpable mass (30.4%), and virilization (26.1%) were the three most common symptoms. The majority were stage I (76.1%), tumor size <15cm (64.9%), and underwent unilateral adnexectomy (80.4%). Fetal conservation surgery was seen in 54.3%. Most cases had live births (78.3%) at full term (60.9%). Among cases proceeded expectant delay of delivery (45.7%), most cases resulted in live birth (95.2%) with median expectant interval of 20.7 weeks. Maternal and/or fetal serious adverse events (SAEs) were observed in 41.3% with maternal shock/hemoperitoneum being the most common complication (13.0%). Logistic regression test identified younger age (<30 versus ≥30, 73.3% versus 26.7%, odds ratio [OR] 11.7, 95%CI 1.35-101, p=0.026), large tumor (size ≥15cm versus <15cm, 64.9% versus 35.1%, OR 10.0, 95%CI 1.29-26.2, p=0.004), and advanced-stage (stages II-IV versus I, 76.1% versus 23.9%, OR 5.82, 95%CI 2.05-48.9, p=0.022) as risk factors of increased SAE. Overall survival of patients diagnosed with ovarian SCST during pregnancy was comparable to ovarian SCST not

  19. Expression of Transcription Factors and Nuclear Receptors in Mixed Germ Cell-Sex Cord Stromal Tumor and Related Tumors of the Gonads.

    PubMed

    Roth, Lawrence M; Cheng, Liang

    2015-11-01

    In this study, we compare the expression of OCT4, SALL4, and TSPYL1 in mixed germ cell-sex cord stromal tumor (MGC-SCST) of either gonad to that of normal adult testis, classic and spermatocytic seminoma, intratubular germ cell neoplasia, unclassified, gonadoblastoma, and dysgerminoma to determine the entity or entities that most closely resemble MGC-SCST by immunohistochemistry of germ cells. The most useful transcription factor was OCT4. In addition, to its already described value in distinguishing germinoma and embryonal carcinoma from yolk sac tumor and in differentiating classic from spermatocytic seminoma, we found that OCT4 is useful in confirming or ruling out potential malignancy in MGC-SCST of either gonad. Expression of OCT4 in most ovarian MGC-SCSTs resembles that of dysgerminoma, whereas most testicular examples resemble that of spermatocytic seminoma and normal adult testis. Thus, most MGC-SCSTs of the ovary are potentially malignant, and corresponding tumors of the testis are mostly benign; however, exceptions likely can be detected by the use of OCT4, potentially leading to more appropriate clinical management in some cases. SALL4 is an underutilized transcription factor that is useful in distinguishing testicular MGC-SCST from sex cord stromal tumor, unclassified in those neoplasms where the germ cells are sparse or unevenly distributed. Compared with other transcription factors studied, TSPY and its congener TSPYL1 have little value in the assessment of germ cell tumors because of their relatively wide range of expression in normal adult testis and in germ cell tumors. PMID:26107563

  20. CT findings of sclerosing stromal tumor of the ovary: A report of two cases and review of the literature

    PubMed Central

    TIAN, TONGTONG; ZHU, QINGQIANG; CHEN, WENXIN; WANG, SHOUAN; SUI, WEIFAN; WU, JINGTAO

    2016-01-01

    Sclerosing stromal tumor (SST) of the ovary, which was first described by Chalvardjian and Scully in 1973, is a rare ovarian neoplasm, occurring predominantly in young women. The most common clinical symptom in patients with SST is menstrual irregularities. Microscopically, the tumor is characterized by the presence of pseudo-lobulated cellular areas, with a prominent tendency to sclerosis, marked vascularity and pronounced variation in cellular size and shape. In the current study, 2 cases of SST of the ovary are presented. These cases were confirmed by imaging, surgical and histological examination. No adjuvant therapy was administered to the patients and the two patients were disease-free with no imaging findings of recurrence or metastasis 24 months following surgery. PMID:27313700

  1. [Occult stromal tumour of the small intestine: a cause of chronic intestinal blood loss in a 70 year-old woman].

    PubMed

    Pentimone, F; Gerini, A; Moncini, C; Di Stefano, S; Pagni, V; Pastine, F; Del Corso, L

    1999-03-01

    The case of a 70 year-old woman with a chronic gastrointestinal blood loss due to a stromal tumor located in the middle third of the small intestine is reported. The peculiarities of the case are the characteristic immunohistochemistry of the neoplasm and, particularly, the mimetic clinical presentation, a kind of ''phantom tumor'' confirmed only with celiotomy and surgical excision. PMID:16498316

  2. Extracellular vesicles from bone marrow mesenchymal stem/stromal cells transport tumor regulatory microRNA, proteins, and metabolites.

    PubMed

    Vallabhaneni, Krishna C; Penfornis, Patrice; Dhule, Santosh; Guillonneau, Francois; Adams, Kristen V; Mo, Yin Yuan; Xu, Rui; Liu, Yiming; Watabe, Kounosuke; Vemuri, Mohan C; Pochampally, Radhika

    2015-03-10

    Human mesenchymal stem/stromal cells (hMSCs) have been shown to support breast cancer cell proliferation and metastasis, partly through their secretome. hMSCs have a remarkable ability to survive for long periods under stress, and their secretome is tumor supportive. In this study, we have characterized the cargo of extracellular vesicular (EV) fraction (that is in the size range of 40-150nm) of serum deprived hMSCs (SD-MSCs). Next Generation Sequencing assays were used to identify small RNA secreted in the EVs, which indicated presence of tumor supportive miRNA. Further assays demonstrated the role of miRNA-21 and 34a as tumor supportive miRNAs. Next, proteomic assays revealed the presence of ≈150 different proteins, most of which are known tumor supportive factors such as PDGFR-β, TIMP-1, and TIMP-2. Lipidomic assays verified presence of bioactive lipids such as sphingomyelin. Furthermore, metabolite assays identified the presence of lactic acid and glutamic acid in EVs. The co-injection xenograft assays using MCF-7 breast cancer cells demonstrated the tumor supportive function of these EVs. To our knowledge this is the first comprehensive -omics based study that characterized the complex cargo of extracellular vesicles secreted by hMSCs and their role in supporting breast cancers. PMID:25669974

  3. Interferon-γ and Tumor Necrosis Factor-α Polarize Bone Marrow Stromal Cells Uniformly to a Th1 Phenotype

    PubMed Central

    Jin, Ping; Zhao, Yuanlong; Liu, Hui; Chen, Jinguo; Ren, Jiaqiang; Jin, Jianjian; Bedognetti, Davide; Liu, Shutong; Wang, Ena; Marincola, Francesco; Stroncek, David

    2016-01-01

    Activated T cells polarize mesenchymal stromal cells (MSCs) to a proinflammatory Th1 phenotype which likely has an important role in amplifying the immune response in the tumor microenvironment. We investigated the role of interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α), two factors produced by activated T cells, in MSC polarization. Gene expression and culture supernatant analysis showed that TNF-α and IFN-γ stimulated MSCs expressed distinct sets of proinflammatory factors. The combination of IFN-γ and TNF-α was synergistic and induced a transcriptome most similar to that found in MSCs stimulated with activated T cells and similar to that found in the inflamed tumor microenvironment; a Th1 phenotype with the expression of the immunosuppressive factors IL-4, IL-10, CD274/PD-L1 and indoleamine 2,3 dioxygenase (IDO). Single cell qRT-PCR analysis showed that the combination of IFN-γ and TNF-α polarized uniformly to this phenotype. The combination of IFN-γ and TNF-α results in the synergist uniform polarization of MSCs toward a primarily Th1 phenotype. The stimulation of MSCs by IFN-γ and TNF-α released from activated tumor infiltrating T cells is likely responsible for the production of many factors that characterize the tumor microenvironment. PMID:27211104

  4. Interferon-γ and Tumor Necrosis Factor-α Polarize Bone Marrow Stromal Cells Uniformly to a Th1 Phenotype.

    PubMed

    Jin, Ping; Zhao, Yuanlong; Liu, Hui; Chen, Jinguo; Ren, Jiaqiang; Jin, Jianjian; Bedognetti, Davide; Liu, Shutong; Wang, Ena; Marincola, Francesco; Stroncek, David

    2016-01-01

    Activated T cells polarize mesenchymal stromal cells (MSCs) to a proinflammatory Th1 phenotype which likely has an important role in amplifying the immune response in the tumor microenvironment. We investigated the role of interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α), two factors produced by activated T cells, in MSC polarization. Gene expression and culture supernatant analysis showed that TNF-α and IFN-γ stimulated MSCs expressed distinct sets of proinflammatory factors. The combination of IFN-γ and TNF-α was synergistic and induced a transcriptome most similar to that found in MSCs stimulated with activated T cells and similar to that found in the inflamed tumor microenvironment; a Th1 phenotype with the expression of the immunosuppressive factors IL-4, IL-10, CD274/PD-L1 and indoleamine 2,3 dioxygenase (IDO). Single cell qRT-PCR analysis showed that the combination of IFN-γ and TNF-α polarized uniformly to this phenotype. The combination of IFN-γ and TNF-α results in the synergist uniform polarization of MSCs toward a primarily Th1 phenotype. The stimulation of MSCs by IFN-γ and TNF-α released from activated tumor infiltrating T cells is likely responsible for the production of many factors that characterize the tumor microenvironment. PMID:27211104

  5. A Case Report: Pseudoangiomatous Stromal Hyperplasia Tumor Presenting as a Palpable Mass

    PubMed Central

    Vo, Q. D.; Koch, G.; Girard, J. M.; Zamora, L.; Bouquet de Jolinière, Jean; Khomsi, F.; Feki, A.; Hoogewoud, H. M.

    2016-01-01

    We report a case of woman with a palpable lump on her left breast. On mammography, a huge mass located between the inner and the outer inferior breast quadrants of the left breast was found. The ultrasound examination realized later revealed a heterogeneous mass with smooth and lobulated borders. An MRI was also performed, showing an oval mass with heterogeneous areas of enhancement. Finally, a core biopsy under sonographic guidance revealed a pseudoangiomatous stromal hyperplasia of the breast. PMID:26835457

  6. Stromal platelet-derived growth factor receptor α (PDGFRα) provides a therapeutic target independent of tumor cell PDGFRα expression in lung cancer xenografts

    PubMed Central

    Gerber, David E.; Gupta, Puja; Dellinger, Michael T.; Toombs, Jason E.; Peyton, Michael; Duignan, Inga; Malaby, Jennifer; Bailey, Timothy; Burns, Colleen; Brekken, Rolf A.; Loizos, Nick

    2012-01-01

    In lung cancer, platelet-derived growth factor receptor α (PDGFRα) is expressed frequently by tumor-associated stromal cells and by cancer cells in a subset of tumors. We sought to determine the effect of targeting stromal PDGFRα in preclinical lung tumor xenograft models (human tumor, mouse stroma). Effects of anti-human (IMC-3G3) and anti-mouse (1E10) PDGFRα mAbs on proliferation and PDGFRα signaling were evaluated in lung cancer cell lines and mouse fibroblasts. Therapy studies were performed using established PDGFRα-positive H1703 cells and PDGFRα-negative Calu-6, H1993, and A549 subcutaneous tumors in immunocompromised mice treated with vehicle, anti-PDGFRα mAbs, chemotherapy, or combination therapy. Tumors were analyzed for growth and levels of growth factors. IMC-3G3 inhibited PDGFRα activation and the growth of H1703 cells in vitro and tumor growth in vivo, but had no effect on PDGFRα-negative cell lines or mouse fibroblasts. 1E10 inhibited growth and PDGFRα activation of mouse fibroblasts, but had no effect on human cancer cell lines in vitro. In vivo, 1E10-targeted inhibition of murine PDGFRα reduced tumor growth as single-agent therapy in Calu-6 cells and enhanced the effect of chemotherapy in xenografts derived from A549 cells. We also identified that low expression cancer cell expression of VEGF-A and elevated expression of PDGF-AA were associated with response to stromal PDGFRα targeting. We conclude that stromal PDGFRα inhibition represents a means for enhancing control of lung cancer growth in some cases, independent of tumor cell PDGFRα expression. PMID:22933705

  7. Estrogen-producing endometrioid adenocarcinoma resembling sex cord-stromal tumor of the ovary: a review of four postmenopausal cases

    PubMed Central

    2012-01-01

    Abstract The 4 present cases with endometrioid adenocarcinoma (EMA) of the ovary were characterized by estrogen overproduction and resemblance to sex cord-stromal tumor (SCST). The patients were all postmenopausal, at ages ranging from 60 to 79 years (av. 67.5), who complained of abdominal discomfort or distention and also atypical genital bleeding. Cytologically, maturation of the cervicovaginal squamous epithelium and active endometrial proliferation were detected. The serum estrogen (estradiol, E2) value was preoperatively found to be elevated, ranging from 48.7 to 83.0 pg/mL (av. 58.4). In contrast, follicle stimulating hormone was suppressed to below the normal value. MR imaging diagnoses included SCSTs such as granulosa cell tumor or thecoma for 3 cases because of predominantly solid growth, and epithelial malignancy for one case because of cystic and solid structure. Grossly, the solid part of 3 cases was homogeneously yellow in color. Histologically, varying amounts of tumor components were arranged in solid nests, hollow tubules, cord-like strands and cribriform-like nests in addition to the conventional EMA histology. In summary, postmenopausal ovarian solid tumors with the estrogenic manifestations tend to be preoperatively diagnosed as SCST. Due to this, in the histological diagnosis, this variant of ovarian EMA may be challenging and misdiagnosed as SCST because of its wide range in morphology. Virtual slides http://www.diagnosticpathology.diagnomx.eu/vs/6096841358065394 PMID:23190574

  8. Oncogenic Activation of the Wnt/β-Catenin Signaling Pathway in Signet Ring Stromal Cell Tumor of the Ovary.

    PubMed

    Kopczynski, Janusz; Kowalik, Artur; Chłopek, Małgorzata; Wang, Zeng-Feng; Góźdź, Stanisław; Lasota, Jerzy; Miettinen, Markku

    2016-01-01

    Signet ring stromal cell tumor (SRSCT) of the ovary is a very rare benign ovarian neoplasm. To date, no underlying genetic mechanism has been identified. In this study, 50 oncogenes and tumor suppressor genes were evaluated for mutations in a typical SRSCT using the next-generation DNA sequencing approach. An in-frame deletion of 30 nucleotides in the glycogen serine kinase-3 beta phosphorylation region of the β-catenin gene (CTNNB1) was identified, and the finding was confirmed by Sanger sequencing. This deletion (c.68_97del) at the protein level would lead to a p.Ser23_Ser33delinsThr oncogenic-type mutation. Subsequent immunohistochemistry showed prominent nuclear accumulation of β-catenin and cyclin D1 in tumor cells. Thus, mutational activation of the Wnt/β-catenin pathway could be a crucial event in the molecular pathogenesis of SRSCT of the ovary. These findings may also assist in the diagnosis of this rare tumor. PMID:26509912

  9. Gastrointestinal neuroendocrine tumors: Searching the optimal treatment strategy--A literature review.

    PubMed

    Berardi, Rossana; Rinaldi, Silvia; Torniai, Mariangela; Morgese, Francesca; Partelli, Stefano; Caramanti, Miriam; Onofri, Azzurra; Polenta, Vanessa; Pagliaretta, Silvia; Falconi, Massimo; Cascinu, Stefano

    2016-02-01

    Neuroendocrine tumors of the gastro-entero-pancreatic system (GEP-NETs) are a heterogeneous group of neoplasms, with different malignant potential and behavior. Many treatment options are available. Surgery should be considered for localized tumors and in some selected cases of metastatic disease. Somatostatin analogs, useful for symptoms control in functioning tumors, are also effective to inhibit tumor progression in specific settings. The multi-TKI sunitinib and of the mTOR-inhibitor everolimus are efficacy for metastatic pancreatic NET (P-NET) treatment. Chemotherapy is generally used in symptomatic and progressive NETs. Peptide receptor radionuclide therapy (PRRT) should be recommended after failure of medical therapy. For tumors confined to the liver ablative techniques should be considered. Nevertheless a shared therapeutic sequence for GEP-NET treatment still does not exist. In this review, we analyzed available data trying to identify the better treatment strategy and to suggest potential therapeutic algorithms distinguishing P-NETs from gastrointestinal NETs (GI-NETs). PMID:26643525

  10. Future Directions in the Treatment of Gastrointestinal and Pancreatic Neuroendocrine Tumors.

    PubMed

    Asmis, Timothy

    2016-07-01

    Recently, the landscape of the diagnosis and treatment of patients with well-differentiated gastrointestinal/pancreatic neuroendocrine tumors (previously referred to as carcinoid tumors) has changed dramatically. We will need to work with all of the stakeholders including clinicians, patients, regulatory agencies, and industry to best navigate future treatment and research. Future protocols will require us to define clinically relevant end points. In designing future clinical trials, we will need to determine which patients will be included in these studies. Future research will need to address the best way to image and follow patient's disease both in the clinic and on research studies. Timely access to new therapies will be the utmost importance to both current and future patients. We must work together to establish relevant clinical questions and to pursue collaborative research that promotes the health of our patients. PMID:27295530

  11. Bilateral Diffuse Tumorous Pseudoangiomatous Stromal Hyperplasia: A Case of Bilateral Mastectomy in a 29-Year-Old Woman

    PubMed Central

    Dai, Hongyan; Connor, Carol; Cui, Wei; Gatewood, Jason; Fan, Fang

    2014-01-01

    Pseudoangiomatous stromal hyperplasia (PASH) is a benign breast lesion commonly encountered as an incidental microscopic finding. However, it can also manifest as a mass-forming lesion (tumorous PASH) capable of recurrence after surgical excision. Most of the previously reported cases of tumorous PASH present as a single dominant mass. Here we reported a rare case of diffuse tumorous PASH involving bilateral breasts clinically mimicking malignancy. A 29-year-old African-American female presented with a one-year history of bilateral breast enlargement and asymmetry. Physical examination revealed multiple palpable nodules in bilateral breasts. Imaging studies demonstrated innumerable homogeneously enhancing masses throughout both breasts, greater on the left, with multiple cysts and edema. Biopsy of the breast nodules demonstrated histopathological changes consistent with PASH. Due to the extent of the lesions and progressive clinical symptoms, decision was made to perform bilateral mastectomy. Macroscopic examination of the bilateral mastectomy specimens revealed markedly enlarged breasts with marked edema and numerous well-defined firm nodules. Microscopic evaluation of the nodules confirmed the diagnosis of PASH. No evidence of malignancy was identified. Recognition of this rare form of PASH is essential for the proper clinical management. PMID:25544925

  12. Bilateral diffuse tumorous pseudoangiomatous stromal hyperplasia: a case of bilateral mastectomy in a 29-year-old woman.

    PubMed

    Dai, Hongyan; Connor, Carol; Cui, Wei; Gatewood, Jason; Fan, Fang

    2014-01-01

    Pseudoangiomatous stromal hyperplasia (PASH) is a benign breast lesion commonly encountered as an incidental microscopic finding. However, it can also manifest as a mass-forming lesion (tumorous PASH) capable of recurrence after surgical excision. Most of the previously reported cases of tumorous PASH present as a single dominant mass. Here we reported a rare case of diffuse tumorous PASH involving bilateral breasts clinically mimicking malignancy. A 29-year-old African-American female presented with a one-year history of bilateral breast enlargement and asymmetry. Physical examination revealed multiple palpable nodules in bilateral breasts. Imaging studies demonstrated innumerable homogeneously enhancing masses throughout both breasts, greater on the left, with multiple cysts and edema. Biopsy of the breast nodules demonstrated histopathological changes consistent with PASH. Due to the extent of the lesions and progressive clinical symptoms, decision was made to perform bilateral mastectomy. Macroscopic examination of the bilateral mastectomy specimens revealed markedly enlarged breasts with marked edema and numerous well-defined firm nodules. Microscopic evaluation of the nodules confirmed the diagnosis of PASH. No evidence of malignancy was identified. Recognition of this rare form of PASH is essential for the proper clinical management. PMID:25544925

  13. Human periprostatic white adipose tissue is rich in stromal progenitor cells and a potential source of prostate tumor stroma.

    PubMed

    Ribeiro, Ricardo; Monteiro, Cátia; Silvestre, Ricardo; Castela, Angela; Coutinho, Helena; Fraga, Avelino; Príncipe, Paulo; Lobato, Carlos; Costa, Carla; Cordeiro-da-Silva, Anabela; Lopes, José Manuel; Lopes, Carlos; Medeiros, Rui

    2012-10-01

    A body of growing evidence now implicates white adipose tissue as a relevant source of stromal progenitor cells recruited to the tumor microenvironment to form supportive tumor stroma. While the role of periprostatic (PP) adipose tissue in prostate cancer progression has been barely appreciated, we sought to determine the progenitor cell population in PP adipose tissue and the association with prostate cancer. We isolated and characterized CD31(-)CD34(+)CD45(-)CD146(-) progenitor cells (adipose-derived stem cells [ASC]) in paired samples of PP and preperitoneal visceral adipose tissue from prostate tissue and peripheral blood mononuclear cells of prostate cancer and nodular prostatic hyperplasia patients. ASC were quantified by flow cytometry and confirmed through target gene expression. Here we show a significantly higher amount of ASC in PP than in visceral adipose tissue, independent of body mass index and prostatic disease. In the prostate, ASC are increased in cancer compared with prostatic nodular hyperplasia patients. Concordantly, adipsin gene (CFD) expression, which is known to be up-regulated in adipose stem cells, was overexpressed in PP adipose tissue, in the prostate of cancer patients and in prostate CD31(-)CD34(+)CD45(-)CD146(-) sorted cells. ASC were found at higher levels in the blood of prostate cancer patients simultaneously overweight/obese. Present findings indicate that PP adipose tissue is a reservoir of progenitor cells with the potential to migrate towards prostate tumors, although its clinical significance merits further evaluation. PMID:23038706

  14. Multipotent mesenchymal stromal cells promote tumor growth in distinct colorectal cancer cells by a β1-integrin-dependent mechanism.

    PubMed

    Widder, Miriam; Lützkendorf, Jana; Caysa, Henrike; Unverzagt, Susanne; Wickenhauser, Claudia; Benndorf, Ralf A; Schmoll, Hans-Joachim; Müller-Tidow, Carsten; Müller, Thomas; Müller, Lutz P

    2016-02-15

    Tumor-stroma interactions play an essential role in the biology of colorectal carcinoma (CRC). Multipotent mesenchymal stromal cells (MSC) may represent a pivotal part of the stroma in CRC, but little is known about the specific interaction of MSC with CRC cells derived from tumors with different mutational background. In previous studies we observed that MSC promote the xenograft growth of the CRC cell-line DLD1. In the present study, we aimed to analyze the mechanisms of MSC-promoted tumor growth using various in vitro and in vivo experimental models and CRC cells of different mutational status. MSC specifically interacted with distinct CRC cells and supported tumor seeding in xenografts. The MSC-CRC interaction facilitated three-dimensional spheroid formation in CRC cells with dysfunctional E-cadherin system. Stable knock-downs revealed that the MSC-facilitated spheroid formation depended on β1-integrin in CRC cells. Specifically in α-catenin-deficient CRC cells this β1-integrin-dependent interaction resulted in a MSC-mediated promotion of early tumor growth in vivo. Collagen I and other extracellular matrix compounds were pivotal for the functional MSC-CRC interaction. In conclusion, our data demonstrate a differential interaction of MSC with CRC cells of different mutational background. Our study is the first to show that MSC specifically compared to normal fibroblasts impact early xenograft growth of distinct α-catenin deficient CRC cells possibly through secretion of extracellular matrix. This mechanism could serve as a future target for therapy and metastasis prevention. PMID:26356035

  15. A Journey to Uncharted Territory: New Technical Frontiers in Studying Tumor-Stromal Cell Interactions

    PubMed Central

    Guldner, Ian H.; Zhang, Siyuan

    2014-01-01

    The crosstalk between tumor cells and cells of the tumor stroma dictate malignant progression and represent an intriguing and viable anticancer therapeutic target. The successful development of therapeutics targeting tumor-stroma interactions is tied to the insight provided by basic research on such crosstalk. Tumor-stroma interactions can be transient and dynamic, and they occur within defined spatiotemporal contexts among genetically and compositionally heterogeneous populations of cells, yet methods currently applied to study the said crosstalk do not sufficiently address these features. Emerging imaging and genetic methods, however, can overcome limitations of traditional approaches and provide unprecedented insight into tumor-stroma crosstalk with unparalleled accuracy. The comprehensive data obtained by applying emerging methods will require processing and analysis by multidisciplinary teams, but the efforts will ultimately rejuvenate hope in developing novel therapies against pro-tumorigenic tumor-stroma crosstalk. PMID:25500646

  16. Gastrointestinal neuroendocrine tumor with unresectable liver metastases: an example of multimodal therapeutic approach.

    PubMed

    Martínez, Jorge; Besa, Santiago; Arab, Juan P; Quintana, Juan C; Regonesi, Carlos; Huete, Alvaro; Jarufe, Nicolás; Guerra, Juan F; Benítez, Carlos; Arrese, Marco

    2015-01-01

    Gastrointestinal neuroendocrine tumors (NET) frequently present with unresectable hepatic metastases, which poses a barrier for curative treatment. Resection of the primary tumor and subsequent orthotopic liver transplantation (OLT) has been proposed as a treatment approach but available data in this regard is limited. We present a clinical case of an otherwise asymptomatic 44-yo man complaining of abdominal pain and dyspepsia that was diagnosed of a 10 cm duodenal tumor with multiple hepatic metastases. A CT-guided biopsy confirmed a NET. He underwent first a Whipple's procedure, and then was listed for liver transplantation. During the waiting time a multimodal therapeutic approach was used including the use of radioactive 177lutetium-labeled somatostatin analogues, long-acting somastostatin analogues and antiangiogenic antibodies (bevacizumab) in order to keep neoplastic disease under control. Two years after Whipple's procedure and given disease stability he underwent OLT with an uneventful postoperative evolution. Patient condition and graft function are optimal after a 4-year follow-up period with no evidence of recurrence. This case report underscores how a multimodal approach involving careful patient selection, resective surgery as well as use of somatostatin analogues and antiangiogenic biological therapy followed by liver transplantation can achieve excellent long-term results in this difficult patient population. PMID:26256906

  17. Intravenous low-grade endometrial stromal sarcoma with intracardiac extension: A CASE OF inaccurate tumor location on contrast-enhanced computed tomography

    PubMed Central

    NOGAMI, YUYA; YAMAGAMI, WATARU; MAKI, JUNKO; BANNO, KOUJI; SUSUMU, NOBUYUKI; TOMITA, KOICHI; MATSUBARA, KENTARO; OBARA, HIDEAKI; KITAGAWA, YUKO; AOKI, DAISUKE

    2016-01-01

    We herein report a case of low-grade endometrial stromal sarcoma with intracardiac extension in a 58-year-old woman with a uterine tumor with intravascular involvement. The tumor was suspected preoperatively to be an endometrial stromal sarcoma by magnetic resonance imaging. The extent of intravascular involvement was determined to be below the level of the renal veins on preoperative contrast-enhanced computed tomography (CT). However, perioperative echography revealed that the tumor extended to the right atrium. An emergency cardiotomy with extracorporeal circulation was required. The risk of tumor embolism was reduced through transection of the inferior vena cava, but the tumor was difficult to remove completely. Postoperative hormonal therapy reduced the size of the residual tumor and no recurrence was detected for 1 year. The preoperative contrast-enhanced CT was unable to detect the free-floating intravascular tumor. This case illustrates a limitation of CT and indicates that accurate determination of the tumor extent for planning a surgical strategy in similar cases should be performed using multiple imaging methods. PMID:26893856

  18. Application of next-generation sequencing in gastrointestinal and liver tumors.

    PubMed

    Mikhail, Sameh; Faltas, Bishoy; Salem, Mohamed E; Bekaii-Saab, Tanios

    2016-05-01

    Malignant transformation of normal cells is associated with the evolution of genomic alterations. This concept has led to the development of molecular testing platforms to identify genomic alterations that can be targeted with novel therapies. Next generation sequencing (NGS) has heralded a new era in precision medicine in which tumor genes can be studied efficiently. Recent developments in NGS have allowed investigators to identify genomic predictive makers and hereditary mutations to guide treatment decision. The application of NGS in gastrointestinal cancers is being extensively studied but continues to face substantial challenges. In our review, we discuss various NGS platforms and highlight their role in identifying familial mutations and markers of response or resistance to cancer therapy. We also provide a balanced discussion of the challenges that limit the routine use of NGS in clinical practice. PMID:26916979

  19. Increased prevalence of eosinophilic gastrointestinal disorders (EGID) in pediatric PTEN hamartoma tumor syndromes (PHTS)

    PubMed Central

    Henderson, Carol J.; Ngeow, Joanne; Collins, Margaret H.; Martin, Lisa J.; Putnam, Philip E.; Abonia, J. Pablo; Marsolo, Keith; Eng, Charis; Rothenberg, Marc E.

    2014-01-01

    Objective: The PTEN hamartoma tumor syndromes (PHTS) are a collection of disorders caused by germline mutations of the tumor suppressor gene PTEN. Eosinophilic gastrointestinal disorders (EGID) are rare diseases characterized by food-induced, eosinophil-dominant inflammation in various segments of the gastrointestinal tract. On the basis of our clinical observations of several patients with EGID-PHTS, we investigated whether there is an association between these two disorders. Methods: Cincinnati Children’s Hospital Medical Center (CCHMC) Informatics for Integrating Biology & the Bedside (i2b2) warehouse was queried for the years 2007-2012 using ICD 9 codes for PTEN-related diseases; the results were cross-referenced with participants enrolled in the Cincinnati Center for Eosinophilic Disorder’s EGID database to identify patients with both disorders. Similarly, the Cleveland Clinic Genomic Medicine Institute PTEN database was queried for cases between 2005 and 2012. Inclusion criteria were age ≥18 years, history of PHTS, and an esophagogastroduodenoscopy (EGD) and/or colonoscopy with at least one histologic EGID diagnosis confirmed by a CCHMC pathologist. Pearson’s Chi-square was used to determine the odds of EGID enrichment in PHTS. Results: Of the 1,058,260 CCHMC distinct patients identified by the i2b2 search, 53 had clinical diagnoses suggestive of PHTS. Thirteen of the 53 had PTEN mutations, with 8/13 (62%) having had an EGD and/or colonoscopy. Five of the 8 had confirmed EGID. At the Cleveland Clinic, 3/75 patients with PHTS had confirmed EGID. CCHMC i2b2 query data showed a substantial enrichment of EGID in PHTS (OR=272; CI 89-831, p<0.0001). An EGID prevalence estimate from the i2b2 query supported a marked enrichment of EGID in PHTS in the Cleveland Clinic database (p<0.0001). Among the 8 subjects with EGID and PHTS, the age at EGID and PHTS diagnosis was 7.6 ± 3.2 and 7.9 ± 5.8 years, respectively. Patients with EGID-PHTS had excess eosinophils

  20. Modeling stromal determinants of 3D tumor growth to inform PDT-mediated combination treatments

    NASA Astrophysics Data System (ADS)

    Rizvi, I.; Anbil, S.; Celli, J. P.; Alagic, N.; Massodi, I.; Hasan, T.

    2013-03-01

    Advanced stage ovarian carcinoma is characterized by poor prognosis and peritoneal micronodules that exhibit treatment resistance. This is partially due to interactions between multifocal disease and the tumor microenvironment, which includes tumor endothelial cells (TECs) and extracellular matrix components (ECM). Here we describe the development of a three-dimensional model of ovarian cancer that incorporates TECs and ECM. A comparison of several methodologies to generate endothelialized ovarian micronodules along with a preliminary physical characterization is described. This model will allow for detailed investigation of tumor-stroma interactions and how they impact disease progression and treatment response.

  1. Unclassified mixed germ cell-sex cord-stromal tumor with multiple malignant cellular elements in a young woman: a case report and review of the literature.

    PubMed

    Pang, Shujie; Zhang, Lin; Shi, Yiquan; Liu, Yixin

    2014-01-01

    Unclassified mixed germ cell-sex cord-stromal tumor composed of germ cells and sex cord derivatives is a rare neoplasm. Approximately 10% of such tumors have malignant germ cell components. We report the case of a 28 year-old female with a right adnexal mass measuring 8 cm in greatest dimension, containing areas with both germ cell and sex cord components. The germ cell portion contained multiple growth patterns with a malignant appearance, while the sex cord element consisted mainly of annular tubules. Within the malignant germ cell elements was a dysgerminoma that accounted for approximately 75% of the tumor volume. Other malignant germ cell elements included yolk sac tumor, embryonal carcinoma, and choriocarcinoma, which comprised about 15% of the tumor volume. The annular tubule structures comprised about 10% of the total tumor volume. To our knowledge, this is the first case reported in the literature of an unclassified mixed germ cell-sex cord-stromal tumor associated with embryonal carcinoma components. The patient had a 46XX karyotype, regular menstrual periods, and no evidence of gross abnormalities in the contralateral ovary. The patient remained clinically well and disease-free 2 years after surgery. In addition to a thorough case description, the literature concerning this entity is reviewed and discussed. PMID:25197407

  2. Mixed germ cell-sex cord stromal tumor of the testis with an intratubular component: a problem in differential diagnosis.

    PubMed

    Roth, Lawrence M; Cheng, Liang

    2016-05-01

    The origin of mixed germ cell-sex cord stromal tumor (MGC-SCST) of the testis is uncertain, and a controversy exists as to whether the germ cells in these tumors are neoplastic. Although intratubular components of the common and several uncommon forms of testicular germ cell tumors have been described, to our knowledge, intratubular MGC-SCST has not previously been reported in detail. In a study of 13 cases of testicular MGC-SCST, we observed entrapped seminiferous tubules in 7 cases and an intratubular component in 2, both of which were associated with extensive entrapped tubules. Intratubular MGC-SCST is distinguished from entrapped tubules by the occurrence of germ cells resembling spermatogonia in the adluminal compartment and the absence of tubular lumens. By way of contrast, the adluminal compartment of entrapped tubules is composed entirely of immature Sertoli cells, and lumen formation is observed in favorably oriented tubules. Although the germ cells in our cases of MGC-SCST do not show histologic features of malignancy, the observation of spermatogonia-like cells in the adluminal compartment of the tubule, sometimes with concomitant germ cell proliferation, and the infiltrative pattern of the germ cells in the extratubular component support their neoplastic nature. The intratubular component tends to be more centrally located than the adjacent entrapped seminiferous tubules suggesting that it originates from the latter. The tubules of intratubular MGC-SCST are not expanded except in the advanced stage and are approximately the same size as entrapped seminiferous tubules but are considerably smaller than those of the uninvolved testis that shows active spermatogenesis. PMID:27067782

  3. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib: an international, multicentre, prospective, randomised, placebo-controlled phase 3 trial (GRID)

    PubMed Central

    Demetri, George D; Reichardt, Peter; Kang, Yoon-Koo; Blay, Jean-Yves; Rutkowski, Piotr; Gelderblom, Hans; Hohenberger, Peter; Leahy, Michael; von Mehren, Margaret; Joensuu, Heikki; Badalamenti, Giuseppe; Blackstein, Martin; Cesne, Axel Le; Schöffski, Patrick; Maki, Robert G; Bauer, Sebastian; Nguyen, Binh Bui; Xu, Jianming; Nishida, Toshirou; Chung, John; Kappeler, Christian; Kuss, Iris; Laurent, Dirk; Casali, Paolo

    2013-01-01

    Summary Background To date, only two agents, imatinib and sunitinib, have shown clinical benefit in patients with gastrointestinal stromal tumours (GISTs), but almost all metastatic GISTs eventually develop resistance to these agents, resulting in fatal disease progression. This phase 3 trial assessed efficacy and safety of regorafenib in patients with metastatic and/or unresectable GIST progressing after failure of at least imatinib and sunitinib. Methods Patients were randomised 2:1 to receive either regorafenib 160 mg orally daily or placebo, plus best supportive care in both arms, for the first 3 weeks of each 4-week cycle. The primary endpoint was progression-free survival (PFS). Upon disease progression, patients on placebo could cross over to regorafenib. Secondary endpoints included overall survival (OS), objective response rate, disease control rate (DCR: rate of durable stable disease lasting for ≥12 weeks plus complete or partial responses), and safety. This trial is registered at ClinicalTrials.gov (NCT01271712). Results From January to August 2011, 240 patients were screened at 57 centres in 17 countries, and 199 patients were randomised to receive regorafenib (n=133) or matching placebo (n=66). Median PFS per independent blinded central review was 4·8 months and 0·9 months, respectively (hazard ratio [HR] 0·27, 95% confidence interval [CI] 0·19–0·39; p<0·0001). Following progression, 56/66 patients (84·8%) on placebo crossed over to regorafenib, resulting in no significant difference in OS between study arms (HR 0·77, 95% CI 0·42–1·41; p=0·199). A best response of partial response or stable disease was observed in 101/133 patients (75·9%) on regorafenib and 23/66 patients (34·8%) on placebo. DCR was 52·6% (70/133 patients) and 9·1% (6/66 patients), respectively. Drug-related adverse events were reported in 130 (98·5%) of 132 regorafenib patients and 45 (68·2%) of 66 placebo patients. The most common grade ≥3 regorafenib

  4. Nilotinib vs imatinib as first-line therapy for patients with unresectable or metastatic gastrointestinal stromal tumours: randomised phase 3 trial results and subgroup analysis of molecular subtypes

    PubMed Central

    Blay, Jean-Yves; Shen, Lin; Kang, Yoon-Koo; Rutkowski, Piotr; Qin, Shukui; Nosov, Dmitry; Wan, Desen; Trent, Jonathan; Srimuninnimit, Vichien; Pápai, Zsuzsanna; Le Cesne, Axel; Novick, Steven; Taningco, Lilia; Mo, Shuyuan; Green, Steven; Reichardt, Peter; Demetri, George D

    2015-01-01

    Background Nilotinib inhibits the tyrosine kinase activity of ABL1/BCR-ABL1, as well as KIT, platelet-derived growth factor receptors (PDGFRs), and the discoidin domain receptor. Gain-of-function mutations in KIT or PDGFRα are key drivers in most gastrointestinal stromal tumours (GISTs). This trial was designed to test the efficacy and safety of nilotinib vs imatinib as first-line therapy for patients with advanced GISTs. Methods This randomised, open-label, multicentre phase 3 trial included 647 adult patients with previously untreated, histologically confirmed, metastatic and/or unresectable GISTs. Patients were stratified by prior adjuvant therapy and randomised in a 1:1 ratio to receive oral imatinib 400 mg once daily or oral nilotinib 400 mg twice daily. Centrally reviewed progression-free survival (PFS) was the primary endpoint. Response rates, toxicity, and overall survival were also analysed for the overall population and for mutation-defined subsets. Efficacy endpoints used the intention to treat principle. Here, the final results are reported. This trial is registered with ClinicalTrials.gov, number NCT00785785. Findings Because the futility boundary was crossed at a preplanned interim analysis, trial accrual terminated in April 2011. At final analysis of the core study (data cutoff, October 2012), PFS was higher with imatinib overall (hazard ratio [HR] 1.47) and in the KIT exon 9 subgroup (HR 32.46) but roughly similar between arms in the KIT exon 11 subgroup (HR 1.12). Sensitivity analyses suggested that informative censoring may have contributed, because of the high proportion of premature nilotinib progressions declared by local investigators and the design changes implemented following the interim analysis, potentially biasing PFS data in favour of the nilotinib arm. The most common adverse events were nausea, diarrhoea, and peripheral oedema in the imatinib arm and rash, nausea, and abdominal pain in the nilotinib arm. The most common serious

  5. Diagnosis and management of gastrointestinal neuroendocrine tumors: An evidence-based Canadian consensus.

    PubMed

    Singh, Simron; Asa, Sylvia L; Dey, Chris; Kennecke, Hagen; Laidley, David; Law, Calvin; Asmis, Timothy; Chan, David; Ezzat, Shereen; Goodwin, Rachel; Mete, Ozgur; Pasieka, Janice; Rivera, Juan; Wong, Ralph; Segelov, Eva; Rayson, Daniel

    2016-06-01

    The majority of neuroendocrine tumors originate in the digestive system and incidence is increasing within Canada and globally. Due to rapidly evolving evidence related to diagnosis and clinical management, updated guidance on the diagnosis and treatment of gastrointestinal neuroendocrine tumors (GI-NETs) are of clinical importance. Well-differentiated GI-NETs may exhibit indolent clinical behavior and are often metastatic at diagnosis. Some NET patients will develop secretory disease requiring symptom control to optimize quality of life and clinical outcomes. Optimal management of GI-NETs is in a multidisciplinary environment and is multimodal, requiring collaboration between medical, surgical, imaging and pathology specialties. Clinical application of advances in pathological classification and diagnostic technologies, along with evolving surgical, radiotherapeutic and medical therapies are critical to the advancement of patient care. We performed a systematic literature search to update our last set of published guidelines (2010) and identified new level 1 evidence for novel therapies, including telotristat etiprate (TELESTAR), lanreotide (CLARINET), everolimus (RADIANT-2; RADIANT-4) and peptide receptor radionuclide therapy (PRRT; NETTER-1). Integrating these data with the clinical knowledge of 16 multi-disciplinary experts, we devised consensus recommendations to guide state of the art clinical management of GI-NETs. PMID:27236421

  6. Neutrophils trigger a NF-κB dependent polarization of tumor-supportive stromal cells in germinal center B-cell lymphomas.

    PubMed

    Grégoire, Murielle; Guilloton, Fabien; Pangault, Céline; Mourcin, Frédéric; Sok, Phaktra; Latour, Maelle; Amé-Thomas, Patricia; Flecher, Erwan; Fest, Thierry; Tarte, Karin

    2015-06-30

    Both tumor-associated neutrophils (TAN) and cancer-associated fibroblasts (CAFs) display specific phenotypic and functional features and contribute to tumor cell niche. However, their bidirectional crosstalk has been poorly studied, in particular in the context of hematological malignancies. Follicular lymphomas (FL) and diffuse large B-cell lymphomas (DLBCL) are two germinal center-derived lymphomas where various cell components of infiltrating microenvironment, including TAN and CAFs, have been demonstrated to favor directly and indirectly malignant B-cell survival, growth, and drug resistance. We show here that, besides a direct and contact-dependent supportive effect of neutrophils on DLBCL B-cell survival, mediated through the BAFF/APRIL pathway, neutrophils and stromal cells cooperate to sustain FL B-cell growth. This cooperation relies on an overexpression of IL-8 by lymphoma-infiltrating stromal cells that could thereafter efficiently promote neutrophil survival and prime them to neutrophil extracellular trap. Conversely, neutrophils are able to activate stromal cells in a NF-κB-dependent manner, inducing their commitment towards an inflammatory lymphoid stroma phenotype associated with an increased capacity to trigger malignant B-cell survival, and to recruit additional monocytes and neutrophils through the release of CCL2 and IL-8, respectively. Altogether, a better understanding of the lymphoma-supporting effects of neutrophils could be helpful to design new anti-tumor therapeutic strategies. PMID:26158216

  7. Biphasic Malignant Testicular Sex Cord–Stromal Tumor in a Cotton-top Tamarin (Saguinus oedipus) with Review of the Literature

    PubMed Central

    Yearley, J. H.; King, N.; Liu, X.; Curran, E. H.; O’Neil, S. P.

    2009-01-01

    A 20-year old male cotton-top tamarin (Saguinus oedipus) was presented with unilateral enlargement of an intrascrotal testicle. Fine-needle aspiration cytology demonstrated a neoplastic population with Call-Exner-like bodies and features of malignancy. The animal was castrated, and histologic examination revealed a biphasic sex cord–stromal tumor, with one region resembling Sertoli-cell tumor and one region resembling granulosa-cell tumor, with extensive microfollicular pattern and many Call-Exner bodies. Eight months after castration, the animal was euthanized on discovery of a caudal abdominal mass that displaced organs, was highly infiltrative, and extended into the paravertebral musculature with lysis of vertebral bone. Metastases to lymph node and lung were also present. Histologic examination of the abdominal tumor showed multifocal formation of Call-Exner bodies in an otherwise highly dedifferentiated population. Positive immunolabeling for alpha inhibin confirmed the sex cord–stromal origin of the abdominal and paravertebral tumor masses. This case has similarities to malignant testicular granulosa-cell tumor of humans. PMID:18984797

  8. Biphasic malignant testicular sex cord-stromal tumor in a cotton-top tamarin (Saguinus oedipus) with review of the literature.

    PubMed

    Yearley, J H; King, N; Liu, X; Curran, E H; O'Neil, S P

    2008-11-01

    A 20-year old male cotton-top tamarin (Saguinus oedipus) was presented with unilateral enlargement of an intrascrotal testicle. Fine-needle aspiration cytology demonstrated a neoplastic population with Call-Exner-like bodies and features of malignancy. The animal was castrated, and histologic examination revealed a biphasic sex cord-stromal tumor, with one region resembling Sertoli-cell tumor and one region resembling granulosa-cell tumor, with extensive microfollicular pattern and many Call-Exner bodies. Eight months after castration, the animal was euthanized on discovery of a caudal abdominal mass that displaced organs, was highly infiltrative, and extended into the paravertebral musculature with lysis of vertebral bone. Metastases to lymph node and lung were also present. Histologic examination of the abdominal tumor showed multifocal formation of Call-Exner bodies in an otherwise highly dedifferentiated population. Positive immunolabeling for alpha inhibin confirmed the sex cord-stromal origin of the abdominal and paravertebral tumor masses. This case has similarities to malignant testicular granulosa-cell tumor of humans. PMID:18984797

  9. Gastrointestinal hormones stimulate growth of Foregut Neuroendocrine Tumors by transactivating the EGF receptor

    PubMed Central

    Di Florio, Alessia; Sancho, Veronica; Moreno, Paola; Fave, Gianfranco Delle; Jensen, Robert T.

    2012-01-01

    Foregut Neuroendocrine Tumors[NETs] usually pursuit a benign course, but some show aggressive behavior. The treatment of patients with advanced NETs is marginally effective and new approaches are needed. In other tumors, transactivation of the EGF receptor(EGFR) by growth factors, gastrointestinal(GI) hormones and lipids can stimulate growth, which has led to new treatments. Recent studies show a direct correlation between NET malignancy and EGFR expression, EGFR inhibition decreases basal NET growth and an autocrine growth effect exerted by GI hormones, for some NETs. To determine if GI hormones can stimulate NET growth by inducing transactivation of EGFR, we examined the ability of EGF, TGFα and various GI hormones to stimulate growth of the human foregut carcinoid, BON, the somatostatinoma QGP-1 and the rat islet tumor, Rin-14B-cell lines. The EGFR tyrosine-kinase inhibitor, AG1478 strongly inhibited EGF and the GI hormones stimulated cell growth, both in BON and QGP-1 cells. In all the three neuroendocrine cell lines studied, we found EGF, TGFα and the other growth-stimulating GI hormones increased Tyr1068 EGFR phosphorylation. In BON cells, both the GI hormones neurotensin and a bombesin analogue caused a time- and dose-dependent increase in EGFR phosphorylation, which was strongly inhibited by AG1478. Moreover, we found this stimulated phosphorylation was dependent on Src kinases, PKCs, matrix metalloproteinase activation and the generation of reactive oxygen species. These results raise the possibility that disruption of this signaling cascade by either EGFR inhibition alone or combined with receptor antagonists may be a novel therapeutic approach for treatment of foregut NETs/PETs. PMID:23220008

  10. Periostin expression in intra-tumoral stromal cells is prognostic and predictive for colorectal carcinoma via creating a cancer-supportive niche

    PubMed Central

    Tan, Xiaojie; Ding, Yibo; Luo, Yanxin; Cai, Hui; Liu, Yan; Gao, Xianhua; Liu, Qizhi; Yu, Yongwei; Du, Yan; Wang, Hao; Ma, Liye; Wang, Jianping; Chen, Kun; Ding, Yanqing; Fu, Chuangang; Cao, Guangwen

    2016-01-01

    Periostin (POSTN) expression in cancer cells and circulation has been related to poor prognosis of colorectal carcinoma (CRC). However, the role of POSTN expressed in intra-tumoral stroma on CRC progression remains largely unknown. This study enrolled 1098 CRC patients who received surgical treatment in Shanghai and Guangzhou, Mainland China. In Shanghai cohort, immunohistochemistry score of stromal POSTN expression increased consecutively from adjacent mucosa, primary CRC tissues, to metastatic CRC tissues (P < 0.001), while medium- and high-stromal POSTN expression, rather than epithelial POSTN expression, independently predicted unfavorable prognoses of CRC, adjusted for covariates including TNM stage and postoperative chemotherapy in multivariate Cox models. The results in Shanghai cohort were faithfully replicated in Guangzhou cohort. Stromal POSTN expression dose-dependently predicted an unfavorable prognosis of stage III CRC patients with postoperative chemotherapy in both cohorts. POSTN derived from colonic fibroblasts or recombinant POSTN significantly promoted proliferation, anchorage independent growth, invasion, and chemo-resistance of CRC cells; whereas these effects were counteracted via targeting to PI3K/Akt or Wnt/β-catenin signaling pathway. CRC cell RKO-derived factor(s) significantly induced POSTN production in colonic fibroblasts and autocrine POSTN promoted proliferation, migration, and anchorage independent growth of fibroblasts. Conclusively, stromal POSTN is prognostic and predictive for CRC via creating a niche to facilitate cancer progression. Targeting POSTN-induced signaling pathways may be therapeutic options for metastatic or chemoresistant CRC. PMID:26556874

  11. Molecular Cytogenetic Analysis of JAZF1, PHF1, and YWHAE in Endometrial Stromal Tumors: Discovery of Genetic Complexity by Fluorescence in Situ Hybridization.

    PubMed

    Hodge, Jennelle C; Bedroske, Patrick P; Pearce, Kathryn E; Sukov, William R

    2016-07-01

    Diagnosis of endometrial stromal tumors (ESTs) can be challenging, particularly endometrial stromal sarcomas (ESSs) because of variable histologic appearance, long latency to recurrence, frequent metastases with unknown primary, and overlap with endometrial stromal nodules and undifferentiated uterine sarcomas. To enhance EST diagnosis, a break-apart strategy fluorescence in situ hybridization panel to detect JAZF1, PHF1, and YWHAE rearrangements was applied to a cohort of primary or metastatic endometrial stromal nodules, ESSs, or undifferentiated uterine sarcomas (36 cases for JAZF1, 24 of which were also assessed for PHF1 and YWHAE), 24 myometrium/endometrium controls, and 37 non-ESTs in the differential diagnosis. JAZF1 was the most frequently altered gene and occurred in all EST types, JAZF1 and/or PHF1 were mutually exclusive from YWHAE involvement, and uterine and extrauterine ESTs have a shared pathogenesis. We further defined frequency of these rearrangements and provided a resource demonstrating the signal complexity that can manifest when evaluating JAZF1. Rearrangement of JAZF1 occurred in 47% of ESTs, most (70%) of which had atypical patterns representing multiple structural alterations and/or more than one clone. YWHAE and PHF1 rearrangements each occurred in 8% of ESTs. An exceptional case was an ESS without JAZF1 or MEAF6 disruption that further disputes correlation of PHF1 involvement with the sex cord-like variant. These results expand our understanding of the genetic heterogeneity that defines ESTs. PMID:27154512

  12. Calcifying nested stromal-epithelial tumor (CNSET) of the liver: a newly recognized entity to be considered in the radiologist's differential diagnosis.

    PubMed

    Schaffer, Lauren R; Shehata, Bahig M; Yin, Julie; Schemankewitz, Erwin; Alazraki, Adina

    2016-01-01

    Calcifying nested stromal-epithelial tumor (CNSET), an extremely rare tumor found in the liver, was first described in 2001 by Ishak et al. The characteristic imaging features include large size, well-circumscribed, enhancing mass with calcification. To our knowledge, since 2001, there have been 29 reported. Typically arising from the right hepatic lobe, it is primarily found in children and shows clear predilection for females. Emphasizing imaging, we report a 14-year-old female with Beckwith-Wiedemann syndrome who presented with CNSET. PMID:26589005

  13. Biologically relevant 3D tumor arrays: treatment response and the importance of stromal partners

    NASA Astrophysics Data System (ADS)

    Rizvi, Imran; Celli, Jonathan P.; Xu, Feng; Evans, Conor L.; Abu-Yousif, Adnan O.; Muzikansky, Alona; Elrington, Stefan A.; Pogue, Brian W.; Finkelstein, Dianne M.; Demirci, Utkan; Hasan, Tayyaba

    2011-02-01

    The development and translational potential of therapeutic strategies for cancer is limited, in part, by a lack of biological models that capture important aspects of tumor growth and treatment response. It is also becoming increasingly evident that no single treatment will be curative for this complex disease. Rationally-designed combination regimens that impact multiple targets provide the best hope of significantly improving clinical outcomes for cancer patients. Rapidly identifying treatments that cooperatively enhance treatment efficacy from the vast library of candidate interventions is not feasible, however, with current systems. There is a vital, unmet need to create cell-based research platforms that more accurately mimic the complex biology of human tumors than monolayer cultures, while providing the ability to screen therapeutic combinations more rapidly than animal models. We have developed a highly reproducible in vitro three-dimensional (3D) tumor model for micrometastatic ovarian cancer (OvCa), which in conjunction with quantitative image analysis routines to batch-process large datasets, serves as a high throughput reporter to screen rationally-designed combination regimens. We use this system to assess mechanism-based combination regimens with photodynamic therapy (PDT), which sensitizes OvCa to chemo and biologic agents, and has shown promise in clinic trials. We show that PDT synergistically enhances carboplatin efficacy in a sequence dependent manner. In printed heterocellular cultures we demonstrate that proximity of fibroblasts enhances 3D tumor growth and investigate co-cultures with endothelial cells. The principles described here could inform the design and evaluation of mechanism-based therapeutic options for a broad spectrum of metastatic solid tumors.

  14. Single cell dual adherent-suspension co-culture micro-environment for studying tumor-stromal interactions with functionally selected cancer stem-like cells.

    PubMed

    Chen, Yu-Chih; Zhang, Zhixiong; Fouladdel, Shamileh; Deol, Yadwinder; Ingram, Patrick N; McDermott, Sean P; Azizi, Ebrahim; Wicha, Max S; Yoon, Euisik

    2016-08-01

    Considerable evidence suggests that cancer stem-like cells (CSCs) are critical in tumor pathogenesis, but their rarity and transience has led to much controversy about their exact nature. Although CSCs can be functionally identified using dish-based tumorsphere assays, it is difficult to handle and monitor single cells in dish-based approaches; single cell-based microfluidic approaches offer better control and reliable single cell derived sphere formation. However, like normal stem cells, CSCs are heavily regulated by their microenvironment, requiring tumor-stromal interactions for tumorigenic and proliferative behaviors. To enable single cell derived tumorsphere formation within a stromal microenvironment, we present a dual adherent/suspension co-culture device, which combines a suspension environment for single-cell tumorsphere assays and an adherent environment for co-culturing stromal cells in close proximity by selectively patterning polyHEMA in indented microwells. By minimizing dead volume and improving cell capture efficiency, the presented platform allows for the use of small numbers of cells (<100 cells). As a proof of concept, we co-cultured single T47D (breast cancer) cells and primary cancer associated fibroblasts (CAF) on-chip for 14 days to monitor sphere formation and growth. Compared to mono-culture, co-cultured T47D have higher tumorigenic potential (sphere formation rate) and proliferation rates (larger sphere size). Furthermore, 96-multiplexed single-cell transcriptome analyses were performed to compare the gene expression of co-cultured and mono-cultured T47D cells. Phenotypic changes observed in co-culture correlated with expression changes in genes associated with proliferation, apoptotic suppression, tumorigenicity and even epithelial-to-mesechymal transition. Combining the presented platform with single cell transcriptome analysis, we successfully identified functional CSCs and investigated the phenotypic and transcriptome effects induced

  15. Basis and consequences of primary and secondary prevention of gastrointestinal tumors.

    PubMed

    Goldin-Lang, P; Kreuser, E D; Zunft, H J

    1996-01-01

    Carcinomas of the gastrointestinal tract (GI) are among the most common malignancies with regard to their incidence and mortality. Nutritional factors play an important role in the tumor development. The strength of their influence varies with the localization in the GI tract. Epidemiological studies focusing on GI cancer incidence or mortality as an endpoint necessitate large numbers of subjects to achieve significant results. Generally, a low energy and fat intake and a high intake of antioxidative vitamins (vitamin C, E, beta-carotene) and secondary plant metabolites (especially polyphenols) appear to be protective in GI carcinogenesis. Moderate drinking of alcohol and increased consumption of whole grain products, as opposed to highly refined carbohydrates, may help to reduce the risk of colon cancer. The recommended type of diet is low in fat, especially in saturated fatty acids, includes monounsaturated fatty acids, and includes moderate amounts of polyunsaturated fatty acids (no more than 10% of calories). Moderate consumption of salt and of highly salted, smoked, and barbecued foods should be encouraged. Obesity should be avoided by trying to match energy intake with expenditure while increasing physical activity levels. The mechanisms by which nutritional factors act especially on molecular events still remain to be examined. The use of molecular biomarkers will help us better understand cancer development as well as the role and significance of nutritional factors in this process. PMID:8893341

  16. Role of Endoscopic Ultrasonography in Guiding Treatment Plans for Upper Gastrointestinal Subepithelial Tumors.

    PubMed

    Moon, Jeong Seop

    2016-05-01

    Gastrointestinal (GI) subepithelial tumors (SETs) are usually observed incidentally by endoscopy and have diverse prognoses, varying from benign to potentially malignant. When a GI SET is suspected, endoscopic ultrasonography (EUS) is the most accurate diagnostic method to differentiate it from extraluminal compression. To determine the nature of GI SETs, EUS is also the most accurate diagnostic method, and reveals the precise sonographic nature of the lesion. There are some SETs with typical EUS findings of GI SETs, but most hypoechoic lesions are difficult to diagnose based on EUS images alone. EUS is also helpful to determine GI wall involvement in SETs and optimal treatment methods. For the diagnosis of GI SETs, obtaining a proper specimen is essential. EUS-guided cytology or biopsy methods such as fine-needle aspiration, Tru-Cut biopsy, and the newly introduced fine-needle biopsy (FNB) provide good results. To increase the diagnostic yield for GI SETs, cytology with immunocytochemical staining is used for cytological interpretation, resulting in good diagnostic yields. Recently, EUS-FNB using cheese slicer technology has been introduced, and has been reported to provide good diagnostic results for GI SETs. PMID:27209643

  17. Role of Endoscopic Ultrasonography in Guiding Treatment Plans for Upper Gastrointestinal Subepithelial Tumors

    PubMed Central

    Moon, Jeong Seop

    2016-01-01

    Gastrointestinal (GI) subepithelial tumors (SETs) are usually observed incidentally by endoscopy and have diverse prognoses, varying from benign to potentially malignant. When a GI SET is suspected, endoscopic ultrasonography (EUS) is the most accurate diagnostic method to differentiate it from extraluminal compression. To determine the nature of GI SETs, EUS is also the most accurate diagnostic method, and reveals the precise sonographic nature of the lesion. There are some SETs with typical EUS findings of GI SETs, but most hypoechoic lesions are difficult to diagnose based on EUS images alone. EUS is also helpful to determine GI wall involvement in SETs and optimal treatment methods. For the diagnosis of GI SETs, obtaining a proper specimen is essential. EUS-guided cytology or biopsy methods such as fine-needle aspiration, Tru-Cut biopsy, and the newly introduced fine-needle biopsy (FNB) provide good results. To increase the diagnostic yield for GI SETs, cytology with immunocytochemical staining is used for cytological interpretation, resulting in good diagnostic yields. Recently, EUS-FNB using cheese slicer technology has been introduced, and has been reported to provide good diagnostic results for GI SETs. PMID:27209643

  18. Tumor-initiating label-retaining cancer cells in human gastrointestinal cancers undergo asymmetric cell division.

    PubMed

    Xin, Hong-Wu; Hari, Danielle M; Mullinax, John E; Ambe, Chenwi M; Koizumi, Tomotake; Ray, Satyajit; Anderson, Andrew J; Wiegand, Gordon W; Garfield, Susan H; Thorgeirsson, Snorri S; Avital, Itzhak

    2012-04-01

    Label-retaining cells (LRCs) have been proposed to represent adult tissue stem cells. LRCs are hypothesized to result from either slow cycling or asymmetric cell division (ACD). However, the stem cell nature and whether LRC undergo ACD remain controversial. Here, we demonstrate label-retaining cancer cells (LRCCs) in several gastrointestinal (GI) cancers including fresh surgical specimens. Using a novel method for isolation of live LRCC, we demonstrate that a subpopulation of LRCC is actively dividing and exhibits stem cells and pluripotency gene expression profiles. Using real-time confocal microscopic cinematography, we show live LRCC undergoing asymmetric nonrandom chromosomal cosegregation LRC division. Importantly, LRCCs have greater tumor-initiating capacity than non-LRCCs. Based on our data and that cancers develop in tissues that harbor normal-LRC, we propose that LRCC might represent a novel population of GI stem-like cancer cells. LRCC may provide novel mechanistic insights into the biology of cancer and regenerative medicine and present novel targets for cancer treatment. PMID:22331764

  19. Endoscopic laser surgery of patients with pretumoral diseases and tumors of the organs of respiration and gastro-intestinal tract

    NASA Astrophysics Data System (ADS)

    Poddubny, Boris K.; Ungiadze, G. V.; Kuvshinov, Yury P.; Efimov, Oleg N.; Mazurov, S. T.

    1996-01-01

    The result of treatment of 566 patients with precancerous diseases, cancer and benign tumors of respiratory and gastro-intestinal tract are presented. The `Raduga-1' as a source of laser radiation has been used. The wavelength of radiation 1060 nm. The maximum of basic radiation at the end of lightguide is 50 W. It is shown that the method of endoscopic laser destruction is a highly effective one and may be recommended for radical treatment.

  20. The utility of STAT6 and ALDH1 expression in the differential diagnosis of solitary fibrous tumor versus prostate-specific stromal neoplasms.

    PubMed

    Guner, Gunes; Bishop, Justin A; Bezerra, Stephania M; Taheri, Diana; Zahavi, David J; Mendoza Rodriguez, Maria Angelica; Sharma, Rajni; Epstein, Jonathan I; Netto, George J

    2016-08-01

    Solitary fibrous tumor (SFT) diagnosis in prostate can be challenging on small biopsies. Prostatic stromal tumors of unknown malignant potential (STUMP) and SFT have overlapping features. NAB2-STAT6 gene fusions that were recently identified in various SFTs lead to nuclear translocalization of STAT6. Nuclear STAT6 immunostaining is now considered an adjunct for SFT diagnosis. We evaluated STAT6 and an emerging stemness marker, ALDH1, in the differential diagnosis of SFT versus prostatic stromal lesions. Sixteen STUMPs, 12 SFTs, and 4 prostatic stromal sarcomas (12 needle biopsies, 13 radical prostatectomies, 7 transurethral resections) were retrieved (1995-2015). Sections were stained with polyclonal STAT6 antibody (Santa Cruz Biotechnology, Santa Cruz, CA; S20, 1:100) and monoclonal ALDH1 antibody (BD Biosciences, San Jose, CA; clone 44, 1:250). In STAT6 cases, only unequivocal nuclear staining (with/without cytoplasmic staining) was considered positive. Cytoplasmic ALDH1 staining was counted positive. Ten of 11 evaluable SFTs demonstrated strong and diffuse nuclear STAT6 positivity; 4 of 16 STUMPs had nuclear staining that was weak (1/4) or focal (1/4). ALDH1 positivity was seen in 10 of 12 evaluable SFTs and 3 of 15 STUMPs. Prostatic stromal sarcomas were STAT6 negative (4/4); 2 of 4 were ALDH1 positive. The sensitivity and specificity for STAT6 for the diagnosis of SFT were 91% and 75%, respectively. Coexpression of STAT6 and ALDH1 yielded the same sensitivity but improved the specificity (100%) for the diagnosis of SFT. STAT6 is a useful marker in the differential diagnosis of SFT versus STUMP. Using STAT6 and ALDH1 together increases specificity. STUMPs can show STAT6 positivity, and when they do, it is likely to be weak or focal. PMID:27068523

  1. CD105 expression on CD34-negative spindle-shaped stromal cells of primary tumor is an unfavorable prognostic marker in early breast cancer patients.

    PubMed

    Martinez, Leandro Marcelo; Labovsky, Vivian; Calcagno, María de Luján; Davies, Kevin Mauro; Garcia Rivello, Hernán; Rivello, Hernán Garcia; Bianchi, Maria Silvia; Wernicke, Alejandra; Vallone, Valeria Beatriz Fernández; Fernández Vallone, Valeria Beatriz; Chasseing, Norma Alejandra

    2015-01-01

    Several studies have confirmed that the breast tumor microenvironment drives cancer progression and metastatic development. The aim of our research was to investigate the prognostic significance of the breast tumor microenvironment in untreated early breast cancer patients. Therefore, we analyzed the association of the expression of α-SMA, FSP, CD105 and CD146 in CD34-negative spindle-shaped stromal cells, not associated with the vasculature, in primary breast tumors with classical prognostic marker levels, metastatic recurrence, local relapse, disease-free survival, metastasis-free survival and the overall survival of patients. In the same way, we evaluated the association of the amount of intra-tumor stroma, fibroblasts, collagen deposition, lymphocytic infiltration and myxoid changes in these samples with the clinical-pathological data previously described. This study is the first to demonstrate the high CD105 expression in this stromal cell type as a possible independent marker of unfavorable prognosis in early breast cancer patients. Our study suggests that this new finding can be useful prognostic marker in the clinical-pathological routine. PMID:25803686

  2. Tumor Necrosis Factor Improves Vascularization in Osteogenic Grafts Engineered with Human Adipose-Derived Stem/Stromal Cells

    PubMed Central

    Hutton, Daphne L.; Kondragunta, Renu; Moore, Erika M.; Hung, Ben P.; Jia, Xiaofeng; Grayson, Warren L.

    2014-01-01

    The innate immune response following bone injury plays an important role in promoting cellular recruitment, revascularization, and other repair mechanisms. Tumor necrosis factor-α (TNF) is a prominent pro-inflammatory cytokine in this cascade, and has been previously shown to improve bone formation and angiogenesis in a dose- and timing-dependent manner. This ability to positively impact both osteogenesis and vascular growth may benefit bone tissue engineering, as vasculature is essential to maintaining cell viability in large grafts after implantation. Here, we investigated the effects of exogenous TNF on the induction of adipose-derived stem/stromal cells (ASCs) to engineer pre-vascularized osteogenic tissue in vitro with respect to dose, timing, and co-stimulation with other inflammatory mediators. We found that acute (2-day), low-dose exposure to TNF promoted vascularization, whereas higher doses and continuous exposure inhibited vascular growth. Co-stimulation with platelet-derived growth factor (PDGF), another key factor released following bone injury, increased vascular network formation synergistically with TNF. ASC-seeded grafts were then cultured within polycaprolactone-fibrin composite scaffolds and implanted in nude rats for 2 weeks, resulting in further tissue maturation and increased angiogenic ingrowth in TNF-treated grafts. VEGF-A expression levels were significantly higher in TNF-treated grafts immediately prior to implantation, indicating a long-term pro-angiogenic effect. These findings demonstrate that TNF has the potential to promote vasculogenesis in engineered osteogenic grafts both in vitro and in vivo. Thus, modulation and/or recapitulation of the immune response following bone injury may be a beneficial strategy for bone tissue engineering. PMID:25248109

  3. The Initiator Methionine tRNA Drives Secretion of Type II Collagen from Stromal Fibroblasts to Promote Tumor Growth and Angiogenesis

    PubMed Central

    Clarke, Cassie J.; Berg, Tracy J.; Birch, Joanna; Ennis, Darren; Mitchell, Louise; Cloix, Catherine; Campbell, Andrew; Sumpton, David; Nixon, Colin; Campbell, Kirsteen; Bridgeman, Victoria L.; Vermeulen, Peter B.; Foo, Shane; Kostaras, Eleftherios; Jones, J. Louise; Haywood, Linda; Pulleine, Ellie; Yin, Huabing; Strathdee, Douglas; Sansom, Owen; Blyth, Karen; McNeish, Iain; Zanivan, Sara; Reynolds, Andrew R.; Norman, Jim C.

    2016-01-01

    Summary Expression of the initiator methionine tRNA (tRNAiMet) is deregulated in cancer. Despite this fact, it is not currently known how tRNAiMet expression levels influence tumor progression. We have found that tRNAiMet expression is increased in carcinoma-associated fibroblasts, implicating deregulated expression of tRNAiMet in the tumor stroma as a possible contributor to tumor progression. To investigate how elevated stromal tRNAiMet contributes to tumor progression, we generated a mouse expressing additional copies of the tRNAiMet gene (2+tRNAiMet mouse). Growth and vascularization of subcutaneous tumor allografts was enhanced in 2+tRNAiMet mice compared with wild-type littermate controls. Extracellular matrix (ECM) deposited by fibroblasts from 2+tRNAiMet mice supported enhanced endothelial cell and fibroblast migration. SILAC mass spectrometry indicated that elevated expression of tRNAiMet significantly increased synthesis and secretion of certain types of collagen, in particular type II collagen. Suppression of type II collagen opposed the ability of tRNAiMet-overexpressing fibroblasts to deposit pro-migratory ECM. We used the prolyl hydroxylase inhibitor ethyl-3,4-dihydroxybenzoate (DHB) to determine whether collagen synthesis contributes to the tRNAiMet-driven pro-tumorigenic stroma in vivo. DHB had no effect on the growth of syngeneic allografts in wild-type mice but opposed the ability of 2+tRNAiMet mice to support increased angiogenesis and tumor growth. Finally, collagen II expression predicts poor prognosis in high-grade serous ovarian carcinoma. Taken together, these data indicate that increased tRNAiMet levels contribute to tumor progression by enhancing the ability of stromal fibroblasts to synthesize and secrete a type II collagen-rich ECM that supports endothelial cell migration and angiogenesis. PMID:26948875

  4. The Initiator Methionine tRNA Drives Secretion of Type II Collagen from Stromal Fibroblasts to Promote Tumor Growth and Angiogenesis.

    PubMed

    Clarke, Cassie J; Berg, Tracy J; Birch, Joanna; Ennis, Darren; Mitchell, Louise; Cloix, Catherine; Campbell, Andrew; Sumpton, David; Nixon, Colin; Campbell, Kirsteen; Bridgeman, Victoria L; Vermeulen, Peter B; Foo, Shane; Kostaras, Eleftherios; Jones, J Louise; Haywood, Linda; Pulleine, Ellie; Yin, Huabing; Strathdee, Douglas; Sansom, Owen; Blyth, Karen; McNeish, Iain; Zanivan, Sara; Reynolds, Andrew R; Norman, Jim C

    2016-03-21

    Expression of the initiator methionine tRNA (tRNAi(Met)) is deregulated in cancer. Despite this fact, it is not currently known how tRNAi(Met) expression levels influence tumor progression. We have found that tRNAi(Met) expression is increased in carcinoma-associated fibroblasts, implicating deregulated expression of tRNAi(Met) in the tumor stroma as a possible contributor to tumor progression. To investigate how elevated stromal tRNAi(Met) contributes to tumor progression, we generated a mouse expressing additional copies of the tRNAi(Met) gene (2+tRNAi(Met) mouse). Growth and vascularization of subcutaneous tumor allografts was enhanced in 2+tRNAi(Met) mice compared with wild-type littermate controls. Extracellular matrix (ECM) deposited by fibroblasts from 2+tRNAi(Met) mice supported enhanced endothelial cell and fibroblast migration. SILAC mass spectrometry indicated that elevated expression of tRNAi(Met) significantly increased synthesis and secretion of certain types of collagen, in particular type II collagen. Suppression of type II collagen opposed the ability of tRNAi(Met)-overexpressing fibroblasts to deposit pro-migratory ECM. We used the prolyl hydroxylase inhibitor ethyl-3,4-dihydroxybenzoate (DHB) to determine whether collagen synthesis contributes to the tRNAi(Met)-driven pro-tumorigenic stroma in vivo. DHB had no effect on the growth of syngeneic allografts in wild-type mice but opposed the ability of 2+tRNAi(Met) mice to support increased angiogenesis and tumor growth. Finally, collagen II expression predicts poor prognosis in high-grade serous ovarian carcinoma. Taken together, these data indicate that increased tRNAi(Met) levels contribute to tumor progression by enhancing the ability of stromal fibroblasts to synthesize and secrete a type II collagen-rich ECM that supports endothelial cell migration and angiogenesis. PMID:26948875

  5. Concomitant surgical treatment of a chondrosarcoma of the chest wall and a desmoid tumor of the gastrointestinal tract

    PubMed Central

    Sadowski, Andrzej; Chruścicka, Iwona; Rak, Piotr; Ptach, Anna; Maliszewski, Daniel; Pęksa, Rafał; Haponiuk, Ireneusz

    2015-01-01

    The co-existence of a chondrosarcoma of the chest wall and a desmoid tumor in the gastrointestinal tract is rare. In both Polish and global literature, cases of chest wall chondrosarcomas are presented in the form of case reports. Desmoids of the gastrointestinal tract are more common; notwithstanding, their incidence in Europe is estimated at approximately 2 cases per 1 million inhabitants per year. We present the case of a 62-year-old female patient who suffered from both a chest wall chondrosarcoma and a desmoid tumor of the intestine; both neoplasms were operated on simultaneously. The former tumor was located in the region of the right costal margin, whereas the latter was located in the mesojejunum. The surgery was performed with two independent surgical incisions. The postoperative period was uneventful. The case is noteworthy in view of the extremely rare synchronous occurrence of the described tumors and due to the fact that any such operation requires an individualized surgical approach. PMID:26336503

  6. Direct Melanoma Cell Contact Induces Stromal Cell Autocrine Prostaglandin E2-EP4 Receptor Signaling That Drives Tumor Growth, Angiogenesis, and Metastasis.

    PubMed

    Inada, Masaki; Takita, Morichika; Yokoyama, Satoshi; Watanabe, Kenta; Tominari, Tsukasa; Matsumoto, Chiho; Hirata, Michiko; Maru, Yoshiro; Maruyama, Takayuki; Sugimoto, Yukihiko; Narumiya, Shuh; Uematsu, Satoshi; Akira, Shizuo; Murphy, Gillian; Nagase, Hideaki; Miyaura, Chisato

    2015-12-11

    The stromal cells associated with tumors such as melanoma are significant determinants of tumor growth and metastasis. Using membrane-bound prostaglandin E synthase 1 (mPges1(-/-)) mice, we show that prostaglandin E2 (PGE2) production by host tissues is critical for B16 melanoma growth, angiogenesis, and metastasis to both bone and soft tissues. Concomitant studies in vitro showed that PGE2 production by fibroblasts is regulated by direct interaction with B16 cells. Autocrine activity of PGE2 further regulates the production of angiogenic factors by fibroblasts, which are key to the vascularization of both primary and metastatic tumor growth. Similarly, cell-cell interactions between B16 cells and host osteoblasts modulate mPGES-1 activity and PGE2 production by the osteoblasts. PGE2, in turn, acts to stimulate receptor activator of NF-κB ligand expression, leading to osteoclast differentiation and bone erosion. Using eicosanoid receptor antagonists, we show that PGE2 acts on osteoblasts and fibroblasts in the tumor microenvironment through the EP4 receptor. Metastatic tumor growth and vascularization in soft tissues was abrogated by an EP4 receptor antagonist. EP4-null Ptger4(-/-) mice do not support B16 melanoma growth. In vitro, an EP4 receptor antagonist modulated PGE2 effects on fibroblast production of angiogenic factors. Our data show that B16 melanoma cells directly influence host stromal cells to generate PGE2 signals governing neoangiogenesis and metastatic growth in bone via osteoclast erosive activity as well as angiogenesis in soft tissue tumors. PMID:26475855

  7. Stromal matrix metalloprotease-13 knockout alters Collagen I structure at the tumor-host interface and increases lung metastasis of C57BL/6 syngeneic E0771 mammary tumor cells

    PubMed Central

    2013-01-01

    Background Matrix metalloproteases and collagen are key participants in breast cancer, but their precise roles in cancer etiology and progression remain unclear. MMP13 helps regulate collagen structure and has been ascribed largely harmful roles in cancer, but some studies demonstrate that MMP13 may also protect against tumor pathology. Other studies indicate that collagen’s organizational patterns at the breast tumor-host interface influence metastatic potential. Therefore we investigated how MMP13 modulates collagen I, a principal collagen subtype in breast tissue, and affects tumor pathology and metastasis in a mouse model of breast cancer. Methods Tumors were implanted into murine mammary tissues, and their growth analyzed in Wildtype and MMP13 KO mice. Following extraction, tumors were analyzed for collagen I levels and collagen I macro- and micro-structural properties at the tumor-host boundary using immunocytochemistry and two-photon and second harmonic generation microscopy. Lungs were analyzed for metastases counts, to correlate collagen I changes with a clinically significant functional parameter. Statistical analyses were performed by t-test, analysis of variance, or Wilcoxon-Mann–Whitney tests as appropriate. Results We found that genetic ablation of host stromal MMP13 led to: 1. Increased mammary tumor collagen I content, 2. Marked changes in collagen I spatial organization, and 3. Altered collagen I microstructure at the tumor-host boundary, as well as 4. Increased metastasis from the primary mammary tumor to lungs. Conclusions These results implicate host MMP13 as a key regulator of collagen I structure and metastasis in mammary tumors, thus making it an attractive potential therapeutic target by which we might alter metastatic potential, one of the chief determinants of clinical outcome in breast cancer. In addition to identifying stromal MMP13 is an important regulator of the tumor microenvironment and metastasis, these results also suggest

  8. Regulation of IL-6 and IL-8 production by reciprocal cell-to-cell interactions between tumor cells and stromal fibroblasts through IL-1α in ameloblastoma

    SciTech Connect

    Fuchigami, Takao; Kibe, Toshiro; Koyama, Hirofumi; Kishida, Shosei; Iijima, Mikio; Nishizawa, Yoshiaki; Hijioka, Hiroshi; Fujii, Tomomi; Ueda, Masahiro; Nakamura, Norifumi; Kiyono, Tohru; Kishida, Michiko

    2014-09-05

    Highlights: • We studied the interaction between tumor cells and fibroblasts in ameloblastoma. • AM-3 ameloblastoma cells secreted significantly high IL-1α levels. • IL-1α derived from AM-3 cells promoted IL-6 and IL-8 secretion of fibroblasts. • IL-6 and IL-8 activated the cellular motility and proliferation of AM-3 cells. - Abstract: Ameloblastoma is an odontogenic benign tumor that occurs in the jawbone, which invades bone and reoccurs locally. This tumor is treated by wide surgical excision and causes various problems, including changes in facial countenance and mastication disorders. Ameloblastomas have abundant tumor stroma, including fibroblasts and immune cells. Although cell-to-cell interactions are considered to be involved in the pathogenesis of many diseases, intercellular communications in ameloblastoma have not been fully investigated. In this study, we examined interactions between tumor cells and stromal fibroblasts via soluble factors in ameloblastoma. We used a human ameloblastoma cell line (AM-3 ameloblastoma cells), human fibroblasts (HFF-2 fibroblasts), and primary-cultured fibroblasts from human ameloblastoma tissues, and analyzed the effect of ameloblastoma-associated cell-to-cell communications on gene expression, cytokine secretion, cellular motility and proliferation. AM-3 ameloblastoma cells secreted higher levels of interleukin (IL)-1α than HFF-2 fibroblasts. Treatment with conditioned medium from AM-3 ameloblastoma cells upregulated gene expression and secretion of IL-6 and IL-8 of HFF-2 fibroblasts and primary-cultured fibroblast cells from ameloblastoma tissues. The AM3-stimulated production of IL-6 and IL-8 in fibroblasts was neutralized by pretreatment of AM-3 cells with anti-IL-1α antibody and IL-1 receptor antagonist. Reciprocally, cellular motility of AM-3 ameloblastoma cells was stimulated by HFF-2 fibroblasts in IL-6 and IL-8 dependent manner. In conclusion, ameloblastoma cells and stromal fibroblasts behave

  9. Inhibitory effect of bone morphogenetic protein-2 on the proliferation of giant cell tumor of bone stromal cells in vitro

    PubMed Central

    HE, BAOHUA; HE, GUANPING; ZHENG, XIAOFEI; LI, LIHUA; LI, MEI; XIA, HONG

    2016-01-01

    The inhibitory effect of bone morphogenetic protein-2 (BMP-2) on the proliferation of giant cell tumor of bone stromal cells (GCTSCs) has not been fully elucidated. Therefore, the aim of this study was to evaluate the role of recombinant human BMP-2 (rhBMP-2) in the growth of GCTSCs. The effects of exposure to different concentrations of rhBMP-2 (0, 10, 100 and 300 ng/ml) for 1, 3, 5 and 7 days on GCTSC proliferation were examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In addition, the effect of treatment with rhBMP-2 (0 or 10 ng/ml) for 48 h on the cell cycle pattern of GCTSCs was examined by flow cytometry. The apoptosis-inducing effect of rhBMP-2 (0 or 10 ng/ml) in GCTSCs was also determined by flow cytometry after 48 and 72 h. In addition, western blot assays were conducted to determine whether rhBMP-2 acts on non-Smad mitogen-activated protein kinase (MAPK) signaling pathways, namely extracellular signal-regulated kinase (ERK1/2), p38 and c-jun-N-terminal kinase (JNK) pathways. The proliferation of GCTSCs treated with rhBMP-2 (10, 100 or 300 ng/ml) for 5 or 7 days was significantly inhibited in a non dose-dependent and non-time-dependent manner (P<0.05). The treatment of GCTSCs with rhBMP-2 (10 ng/ml) for 48 h had no effect on cell cycle distribution. The apoptosis of GCTSCs induced by exposure to rhBMP-2 (10 ng/ml) for 48 or 72 h was significant (P<0.05). Expression levels of phospho-ERK1/2, phospho-p38 and phospho-JNK increased significantly when GCTSCs were treated with rhBMP-2 (10 ng/ml) for 72 h (P<0.05). The results indicate that rhBMP-2 has no stimulatory effect on GCTSC growth. However, it may lead to the apoptosis of GCTSCs by non-Smad MAPK signaling pathways. PMID:26889259

  10. Romidepsin in Treating Patients With Locally Advanced or Metastatic Neuroendocrine Tumors

    ClinicalTrials.gov

    2013-06-03

    Gastrinoma; Glucagonoma; Insulinoma; Metastatic Gastrointestinal Carcinoid Tumor; Pancreatic Polypeptide Tumor; Pulmonary Carcinoid Tumor; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Regional Gastrointestinal Carcinoid Tumor; Somatostatinoma

  11. RNA Sequencing of Tumor-Associated Microglia Reveals Ccl5 as a Stromal Chemokine Critical for Neurofibromatosis-1 Glioma Growth1

    PubMed Central

    Solga, Anne C.; Pong, Winnie W.; Kim, Keun-Young; Cimino, Patrick J.; Toonen, Joseph A.; Walker, Jason; Wylie, Todd; Magrini, Vincent; Griffith, Malachi; Griffith, Obi L.; Ly, Amy; Ellisman, Mark H.; Mardis, Elaine R.; Gutmann, David H.

    2015-01-01

    Solid cancers develop within a supportive microenvironment that promotes tumor formation and growth through the elaboration of mitogens and chemokines. Within these tumors, monocytes (macrophages and microglia) represent rich sources of these stromal factors. Leveraging a genetically engineered mouse model of neurofibromatosis type 1 (NF1) low-grade brain tumor (optic glioma), we have previously demonstrated that microglia are essential for glioma formation and maintenance. To identify potential tumor-associated microglial factors that support glioma growth (gliomagens), we initiated a comprehensive large-scale discovery effort using optimized RNA-sequencing methods focused specifically on glioma-associated microglia. Candidate microglial gliomagens were prioritized to identify potential secreted or membrane-bound proteins, which were next validated by quantitative real-time polymerase chain reaction as well as by RNA fluorescence in situ hybridization following minocycline-mediated microglial inactivation in vivo. Using these selection criteria, chemokine (C-C motif) ligand 5 (Ccl5) was identified as a chemokine highly expressed in genetically engineered Nf1 mouse optic gliomas relative to nonneoplastic optic nerves. As a candidate gliomagen, recombinant Ccl5 increased Nf1-deficient optic nerve astrocyte growth in vitro. Importantly, consistent with its critical role in maintaining tumor growth, treatment with Ccl5 neutralizing antibodies reduced Nf1 mouse optic glioma growth and improved retinal dysfunction in vivo. Collectively, these findings establish Ccl5 as an important microglial growth factor for low-grade glioma maintenance relevant to the development of future stroma-targeted brain tumor therapies. PMID:26585233